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Introduction: Lenvatinib plus an anti-PD-1 antibody has shown promising antitumor effects in patients with advanced hepatocellular carcinoma (HCC), but with clinical benefit limited to a subset of patients. We developed and validated a radiomic-based model to predict objective response to this combination therapy in advanced HCC patients. Methods: Patients (N = 170) who received first-line combination therapy with lenvatinib plus an anti-PD-1 antibody were retrospectively enrolled from 9 Chinese centers; 124 and 46 into the training and validation cohorts, respectively. Radiomic features were extracted from pretreatment contrast-enhanced MRI. After feature selection, clinicopathologic, radiomic, and clinicopathologic-radiomic models were built using a neural network. The performance of models, incremental predictive value of radiomic features compared with clinicopathologic features and relationship between radiomic features and survivals were assessed. Results: The clinicopathologic model modestly predicted objective response with an AUC of 0.748 (95% CI: 0.656–0.840) and 0.702 (95% CI: 0.547–0.884) in the training and validation cohorts, respectively. The radiomic model predicted response with an AUC of 0.886 (95% CI: 0.815–0.957) and 0.820 (95% CI: 0.648–0.984), respectively, with good calibration and clinical utility. The incremental predictive value of radiomic features to clinicopathologic features was confirmed with a net reclassification index of 47.9% (p < 0.001) and 41.5% (p = 0.025) in the training and validation cohorts, respectively. Furthermore, radiomic features were associated with overall survival and progression-free survival both in the training and validation cohorts, but modified albumin-bilirubin grade and neutrophil-to-lymphocyte ratio were not. Conclusion: Radiomic features extracted from pretreatment MRI can predict individualized objective response to combination therapy with lenvatinib plus an anti-PD-1 antibody in patients with unresectable or advanced HCC, provide incremental predictive value over clinicopathologic features, and are associated with overall survival and progression-free survival after initiation of this combination regimen. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer in adults. Previous studies in our laboratory found that long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was upregulated in HCC cells, which could affect the metastasis and invasion of HCC. However, the underlying mechanism remains unknown. Herein, we studied the interaction between MALAT1 and miR-140 on the regulation of angiogenesis and immunosuppressive properties. We revealed that the expression of MALAT1 and VEGF-A was significantly increased in HCC cells. Knockdown of MALAT1 in HCC cells suppressed the production of VEGF-A, impaired the angiogenesis of HUVECs, and facilitated the polarization of macrophage toward the M1 subset. Mechanistically, the interaction between MALAT1 and miR-140 or between miR-140 and VEGF-A was confirmed by multiple assays. Besides, a negative correlation between MALAT1 and miR-140 was found in HCC tissues. Furthermore, miR-140 inhibition significantly increased VEGF-A expression, promoted angiogenesis of HUVECs, and redirected the polarization of macrophages toward the M2 subset. In addition, in vivo studies also verified the regulatory network of the MALAT1/miR-140 axis on VEGF-A in HCC progression. In summary, this study revealed the mechanism that MALAT1 worked as a putative HCC promotor via inhibiting miR-140. Therefore, targeting MALAT1 or miR-140 might alleviate the progression of HCC in the future.

Background/aims: Recent studies have found that Cyclooxygenase-2(Cox-2) is frequently inappropriately expressed in primary hepatocellular carcinoma (HCC), suggesting that abnormal Cox-2 expression plays an important role in hepatocarcinogenesis. But it remains controversial in these reports. Moreover, there are only a few studies on the correlation between Cox-2 and infiltrating immunocytes in the tumor-microenvironment. CD4+ tumor-infiltrating lymphocytes (TIL) and infiltrating immunocytes around the tumor are closely correlated to the development of the tumor, but so far no reports are available showing the relationship among Cox-2, CD4+ TIL of tumor and CD4+ infiltrating T-lymphocytes of adjoining non-tumorous (ANT) tissues in tumor-microenvironment. This study is designed to appropriately select and collect patients' specimens to better reflect Cox-2 expression in human HCC, and also to stress the correlation among Cox-2, CD4+ TIL and CD4+ infiltrating T-lymphocytes in the tumor-microenvironment., Methodology: Tumor tissue, and its matched ANT tissue removed less than 1 cm from the solid tumor border, were obtained from 25 HCC patients all of whom came from Hunan province, China, and were infected with hepatitis B virus (HBV). Normal liver tissues of 10 hemangiomas were collected as controls. Both Cox-2 expression and the number of CD4+ TIL and CD4+ infiltrating T-lymphocyte were detected by immunohistochemistry, and data were analyzed closely with patients' clinical figures so as to investigate the correlation between the 3 elements., Results: In 25 HCC patients, remarkably higher Cox-2 expression in both tumor and ANT tissues was observed compared with normal liver tissues (p < 0.001). The percentage of Cox-2 positive cells was, remarkably, higher in ANT tissues than in tumors (p < 0.001). Similarly the distribution of CD4+ T cells was significantly higher in ANT tissue than in tumor tissue (p < 0.0001), and also significantly higher in tumor tissue than in normal tissue (p < 0.0001). Importantly, in the group of patients with Cox-2-expressing tumors, the number of CD4+ infiltrating T-lymphocyte in ANT tissues was 79.4(+)9.92/hpf, which is obviously lower (p = 0.019) than that of the group with non-Cox-2-expressing tumors with the number of CD4+ infiltrating T-lymphocyte in ANT tissues at 118.13(+)12.47/hpf. Cox-2 expression of tumors showed a significant negative correlation with number of CD4+ infiltrating T cells of ANT tissues (r = 0.499, p = 0.024). The number of CD4+ TILs are lower in Cox-2-expressing tumors than in non-Cox-2-expressing tumors, but there was not statistical significance (p = 0.057)., Conclusions: Taken together we suggest in the tumor-microenvironment of HCC the expression of Cox-2 may inhibit the number CD4+ infiltrating T-lymphocyte in ANT tissues. As a result, Cox-2 overexpression may contribute to both suppression of local immune responses and enhancement of metastatic potential in human HCC.

Objective: To study the surgical treatment of recurrent laryngeal nerve (RLN) injury caused by thyroid operation., Methods: From 1970 to 2001, 50 patients with RLN injury were caused by thyroid operation. The causes, location, type, operative procedures and follow-up were retrospectively analyzed., Results: Unilateral RLN injury occurred in 46 cases and bilateral nerve injury in 4 cases. The RLN injuries were located within 2cm below the point of RLN entering to throat in 45 nerves (83.3%), other places in 6 nerves (11.3%), and unknown location in 3 nerves (5.4%). Transection of the nerve was found in 19 nerves (36.5%), suture or scare pressing the nerve in 35 nerves (64.8%). All the injured nerves were repaired surgically. Meanwhile all 4 patients with bilateral RLN injuries underwent tracheotomy. Of the 50 cases, 44 cases (88.0%) were followed up for more than 1.5 years. Among the 44 followed-up patients, phonation was restored to normal or obvious improvement in 42 cases (95.5%), and improvement in 2 (4.5%). Of the 35 patients with 39 nerves underwent indirect or direct laryngoscopy, the affected vocal cord movement entirely recovered in 21 cords (53.8%), partially recovered in 7 cords (17.9%), uncovered in 11 cords (28.3%). There was no relation between the recovery of phonation or vocal cord movement with the timing or the procedure of repairing operation., Conclusions: The location of most RLN injuries caused by thyroid surgery are just below the point of RLN entering to throat, and most are mechanical injury, and need operation to resolve the cause. Once the RLN injury is made, an operation should be performed as early as possible.