Development and experimental validation of a machine learning-based disulfidptosis-related ferroptosis score for hepatocellular carcinoma.

Disulfidoptosis and ferroptosis are two distinct programmed cell death pathways that have garnered considerable attention due to their potential as therapeutic targets. However, despite their significance of these pathways, the role of disulfidoptosis-related ferroptosis genes in hepatocellular carcinoma (HCC) remains unclear. In this study, we employed a comprehensive approach that utilized various sophisticated techniques such as Pearson analysis, differential analysis, uniCox regression, lasso, ranger, and multivariable Cox regression to develop the disulfidoptosis-related ferroptosis (DRF) score. We then classified patients with HCC into high- and low-score groups to examine the association between the DRF score and various outcomes, including prognosis, functional enrichment, immune infiltration, immunotherapy, TACE sensitivity, drug sensitivity, and single-cell level function. Finally, we conducted in vitro experiments to validate the function of KIF20A. Our analysis revealed that KIF20A, G6PD, SLC7A11, and SLC2A1 were integral to constructing the DRF score. Our findings showed that patients with low DRF scores had significantly better prognoses and were more responsive to immunotherapy, TACE, and chemotherapy than those with high DRF scores. Based on our results obtained from bulk RNA-seq, single-cell RNA-seq, and in vitro experiments, we identified the cell cycle pathway as the primary distinguished factor between high-score and low-score groups. This study sheds light on the contribution of disulfidoptosis-related ferroptosis genes to the development and progression of HCC. The information gleaned from this study can be leveraged to improve our understanding of their potential as therapeutic targets for HCC treatment.

Development of predictive models for assessing the progression and invasiveness of satellite lesions in patients with multiple pulmonary ground glass nodules.

Background: Currently, the appropriate treatment of satellite lesions is still controversial. With this study, we aimed to construct a set of nomograms to determine the characteristics of satellite lesions in patients with multiple pulmonary ground glass nodules (MPGGNs) and propose a reference for the management of satellite lesions. Methods: We retrospectively analyzed patients with MPGGNs who had undergone multiple rounds of surgical resection of primary and satellite lesions, including pathologic examinations after surgical resection. Results: A total of 125 lesions from 105 patients were included in the analysis; 85 lesions were advanced and 40 lesions were not advanced. Among them, 55 invasive pulmonary adenocarcinomas (IPA) and 70 noninvasive pulmonary adenocarcinomas were identified. After the final regression analysis, the patients' age, satellite lesion location, consolidation tumor ratio (CTR), lesion border clarity, and lesion diameter were used to predict satellite lesion progression. Patients' gender, satellite lesion location, lesion diameter, and computed tomography (CT) attenuation values were used to predict the invasiveness of the satellite lesion. The constructed nomograms showed strong discrimination with concordance indices (C indices) of 0.816 and 0.823, respectively. Conclusions: We developed a set of nomograms that can predict the risk of advanced or invasive satellite lesions in patients with MPGGNs. The area under the receiver operating characteristic (ROC) curve (AUC), the C-index, and the calibration curve suggest that the nomogram may be useful in the clinical setting. This model has the potential to help clinicians make treatment recommendations for the remaining lesions while treating the primary lesion in patients with MPGGNs.

Preoperative MRI features to predict vessels that encapsulate tumor clusters and microvascular invasion in hepatocellular carcinoma.

OBJECTIVE: To estimate the potential of preoperative MRI features in the prediction of the integration patterns of vessels that encapsulate tumor clusters (VETC) and microvascular invasion (MVI) (VM) patterns in hepatocellular carcinoma (HCC) patients after resection and to assess the prognostic value of VM patterns. MATERIALS AND METHODS: Patients who underwent surgical resection for HCC between July 2019 and July 2020 were retrospectively included in the training cohort and validation cohort. In the training cohort, patients were classified into VM-positive HCC (VM-HCC) and VM-negative HCC (non-VM HCC). Predictors associated with VM-HCC were determined by using logistic regression analyses and used to build a prediction model of VM-HCC. The model was tested in the validation cohort by area under the receiver operating characteristic curve (AUC) analysis. Prognostic factors associated with early recurrence of HCC were evaluated by use of Cox logistic regression analyses. RESULTS: Alpha-fetoprotein (AFP) level higher than 400 ng/mL (odds ratio [OR] = 8.0; 95% CI: 2.6-25.2; P < 0.001), non-smooth tumor margin (OR = 3.1; 95% CI: 1.4-6.0; P < 0.001) and peritumoral arterial enhancement (OR = 2.9; 95% CI: 1.4-6.2; P = 0.004) were independent predictors of VM-HCC. The AUCs of the prediction model for VM-HCC were 0.81 for the training cohort and 0.79 for the validation cohort. The high risk of VM-HCC predicted by the three preoperative predictors derived from the prediction model (hazard ratio [HR] 2.0; 95% CI: 1.3, 3.2; P = 0.003) were independently associated with early recurrence, while pathologically confirmed VM-HCC (HR 2.8; 95% CI: 1.6, 3.8; P < 0.001) and satellite nodules (HR 1.8; 95% CI: 1.1, 3.1; P = 0.025) were independently associated with early recurrence after surgical resection. CONCLUSION: The predictive model can be used to predict VM patterns. VM-HCC is associated with increased risk of early recurrence after surgical resection in HCC.

Body mass index and serum alpha-fetoprotein level associated with PD1 expression and prognosis in patients with hepatocellular carcinoma.

Background: Many factors affect the outcome of treatment with programmed death 1 (PD1) inhibitors for hepatocellular carcinoma (HCC). The objective of this study was to investigate the associations of clinicopathological parameters with PD1 expression and HCC prognosis. Methods: A total of 372 HCC patients (Western population) from The Cancer Genome Atlas (TCGA), and 115 primary HCC tissues and 52 adjacent tissues (Dataset GSE76427, Eastern population) from Gene Expression Omnibus (GEO) database were enrolled in this study. The primary outcome was 2-year relapse-free survival. Kaplan-Meier survival curves with the log-rank test were used to analyze the differences in prognosis between the two groups. X-tile software was used to confirm the optimal cut-off for clinicopathological parameters while assessing the outcome. Immunofluorescence was performed on HCC tissues to evaluate PD1 expression. Results: Expression of PD1 was up-regulated in tumor tissue from both TCGA and GSE76427 patients, which positively correlated with body mass index (BMI), serum alpha-fetoprotein (AFP) level, and prognosis. Patients with higher PD1, lower AFP, or lower BMI had longer overall survival than those with lower PD1, higher AFP, or higher BMI, respectively. AFP and PD1 expression were validated in 17 primary HCC patients from the first affiliated hospital, Zhejiang University School of Medicine. Finally, we confirmed longer relapse-free survival with higher PD1 or lower AFP. Conclusion: The findings indicate that BMI and AFP are associated with PD1 expression and HCC prognosis, offering insight for clinical management and personalized immunotherapy for HCC.

The role of enhancing capsule and modified capsule appearances in LI-RADS for diagnosing HCC ≤ 3.0 cm on gadoxetate disodium-enhanced MRI.

OBJECTIVES: To evaluate the value of using enhancing capsule (EC) or modified capsule appearance as a major feature in LI-RADS for diagnosing HCC ≤ 3.0 cm on gadoxetate disodium-enhanced MRI (Gd-EOB-MRI), and to explore the relationship between the imaging features and the histological fibrous capsule. METHODS: This retrospective study enrolled 342 hepatic lesions ≤ 3.0 cm in 319 patients that underwent Gd-EOB-MRIs from January 2018 to March 2021. During dynamic phases and hepatobiliary phase, the modified capsule appearance added the nonenhancing capsule (NEC) (modified LI-RADS + NEC) or corona enhancement (CoE) (modified LI-RADS + CoE) to EC as an alternative capsule appearance. Inter-reader agreement of imaging features was assessed. The diagnostic performances of LI-RADS, LI-RADS with EC ignored, and two modified LI-RADS were compared, followed by Bonferroni correction. Multivariable regression analysis was performed to identify the independent features associated with the histological fibrous capsule. RESULTS: The inter-reader agreement on EC (0.64) was lower than that on the NEC alternative (0.71) but better than that on CoE alternative (0.58). For HCC diagnosis, compared to LI-RADS, LI-RADS with EC ignored showed significantly lower sensitivity (72.7% vs. 67.4%, p < 0.001) with comparable specificity (89.3% vs. 90.7%, p = 1.000). Two modified LI-RADS showed slightly higher sensitivity and lower specificity than LI-RADS, without statistical significance (all p ≥ 0.006). The AUC was highest with modified LI-RADS + NEC (0.82). Both EC and NEC were significantly associated with the fibrous capsule (p < 0.05). CONCLUSION: EC appearance improved the diagnostic sensitivity of LI-RADS for HCC ≤ 3.0 cm on Gd-EOB-MRI. Considering NEC as an alternative capsule appearance allowed for better inter-reader reliability and comparable diagnostic ability. KEY POINTS: • Using the enhancing capsule as a major feature in LI-RADS significantly improved the sensitivity of diagnosing HCC ≤ 3.0 cm without reducing specificity on gadoxetate disodium-enhanced MRI. • Compared to the corona enhancement, the nonenhancing capsule might be a preferable alternative capsule appearance for diagnosing HCC ≤ 3.0 cm. • Capsule appearance should be considered a major feature in LI-RADS for diagnosing HCC ≤ 3.0 cm, regardless whether the capsule appears to be enhancing or nonenhancing.

Corona enhancement combined with microvascular invasion for prognosis prediction of macrotrabecular-massive hepatocellular carcinoma subtype.

Objectives: The macrotrabecular-massive (MTM) subtype of hepatocellular carcinoma (HCC) is aggressive and associated with an unfavorable prognosis. This study aimed to characterize MTM-HCC features based on contrast-enhanced MRI and to evaluate the prognosis of imaging characteristics combined with pathology for predicting early recurrence and overall survival after surgery. Methods: This retrospective study included 123 patients with HCC that underwent preoperative contrast-enhanced MRI and surgery, between July 2020 and October 2021. Multivariable logistic regression was performed to investigate factors associated with MTM-HCC. Predictors of early recurrence were determined with a Cox proportional hazards model and validated in a separate retrospective cohort. Results: The primary cohort included 53 patients with MTM-HCC (median age 59 years; 46 male and 7 females; median BMI 23.5 kg/m2) and 70 subjects with non-MTM HCC (median age 61.5 years; 55 male and 15 females; median BMI 22.6 kg/m2) (All P>0.05). The multivariate analysis identified corona enhancement (odds ratio [OR]=2.52, 95% CI: 1.02-6.24; P=0.045) as an independent predictor of the MTM-HCC subtype. The multiple Cox regression analysis identified corona enhancement (hazard ratio [HR]=2.56, 95% CI: 1.08-6.08; P=0.033) and MVI (HR=2.45, 95% CI: 1.40-4.30; P=0.002) as independent predictors of early recurrence (area under the curve=0.790, P<0.001). The prognostic significance of these markers was confirmed by comparing results in the validation cohort to those from the primary cohort. Corona enhancement combined with MVI was significantly associated with poor outcomes after surgery. Conclusions: A nomogram for predicting early recurrence based on corona enhancement and MVI could be used to characterize patients with MTM-HCC and predict their prognosis for early recurrence and overall survival after surgery.

A new classification and regression tree algorithm: Improved diagnostic sensitivity for HCC ≤ 3.0 cm using gadoxetate disodium-enhanced MRI.

PURPOSE: To develop and validate an effective algorithm, based on classification and regression tree (CART) analysis and LI-RADS features, for diagnosing HCC ≤ 3.0 cm with gadoxetate disodium­enhanced MRI (Gd-EOB-MRI). METHOD: We retrospectively included 299 and 90 high-risk patients with hepatic lesions ≤ 3.0 cm that underwent Gd-EOB-MRI from January 2018 to February 2021 in institution 1 (development cohort) and institution 2 (validation cohort), respectively. Through binary and multivariate regression analyses of LI-RADS features in the development cohort, we developed an algorithm using CART analysis, which comprised the targeted appearance and independently significant imaging features. On per-lesion basis, we compared the diagnostic performances of our algorithm, two previously reported CART algorithms, and LI-RADS LR-5 in development and validation cohorts. RESULTS: Our CART algorithm, presenting as a decision tree, included targetoid appearance, HBP hypointensity, nonrim arterial phase hyperenhancement (APHE), and transitional phase hypointensity plus mild-moderate T2 hyperintensity. For definite HCC diagnosis, the overall sensitivity of our algorithm (development cohort 93.2%, validation cohort 92.5%; P < 0.006) was significantly higher than those of Jiang's algorithm modified LR-5 (defined as targetoid appearance, nonperipheral washout, restricted diffusion, and nonrim APHE) and LI-RADS LR-5, with the comparable specificity (development cohort: 84.3%, validation cohort: 86.7%; P ≥ 0.006). Our algorithm, providing the highest balanced accuracy (development cohort: 91.2%, validation cohort: 91.6%), outperformed other criteria for identifying HCCs from non-HCC lesions. CONCLUSIONS: In high-risk patients, our CART algorithm developed with LI-RADS features showed promise for the early diagnosis of HCC ≤ 3.0 cm with Gd-EOB-MRI.

Do transition and hepatobiliary phase hypointensity improve LI-RADS categorization as an alternative washout: a systematic review and meta-analysis.

OBJECTIVE: The definition of washout in gadoxetate disodium-enhanced MRI (Gd-EOB-MRI) is controversial. The current Liver Imaging Reporting and Data System (LI-RADS) defines washout only in the portal venous phase on Gd-EOB-MRI, leading to low diagnostic sensitivity for HCC. We performed a meta-analysis to compare the diagnostic performance of Gd-EOB-MRI using conventional (cWO) and modified (mWO) definitions of washout. METHODS: The PubMed and EMBASE databases were searched to identify studies published between January 1, 2010, and August 1, 2021, that compared the diagnostic performance of cWO and mWO for HCC. The mWOs added transition phase (TP) hypointensity (mWO-1), hepatobiliary phase (HBP) hypointensity (mWO-2), or both (mWO-3). The pooled sensitivity and specificity were calculated using a bivariate random-effects model. Study heterogeneity was explored by subgroup analysis and meta-regression analysis. RESULTS: Ten comparative studies with 2391 patients were included. Compared to cWO, the overall mWO yielded significantly higher sensitivity (71% vs. 81%, p = 0.00) and lower specificity (97% vs. 93%, p = 0.01) for diagnosing HCC. The area under the curve (AUC) was 0.90 and 0.94 for the cWO and mWO, respectively. Regarding the three types of mWOs, mWO-2 showed the highest sensitivity (85%) and specificity (96%) for diagnosing HCC. mWO-2 achieved the highest AUC (0.97), followed by mWO-1 (0.90), and mWO-3 (0.89). Average reviewer experience and scanner field strength were significantly associated with study heterogeneity (p < 0.05). CONCLUSIONS: Inclusion of TP and HBP hypointensity in the definition of washout improved the sensitivity with slightly lower specificity for diagnosing HCC in LI-RADS. KEY POINTS: • Compared to the conventional definition of washout, studies using a modified definition had higher sensitivity (71% vs. 81%) but lower specificity (97% vs. 93%) in LI-RADS for the diagnosis of HCC. • Hepatobiliary phase hypointensity may be a preferred alternative washout for HCC diagnosis with the highest area under the curve. • Studies with experienced reviewer or 3.0T MRI showed higher sensitivity and lower specificity for diagnosing HCC when using modified washout (p < 0.05).

Imaging Findings for Identifying and Evaluating Complications After Lung Transplantation in Patients with Advanced COVID-19: Two Case Reports.

BACKGROUND: Lung transplantation might be a viable alternative for patients with irreversible lung injury secondary to coronavirus disease 2019 (COVID-19). Here, we describe two patients with end-stage COVID-19 that received lung transplantations, the clinical-radiologic manifestations of postoperative complications, and the imaging features of allograft rejection. CASE PRESENTATION: In case 1, a 66-year-old woman presented severe hypoxia after lung transplantation. Chest imaging revealed diffuse homogeneous infiltration in the donor's lung. Dramatic resolution of the imaging abnormalities after intravenous administration of methylprednisolone favored a diagnosis of hyperacute rejection. The second is a 70-year-old man who was infected with bacterial postoperatively. During the empiric antibiotic therapy, chest CT showed newly developed groundglass opacities with septal thickening, suggesting a diagnosis of acute rejection. High-dose corticosteroids therapy was initiated, and the patient recovered gradually. CONCLUSION: This is the first report describing postoperative complications of lung transplantation in patients with advanced COVID-19. We presumed that imaging procedures could be a useful tool in early detecting lung transplant complications and selecting specific interventions for patients with COVID-19.

Fast kilovoltage (KV)-switching dual-energy computed tomography hydroxyapatite (HAP)-water decomposition technique for identifying bone marrow edema in vertebral compression fractures.

BACKGROUND: Hydroxyapatite (HAP) is the main component of bone mineral. The utility of using HAP-water decomposition technique with fast kilovoltage (KV)-switching dual-energy computed tomography (DECT) to detect abnormal edema in vertebral compression fractures (VCFs) has not been widely reported. METHODS: A total of 31 consecutive patients with 80 VCFs who underwent DECT and magnetic resonance imaging (MRI) of the spine were retrospectively enrolled in our study between October 2018 and January 2019. VCFs in MR examinations served as the standard of reference. Two radiologists blindly and independently evaluated color-coded overlay virtual nonhydroxyapatite (VNHAP) images for the presence of abnormal edema. The inter-reader agreement, specificity, sensitivity, accuracy, and predictive values of VNHAP images for edema detection were calculated. The diagnostic accuracy of two readers was compared using McNemar's test. Two additional radiologists performed a quantitative analysis on VNHAP images, receiver operating characteristic (ROC) curve analysis was conducted, and the threshold was calculated. RESULTS: MRI depicted 45 edematous and 35 nonedematous VCFs. For visual analysis, the VNHAP technique showed a sensitivity of 93.3%, a specificity of 97.1%, a positive predictive value (PPV) of 97.7%, a negative predictive value (NPV) of 91.9%, and an accuracy of 95.0%. The inter-reader agreement was almost perfect (k=0.90). The diagnostic accuracy of the two readers showed no significant differences in the assessment of VNHAP images (P=1.00). Significant differences in CT numbers between vertebrae with and without bone marrow edema were found by quantitative analysis (P<0.01). The area under the curve (AUC) of the VNHAP images was estimated to be 0.917. The threshold of 1,003.2 mg/cm3 yielded a sensitivity of 88.9% and a specificity of 82.9% for the differentiation of fresh and old VCFs. CONCLUSIONS: Fast KV-switching DECT HAP-water decomposition technique had excellent diagnostic performance for identifying acute and chronic VCFs in visual and quantitative analyses.

Does ultrasound measurement improve the accuracy of electronic brachytherapy in the treatment of superficial non-melanomatous skin cancer?

PURPOSE: Electronic brachytherapy (eBT) is a form of contact radiation therapy used for thin superficial non-melanomatous skin cancers (NMSCs). An accurate measurement of diameter and depth is important for eBT treatment planning. Therefore, we compared clinical measurements by an experienced physician to measurements obtained using ultrasound (US), an objective imaging modality, in order to determine if clinical measurements were accurate enough for adequate NMSC treatment. MATERIAL AND METHODS: Eighteen patients with 20 biopsy-proven NMSCs first had a clinical examination and then an US evaluation prior to starting eBT. One physician provided a clinical measurement for diameter and depth based on physical examination during radiation oncology consultation. The patients then had an US evaluation with a 14 or 18 MHz US unit, to determine both the diameter and depth measurements; eBT dose prescription was done using the US derived measurements. The clinical measurements and US measurements were compared using a t-test. RESULTS: Seventeen lesions were basal cell carcinoma and 3 lesions were squamous cell carcinoma. The most common location was the nose (10 lesions). The difference between the clinical and the US derived measurements for the second largest diameter was found to be statistically significant (p = 0.03), while the difference for the largest diameter of the lesions was not (p = 0.24). More importantly, the depth measurements obtained with US were also found to be significantly different from the clinical estimates (p = 0.02). All patients have had a complete response to therapy with a median follow-up of 24 months. CONCLUSIONS: Statistically different measurements were obtained in 2 of 3 parameters used in choosing applicator size and prescription depth using an US assessment. The data presented suggests that US is a more objective modality than clinical judgment for determining superficial NMSC diameter and prescription depth for personalized eBT planning.

SENSING DNA WITH ALTERNATING CURRENTS USING A NANOGAP SENSOR EMBEDDED IN A NANOCHANNEL DEVICE.

We report an integrated nanochannel/nanoelectrode sensor for the detection of DNA using alternating currents. We find that DNA can be detected using platinum as the metal for the detecting electrodes, with a signal to noise ratio exceeding 10. We argue that the signal is at least in part electrochemical in nature, thus holds the promise to yield a sequence-dependent signal. However, we also find that for large voltages, DNA attaches irreversibly to the driving electrodes.

Fluctuation modes of nanoconfined DNA.

We report an experimental investigation of the magnitude of length and density fluctuations in DNA that has been stretched in nanofluidic channels. We find that the experimental data can be described using a one-dimensional overdamped oscillator chain with nonzero equilibrium spring length and that a chain of discrete oscillators yields a better description than a continuous chain. We speculate that the scale of these discrete oscillators coincides with the scale at which the finite extensibility of the polymer manifests itself. We discuss how the measurement process influences the apparent measured dynamic properties, and outline requirements for the recovery of true physical quantities.

Density fluctuations dispersion relationship for a polymer confined to a nanotube.

DNA confined to rigid nanotubes shows density fluctuations around its stretched equilibrium conformation. We report an experimental investigation of the length-scale dependent dynamics of these density fluctuations. We find that for highly elongated molecules a Rouse description is consistent with observations at sufficiently large length scales. We further find that for strongly fluctuating molecules, or short length scales, such Rouse modes cannot be detected due to strong mixing of fluctuation modes.

Stretching chromatin through confinement.

We present a method for the stretching of chromatin molecules in nanofluidic channels width a cross-section of about 80 x 80 nm(2), and hundreds of microns long. The stretching of chromatin to about 12 basepairs/nm enables location-resolved optical investigation of the nucleic material with a resolution of up to 6 kbp. The stretching is based on the equilibrium elongation that polymers experience when they are introduced into nanofluidic channels that are narrower than the Flory coil corresponding to the whole chromatin molecule. We investigate whether the elongation of reconstituted chromatin can be described by the de Gennes model. We compare nanofluidic stretching of bare DNA and chromatin of equal genomic length, and find that chromatin is 2.5 times more compact in its stretched state.