Efficacy and safety of sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a two-center study in China.

Background: Regorafenib is a standard 2nd-line treatment for patients with advanced hepatocellular carcinoma (HCC), but the efficacy and safety of sequential therapy with sorafenib and regorafenib among advanced HCC patients in China is not clear. Methods: This was a retrospective, two-center, cohort study of advanced HCC patients who received sequential therapy of sorafenib and regorafenib from October 2018 to April 2020 at 2 Chinese institutions. The patients were converted directly to regorafenib after failing to respond to sorafenib monotherapy. The patients underwent evaluations every 4-6 weeks to determine the efficacy and safety of the treatment according to physiological, laboratory, and radiological results. A radiological evaluation using computed tomography or magnetic resonance imaging scans was conducted. The outcomes included overall survival (OS) and progression-free survival (PFS). Results: A total of 43 patients received regorafenib as a 2nd-line treatment after sorafenib progression. Of these patients, 26 (60.5%) and 17 (39.5%) were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stages B and C, respectively. The median PFS was 11.0 [95% confidence interval (CI): 5.8-16.2] months, and the median OS was 17.0 (95% CI: 12.8-21.2) months. Conversely, the most common toxicities were hand-foot skin reaction (48.8%), diarrhea (32.6%), and hypertension (14%). The most common grade 3-4 toxicities were hypoalbuminemia (4.7%), anemia (4.7%), and thrombocytopenia (4.7%). Alpha-fetoprotein (AFP) ≥400, alanine transaminase (ALT) ≥60 IU/L, and aspartate aminotransferase (AST) ≥60 IU/L before 2nd-line treatment were associated with PFS in the univariable analyses. The Cox proportional-hazards regression analysis showed that AFP [hazard ratio (HR) =0.225; 95% CI: 0.073-0.688; P=0.009], ALT (HR =0.195; 95% CI: 0.051-0.741; P=0.016), AST (HR =0.209; 95% CI: 0.063-0.697; P=0.011), and presence of extrahepatic metastasis (HR =0.074; 95% CI: 0.009-0.608; P=0.015) before 2nd-line treatment were independently associated with PFS. Conclusions: The sequential therapy of sorafenib and regorafenib is well-tolerated and effective in advanced HCC patients after sorafenib progression based on our two-center real-world data. Patients with good liver function reserve and a high level of AFP before 2nd-line treatment may benefit from sequential treatment. These results still need further validation.

Effects of serum from mismatched patients with solid organ transplantation on the activation of microvascular cultures isolated from adipose tissues.

BACKGROUND: Aggregating the human leukocyte antigen (HLA) Class I antigens on the endothelial membrane has been known to elicit an activation, an underlying mechanism of chronic rejection in organ transplant recipients. The current study aims at examining the endothelial responses using HLA typed microvascular cultures from human adipose tissues upon exposure to the serum that contain corresponding antibodies collected from mismatched transplant recipients. METHODS: We have successfully cultured 30 microvascular cultures and typed their HLAs. They are functionally competent to respond to inflammatory TNF-α stimulation and the aggregating monoclonal antibody against HLA Class I. The post-transplantation serum was collected either from the recipients with pathologically diagnosed chronic rejection or from the recipients without rejection. We determined their activation either by double-staining the endothelial cells in crude cultures with flow cytometry or by quantifying cytokine releases in purified endothelial cells using ELISA. RESULTS: Under our current protocol, adipose tissue cultures are functionally intact in regard to its responses to TNF-alpha and anti-HLA Class I antibody. We observed that the post-transplantation serum with rejection contained the pathogenic antibodies and led to proinflammatory activation, as demonstrated by not only increased CD54+/CD31+ and CD106+/CD31+ cell counts but also inflammatory cytokine releases including MCP-1, IL-8 and RANTES. CONCLUSION: This methodological study provides the feasibility of examining the pathogenicity of the alloantibodies in mis-transplant serum. Potentially, the endothelial activation elicited as a result of exposure can be used as an alternative readout for chronic rejection. SIGNIFICANCE: We prototype an ex vivo model that enables us to examine whether allogenic antibodies from the recipient can functionally activate microvascular endothelial cells from the donor adipose tissues. This system can be further developed as crossmatch using cellular responses as readouts for chronic rejection for post-transplant surveillance.

Somatic gene mutation signatures predict cancer type and prognosis in multiple cancers with pan-cancer 1000 gene panel.

Most cancers are caused by somatic mutations. Some common mutations in the same cancer type can form a "signature" to specifically predict the prognosis or to distinguish it from other cancers. In this study, 710 somatic cell mutations were identified in 142 cases, including digestive, lung and urogenital cancers, and the digestive cancers were further divided into liver, stomach, intestinal, esophageal and cardia cancer. The above mutations were located in 166 genes. In addition, a group of high-frequency mutation genes with specific characteristics were screened to form predictive signatures for each cancer. Verification using TCGA suggested that the signatures could predict the stages, progression-free survival, and overall survival of digestive, intestinal, and liver cancers (P < 0.05). The validation cases further confirmed the predictive role of digestive and liver cancers signatures in diagnosis and prognosis. Overall, this study established predictive signatures for different cancer systems and their subtypes. These findings enable a better understanding in cancer genome, and contribute to the personalized diagnosis and treatment.

The indications for hepatectomy for multinodular hepatocellular carcinoma: experience from a single institution.

AIMS: This study was conducted in order to investigate the indications for hepatecomy for multinodular hepatocellular carcinoma (MNHCC) in single institution. METHODS: We retrospectively analyzed the medical records from 55 MNHCC patients, mainly with Child-Pugh A liver function, who underwent hepatectomy from January 2006 to December 2008. Both short- and long-term outcomes were analyzed. In addition, the prognostic significance of clinicopathological factors on overall survival (OS) was investigated by univariate analysis using the log-rank test. A Cox proportional hazards model was used in a subsequent multivariate analysis. RESULTS: The perioperative morbidity rate (grade II or higher) was 18.2% (n = 10), and the in-hospital mortality rate was 3.6%. The median OS was 23.9 months (range, 2.5-84 months), whereas the median disease-free survival was 8.75 months (range, 1-65 months). Independent prognostic risk factors of 5-year OS included the number of tumors >2 (p = 0.032) and gross morphology indicating multiple tumor nodules scattered throughout the liver (p = 0.009). CONCLUSIONS: The postoperative morbidity and mortality rates were acceptable. The number of tumors >2 and gross morphology indicating multiple tumor nodules scattered throughout the liver were independent prognostic risk factors for patients with MNHCC after hepatectomy. Patients with both of these features had a very poor prognosis and were not considered suitable for surgery.

[Effect of Chinese drugs for benefiting-qi, activating-blood, dissolving-phlegm and removing-toxin combined with conventional treatment in preventing and treating post-operative vascular restenosis in patients with diabetic lower extremity arterial disease underwent percutaneous transluminal angioplasty].

OBJECTIVE: To verify the clinical efficacy of Chinese drugs for benefiting-qi, activating-blood, dissolving phlegm and removing-toxin (CDs) Combined with Conventional Treatment on post-operative vascular restenosis in patients with diabetic lower extremity arterial disease (DLEAD) underwent percutaneous transluminal angioplasty (PTA). METHODS: Fifty-six DLEAD patients underwent PTA of below-knee artery were assigned to the treatment group (32 patients) treated by basic therapy combined with CDs and the control group (24 patients) treated by basic therapy only. The changes in symptoms and signs, ankle/brachial index (ABI) and transcutaneous oxygen pressure (TCPO2) of affected limb, and blood flow (BF) in operated vessels checked with color Doppler examination were monitored and analyzed with SPSS software 16. 0. RESULTS: Overall effectiveness, including symptom score, ABI, TCPO2 and BF in patients after operation were all better in both groups significantly (P < 0.05), the improvements began to reveal in 3-6 months, and be stabilized in the treatment group, but declined gradually in the control group after then. So, the effective rate in the treatment group became significantly higher than that in the control group (75.00% vs. 41.67%, P < 0.01) at the end of the 6th month, meanwhile levels of ABI (0.65 +/- 0.12), TCPO2 (68.00 +/- 4.21 mm Hg), and BF (35.00 +/- 2.11 cm/s) in the former were better than those in the control group, respectively (0.44 +/- 0.12, 41.00 +/- 2.02 mm Hg and 21.00 +/- 1.85 cm/s, P < 0.05). CONCLUSION: CDs shows definite effect in post-PTA prevention of vascular restenosis in DLEAD patients.

Therapeutic effects of Clostridium butyricum on experimental colitis induced by oxazolone in rats.

AIM: To evaluate the therapeutic effects of a probiotic supplement (Clostridium butyricum, CGMCC0313) in a chemically-induced rat model of experimental colitis. METHODS: An experimental ulcerative colitis model was established by rectal injection of oxazolone into the colon of 40 Wistar rats randomly divided into four groups. The positive control group was sacrificed 3 d after colitis onset. The remaining groups were fed daily with either 2 mL of C. butyricum (2.3 x 10(11) CFU/L), 2 mL of mesalamine (100 g/L), or 1 mL of sodium butyrate (50 mmol/L) for 21 d. The animals' body weight, behavior, and bowel movements were recorded weekly. After sacrifice, visual and microscopic observations of pathological changes of colon tissue were made, body weight and wet colon mass index were measured and recorded, and serum levels of interleukin-23 (IL-23) and TNF-alpha were measured using ELISA. Expression of calcitonin gene-related peptide in colon tissue was measured by RT-PCR. Finally, changes in rat intestinal microflora status were measured in all groups. RESULTS: We found that treatment with C. butyricum lowered the serum levels of both IL-23 and tumor necrosis factor-alpha (TNF-alpha) with similar or even better efficiency than that of mesalamine or sodium butyrate. The rat intestinal flora appeared to recover more quickly in the group treated with C. butyricum than in the mesalamine and sodium butyrate groups. Finally, we found that the expression level of calcitonin gene related peptide was elevated in colon tissue in the sodium butyrate treated group but not in the C. butyricum or mesalamine treated groups, indicating a sensitization of colon following sodium butyrate treatment. CONCLUSION: In our experimental colitis model, treatment with C. butyricum CGMCC0313, a probiotic supplement, is at least as efficient as treatment with mesalamine.