Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Magnesium and liver disease.

Magnesium is a vital cation that takes part in many cellular processes. Magnesium balance can be disturbed in multiple conditions, and differences in magnesium concentration can be responsible for numerous physiological and pathological processes. Magnesium deficiency is commonly associated with liver diseases, and may result from low nutrient uptake, greater urinary secretion, low serum albumin concentration, or hormone inactivation. In turn, low magnesium content in serum and liver tissue can lead to the progression of these diseases, due to a disruption in mitochondrial function, defective protein kinase C (PKC) translocation, inflammatory responses, oxidative stress, or metabolic disorders. Furthermore, magnesium supplementation can improve liver function in certain liver diseases. This paper comprehensively reviews the changes in magnesium concentrations associated with liver cirrhosis, alcoholic liver disease (ALD), liver cancer, and viral hepatitis, and explains how such changes may in turn impact these disease processes.

Magnesium isoglycyrrhizinate inhibits inflammatory response through STAT3 pathway to protect remnant liver function.

AIM: To investigate the protective effect of magnesium isoglycyrrhizinate (MgIG) on excessive hepatectomy animal model and its possible mechanism. METHODS: We used the standard 90% hepatectomy model in Sprague-Dawley rats developed using the modified Emond's method, in which the left, middle, right upper, and right lower lobes of the liver were removed. Rats with 90% liver resection were divided into three groups, and were injected intraperitoneally with 3 mL saline (control group), 30 mg/kg (low-dose group) and 60 mg/kg (high-dose group) of MgIG, respectively. Animals were sacrificed at various time points and blood was drawn from the vena cava. Biochemical tests were performed with an automatic biochemical analyzer for the following items: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyl endopeptidase, total bilirubin (TBil), direct bilirubin (DBil), total protein, albumin, blood glucose (Glu), hyper-sensitivity C-reactive protein, prothrombin time (PT), and thrombin time (TT). Postoperative survival time was observed hourly until death. Hepatocyte regeneration was analyzed by immunohistochemistry. Serum inflammatory cytokines (IL-1, IL-6, IL-10, and iNOS) was analyzed by ELISA. STAT3 protein and mRNA were analyzed by Western blot and quantitative reverse-transcription PCR, respectively. RESULTS: The high-dose group demonstrated a significantly prolonged survival time, compared with both the control and the low-dose groups (22.0 ± 4.7 h vs 8.9 ± 2.0 vs 10.3 ± 3.3 h, P = 0.018). There were significant differences among the groups in ALT, Glu and PT levels starting from 6 h after surgery. The ALT levels were significantly lower in the MgIG treated groups than in the control group. Both Glu and PT levels were significantly higher in the MgIG treated groups than in the control group. At 12 h, ALT, AST, TBil, DBil and TT levels showed significant differences between the MgIG treated groups and the control group. No significant differences in hepatocyte regeneration were found. Compared to the control group, the high-dose group showed a significantly increase in serum inflammatory cytokines IL-1 and IL-10, and a decrease in IL-6. Both STAT3 protein and mRNA levels were significantly lower in the MgIG treated groups than in the control group at 6 h, 12 h, and 18 h after surgery. CONCLUSION: High-dose MgIG can extend survival time in rats after excessive hepatectomy. This hepatoprotective effect is mediated by inhibiting the inflammatory response through inhibition of the STAT3 pathway.

Severe adult ileosigmoid intussusception prolapsing from the rectum: A case report.

Intussusception is a pediatric condition that rarely presents in adults. In this article, we report a case of a 36 year-old man initially presenting with abdominal pain and rectal prolapse, however, surgical reduction of the rectal prolapse did no relief his symptoms. Physical examination, abdominal plain film, barium enema and colonoscopy confirmed the presence of a large intra-abdominal mass, but the origin of the mass was revealed only upon laparotomy. During the surgery, it was noted that the ileum and the sigmoid colon was connected by a 15 cm x 12cm mass, covered by an extremely dilated intestinal tissue. The resected tissue pathology demonstrated a 9 cm x 6 cm x 5 cm submucosal lipoma at the ileocecal junction without evidence of malignancy. The patient's post-surgical course was uneventful. Diagnostic and therapeutic problems related to adult intussusception are reviewed.

[Diagnosis and treatment of pancreatic metastasis from renal cell carcinoma].

OBJECTIVE: Pancreatic metastasis from renal cell carcinoma (RCC) is a rare event and has not been reported in our country. We report a series of 3 patients with metastatic RCC to the pancreas after radical nephrectomy at our institution. The published reports in the literature were reviewed, and the diagnosis, treatment as well as prognosis of this rare event were discussed. METHODS: The data of 3 RCC patients with metastasis to the pancreas were reviewed retrospectively, including radical nephrectomy, metastatic interval, the second and third surgical removal. Survival of the three patients was analyzed and the reports in the literature were compared as well. RESULTS: The average interval from radical nephrectectomy to the comfirmed pancreatic metastasis was 6.6 years (range, 1.2 to 12 years). The pathological stage revealed T2N0M0 (n = 2) or T3N0M0 (n = 1), with right-sided tumor in 2 patients and left side in 1. One patient was asymptomatic, while the other two cases were symptomatic at presentation, including upper abdominal pain, weight loss, slight xanthochromia of the skin and titillation, clay stool (n = 1); irregular fever, weight loss and jaundice (n = 1). All pancreatic metastases were hypervascular on arterial stage of CT imaging. One patient had only a solitary pancreatic metastasis (n = 1), the another showed two metastatic lesions (n = 1), the third one had multiple lesions (n = 1). Surgical removal was accomplished in 2 patients: including pylorus-preserving pancreaticoduodenectomy in one, and pylorus-preserving pancreaticoduodenectomy together with partial tail resection in another one. The third one only received interventional therapy due to widespread extrapancreatic metastasis, and died of disseminated disease 11 months after the therapy. One of the above two surgically treated patients underwent the second removal due to local recurrence 2.5 years after the first removal of pancreatic metastasis. These two patients were still alive after follow-up of 8.6 years and 16.1 years, respectively. CONCLUSION: Renal cell carcinoma is an unpredictable tumor that may demonstrate very delayed metastasis even from early-stage of the disease. The pancreas is a rare site of metastasis from renal cell carcinoma. We advocate careful long-term follow-up of patients with a history of RCC. Aggressive surgical management of pancreatic metastatic lesions may provide a chance of long-term survival.

[One-day bowel preparation with sodium phosphate prior to colorectal surgery: a prospective, randomized, controlled clinical trial].

OBJECTIVES: To investigate the feasibility and safety of one-day bowel preparation for colorectal surgery. METHODS: Forty patients undergone colorectal surgery were divided randomly into the Control group and the Experimental group and received 3-day magnesium sulfate and 1-day sodium phosphate bowel preparations before the operation, respectively. The levels of hemoglobin, hematocrit, serum electrolytes, and anaerobe counts in the stool prior and post bowel preparation were examined. The general status, surgical complications, and structure of intestinal mucosa in the patients were observed after the operation. RESULTS: There was no significant difference in the anastomoses healing, infectious complications, serum tests and intestinal mucosa structures between the two groups. Less diarrhea occurred prior and post the surgery in the experimental group, and they felt better with the bowel preparation. The anaerobe counts in stool were higher after the bowel preparation than before in both groups. CONCLUSIONS: One-day bowel preparation with sodium phosphate is a safe and reliable method for colorectal surgery. The shortening of preparation time can reduce the degrees of uncomfortable feeling and disruptions of intestinal micro-ecology and barrier.