Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040.

BACKGROUND: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.

[Applied research of ultrasound attenuation parameter in the diagnosis of metabolic dysfunction-associated fatty liver disease].

Objective: To evaluate the efficacy, establish a diagnostic model, and value of ultrasound attenuation parameters (UAP) to diagnose hepatic steatosis in metabolic dysfunction-associated fatty liver disease (MAFLD) and its relevant disorders. Methods: 3770 cases were selected from the Health Examination Center of the Third Hospital of Hebei Medical University between October to December 2020. MAFLD diagnosis was based on the Asia-Pacific region MAFLD clinical diagnosis and treatment guidelines. The degree of hepatic steatosis was divided into mild, moderate and severe according to ultrasound imaging. UAP, clinical characteristic indexes, serum biochemical indexes, characteristics of hepatic steatosis and related factors were compared and analyzed in MAFLD patients and healthy controls. Logistic regression method was used to analyze the independent risk factors affecting the progression of hepatic steatosis in MAFLD to establish the diagnostic model. The clinical efficacy of UAP and the new model in diagnosing MAFLD was evaluated by the receiver operating characteristic curve (ROC). One-way ANOVA was used to compare means among multiple groups. Mann-Whitney U test was used to compare non-normally distributed measurement data between the two groups, and rank-sum test was used to compare multiple groups. χ2 test was used to compare count data between groups. Results: Among the 3 770 cases, 650 were MAFLD, with a prevalence rate of 17.24%, and the highest prevalence was 37.23% in the age group of 60-69. The prevalence rate was significantly higher in male than female (30.34% vs. 9.17%). Age-sex analysis showed that the prevalence rate in males aged 30-69 years was 38.26%, and that in females aged over 60 years was 31.94%. UAP was significantly higher in patients with MAFLD than healthy controls (278.55 dB/m vs. 220.90 dB/m, Z=-12.592, P＜0.001), and an increasing trend with increased degree of hepatic steatosis (mild:257.20 dB/m, moderate:286.20 dB/m, and severe: 315.00 dB/m) were observed. The cut-off values of UAP for the diagnosis of mild, moderate and severe hepatic steatosis were 243≤UAP＜258 dB/m, 258≤UAP＜293 dB/m, ≥293 dB/m in MAFLD. The sensitivity and specificity were 67.20%, 93.60%, 95.90%, and 82.10%, 72.00%, and 84.80%, respectively. UAP, alanine aminotransferase and fasting blood glucose were independent risk factors for the progression of hepatic steatosis in MAFLD. The combined MAFLD classification model (UAG model) was established. The AUC of mild, moderate and severe hepatic steatosis in MAFLD were 0.906, 0.907, and 0.946, respectively, and the sensitivity and specificity were 76.50%, 82.10%, 98.00%, and 90.80%, 83.30% and 76.10%, respectively. Conclusion: MAFLD is a common disease in the general population, with a higher incidence in male and elderly female over 30 years of age. UAP can be used as a new noninvasive diagnostic technique to evaluate hepatic steatosis in MAFLD. The UAG model has a good diagnostic efficacy on MAFLD and its relevant disorders, and thus can be used as a guide for evaluating clinical diagnosis and prognosis.

Predictive value of nodal maximum standardized uptake value of pretreatment [18F]fluorodeoxyglucose positron emission tomography imaging in patients with esophageal cancer.

We retrospectively reviewed 102 patients with esophageal cancer (97.1% squamous cell carcinoma, 96.1% stage III) received FDG-PET staging and were treated by chemoradiotherapy with or without resection to assess whether the pretreatment [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) maximum standardized uptake value (SUVmax) of the primary tumor and metastatic lymph nodes can predict the prognosis of patients with esophageal cancer. Receiver operating characteristic analysis was performed to find the cutoff values for primary tumor SUVmax and nodal SUVmax. The influence of clinical factors including primary tumor SUVmax and nodal SUVmax on local progression-free survival, nodal progression-free survival (NPFS), distant metastases-free survival (DMFS), and overall survival (OS) were evaluated using univariate and multivariate analyses. A total of 40 patients received esophagectomy after neoadjuvant chemoradiotherapy (trimodality), while 62 patients received definitive chemoradiotherapy (dCRT). The median follow-up was 26.4 months. The SUVmax of primary tumor had no significant predictive value on all outcomes, while the SUVmax of metastatic lymph nodes had predictive value on several outcomes. High nodal SUVmax (≥7) predicted for worse outcomes than low nodal SUVmax (<7) in the patients who received dCRT (two-year DMFS, 17% vs. 92%, P < 0.001; NPFS, 14% vs. 81%, P = 0.001; OS, 21% vs. 50%, P = 0.003), but not in those received trimodality. On multivariate analysis of patients receiving dCRT, nodal SUVmax was the strongest independent predictor on DMFS (hazard ratio [HR] 13.93, P < 0.001), NPFS (HR 3.99, P = 0.026), PFS (HR 2.90, P = 0.003), and OS (HR 3.80, P = 0.001). High pretreatment nodal SUVmax predicts worse treatment outcomes for the patients treated with dCRT.

Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation.

BACKGROUND: We carried out a phase I trial of the vascular endothelial growth factor inhibitor pazopanib and the histone deacetylase inhibitor vorinostat to determine the safety and efficacy. Because these agents are known to target factors activated by TP53 mutation and facilitate mutant p53 degradation, a subgroup analysis may be interesting in patients with TP53 mutant malignancies. PATIENTS AND METHODS: Patients with advanced solid tumors (n = 78) were enrolled following a 3 + 3 design, with dose expansion for those with responsive tumors. Hotspot TP53 mutations were tested when tumor specimens were available. RESULTS: Adverse events of ≥grade 3 included thrombocytopenia, neutropenia, fatigue, hypertension, diarrhea and vomiting. Overall, the treatment produced stable disease for at least 6 months or partial response (SD ≥6 months/PR) in 19% of the patients, median progression-free survival (PFS) of 2.2 months, and median overall survival (OS) of 8.9 months. In patients with detected hotspot TP53 mutant advanced solid tumors (n = 11), the treatment led to a 45% rate of SD ≥6 months/PR (1 PR and 3 SD ≥6 months), median PFS of 3.5 months, and median OS of 12.7 months, compared favorably with the results for patients with undetected hotspot TP53 mutations (n = 25): 16% (1 PR and 3 SD ≥6 months, P = 0.096), 2.0 months (P = 0.042), and 7.4 months (P = 0.1), respectively. CONCLUSION: The recommended phase II dosage was oral pazopanib at 600 mg daily plus oral vorinostat at 300 mg daily. The preliminary evidence supports further evaluation of the combination in cancer patients with mutated TP53, especially in those with metastatic sarcoma or metastatic colorectal cancer. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01339871.

Identification and expression analysis of components involved in rice Xa21-mediated disease resistance signalling.

Rice Xa21 gene encodes a receptor-like kinase that confers broad-spectrum resistance against Xanthomonas oryzae pv. oryzae (Xoo). Recently, a number of genes involved in the Xa21-mediated disease resistance pathway have been identified. Based on our previous data and the literature, we chose 16 candidate proteins and made corresponding antibodies. Using Western blotting, we systematically investigated the expression profile of the proteins in Xa21-mediated disease resistance response. We found nine proteins with altered expression. We further compared their expression in resistance, susceptible and mock responses, and found that GST expression was up-regulated during the resistance process, indicating GST is a positive regulator in resistance responses. ATPsB expression was down-regulated during both the resistance and susceptible response processes, although it was higher in the resistance response than that in the susceptible response. The total amount of MYB, GAPDH, CatB, Trx and NB-ARC proteins was lower in the resistance than in the susceptible response, but their abundance per unit bacteria in the resistance response was still higher than in the susceptible response, suggesting that these proteins might be positive regulators in the resistance response. In addition, expression of another ERF was induced by inoculation with bacterial blight pathogen, and expression of Zf-LSD1 was activated by wounding stress alone. Interestingly, most proteins showed similar altered expression patterns in the resistance and susceptible responses, but differed to some extents, implying that both responses might share common molecular mechanisms. This study revealed evidence of resistance-related protein expression, providing a foundation for better understanding of their functions.

The correlation between skin electrical conductance and the score of qi vacuity.

In traditional Chinese medicine, the syndrome of qi vacuity means that the patient's body has a low level of energy to react to stress. Recently, we used a score, the QV score, by scaling the severity of symptoms and signs of qi vacuity in patients with tiredness. The aim of this study was to investigate the relationship between QV score and skin electrical conductance in patients with tiredness. One hundred and forty-three healthy controls and 103 patients with tiredness were involved. Each subject received a weak electrical stimulation with constant voltage (1.75 volt), and conductance was measured between two different limbs. The mean value of skin conductance among four limbs was calculated and expressed by a special unit, namely Chin. The correlation between the skin conductance and QV score was analyzed by a linear regression analysis. The results showed that skin electrical conductance of healthy controls was negatively correlated with age (r-coefficient = -0.51, P = 0.000). The skin conductance of patients with tiredness was significantly lower than that of healthy controls with matching age (P = 0.000 by Student's t-test). Moreover, there was a positive correlation between the decrease of skin conductance and the QV score in patients with tiredness (r-coefficient = +0.68, P = 0.000). These results suggest that a decrease in skin electrical conductance may be closely related to the severity of qi vacuity. The skin conductance test is a simple, reliable, and quantitative method for detection of syndrome of qi vacuity.