Cutaneous adverse events in patients treated with PD-1/PD-L1 checkpoint inhibitors and their association with survival: a systematic review and meta-analysis.

Immune-related cutaneous adverse events (irCAEs) in patients treated with programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors may be associated with better clinical outcomes. However, the extent to which these results can be extrapolated to all tumour types remains unclear. Herein, we conducted a meta-analysis of patients with cancer receiving anti-PD-1/PD-L1 immunotherapy, to determine the cumulative incidence of irCAEs and their association with survival. We systematically searched six databases (PubMed, Embase, Cochrane, CNKI, CSPD, and CQVIP database) for all cohort studies reporting the relationship between irCAEs and patient survival from the time of database construction to 1 November, 2020. The primary outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), with complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) as secondary outcomes. Patients with irCAEs exhibited higher ORR, and were more likely to report CR and PR and less likely to develop PD than those who did not experience irCAEs. Moreover, the occurrence of irCAEs was significantly associated with both favourable PFS and OS. Therefore, patients with irCAEs have better survival benefit and a significantly lower risk of tumour progression or death. Hence, the occurrence of irCAEs may be a useful marker for predicting the clinical efficacy of anti-PD-1/PD-L1 immunotherapy.

Neoadjuvant therapy of cetuximab combined with chemoradiotherapy in rectal cancer: A single-arm meta-analysis of noncomparative clinical studies and randomized controlled trials.

OBJECTIVE: Preoperative chemoradiotherapy combined with radical resection has reduced local recurrence rates in rectal cancer. Cetuximab shows improvement in rectal cancer treatment. But the role for neoadjuvant therapy of cetuximab combined with chenmoradiotherapy in rectal cancer remains unclear. The present study aimed to use meta-analytical techniques to assess its benefit and risk. MATERIALS AND METHODS: We searched PubMed, the Cochrane Library, Embase to identify the correlational non-comparative clinical studies and randomized controlled trials (RCTs). The primary endpoints of interest were pathological complete response (pCR), complete response (CR), partial response (PR), stable disease, progressive disease (PD), R0-resection, R1-resection, and R2-resection. The secondary included any grade of toxicity. RESULTS: Eleven investigations (9 noncomparative open-label cohort studies and 2 randomized controlled trials) involving 550 patients were ultimately included. The pooled estimates of pCR was 10% (95% confidence interval [CI]: 7%-13%, I2 = 55.9%). Simultaneously, only a small amount of patients achieved CR (11%, 95% CI: 7%-15%, I2 = 44.0%), which was consistent with pCR. Besides, R0 resection (93%, 95% CI: 90%-96%, I2 = 16.5%) seemed to be increased but need further exploration. The safety was also calculated, and most of the toxicities were moderate. CONCLUSION: Neoadjuvant therapy of cetuximab combined with chemoradiotherapy could not improve pCR. The raise of R0-resection rate needed to be verified by more high-quality and well-designed RCTs. Meanwhile, the morbidity of toxicity was relatively mild and acceptable.

Human cardiotoxic drugs delivered by soaking and microinjection induce cardiovascular toxicity in zebrafish.

Cardiovascular toxicity is a major challenge for the pharmaceutical industry and predictive screening models to identify and eliminate pharmaceuticals with the potential to cause cardiovascular toxicity in humans are urgently needed. In this study, taking advantage of the transparency of larval zebrafish, Danio rerio, we assessed cardiovascular toxicity of seven known human cardiotoxic drugs (aspirin, clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride) and two non-cardiovascular toxicity drugs (gentamicin sulphate and tetracycline hydrochloride) in zebrafish using six specific phenotypic endpoints: heart rate, heart rhythm, pericardial edema, circulation, hemorrhage and thrombosis. All the tested drugs were delivered into zebrafish by direct soaking and yolk sac microinjection, respectively, and cardiovascular toxicity was quantitatively or qualitatively assessed at 4 and 24 h post drug treatment. The results showed that aspirin accelerated the zebrafish heart rate (tachycardia), whereas clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride induced bradycardia. Quinidine and terfenadine also caused atrioventricular (AV) block. Nimodipine treatment resulted in atrial arrest with much slower but regular ventricular heart beating. All the tested human cardiotoxic drugs also induced pericardial edema and circulatory disturbance in zebrafish. There was no sign of cardiovascular toxicity in zebrafish treated with non-cardiotoxic drugs gentamicin sulphate and tetracycline hydrochloride. The overall prediction success rate for cardiotoxic drugs and non-cardiotoxic drugs in zebrafish were 100% (9/9) as compared with human results, suggesting that zebrafish is an excellent animal model for rapid in vivo cardiovascular toxicity screening. The procedures we developed in this report for assessing cardiovascular toxicity in zebrafish were suitable for drugs delivered by either soaking or microinjection.

Secretion of intestinal goblet cells: a novel excretion pathway of nanoparticles.

Understanding the excretion pathway is one of the most important prerequisites for the safe use of nanoparticles in biomedicine. However, the excretion of nanoparticles in animals remains largely unknown, except for some particles very small in size. Here we report a novel natural pathway for nanoparticle excretion, the intestinal goblet cell (GC) secretion pathway (IGCSP). Direct live observation of the behavior of 30-200nm activated carbon nanoparticles (ACNP) demonstrated that ACNP microinjected into the yolk sac of zebrafish can be excreted directly through intestinal tract without involving the hepato-biliary (hap-bile) system. Histopathological examination in mice after ligation of the common bile duct (CBD) demonstrated that the intravenously-injected ACNP were excreted into the gut lumen through the secretion of intestinal GCs. ACNP in various secretion phases were revealed by histopathological examination and transmission electron microscopy (TEM). IGCSP, in combination with renal and hap-bile pathways, constitutes a complete nanoparticle excretion mechanism. FROM THE CLINICAL EDITOR: Nanoparticle elimination pathways are in the forefront of interest in an effort to optimize and enable nanomedicine applications. This team of authors reports a novel natural pathway for nanoparticle excretion, the intestinal goblet cell (GC) secretion pathway (IGCSP). Direct live observation of the behavior of activated carbon nanoparticles has shown excretion directly through the intestinal tract without involving the hepato-biliary (hap-bile) system in a zebrafish model.

A zebrafish phenotypic assay for assessing drug-induced hepatotoxicity.

INTRODUCTION: Numerous studies have confirmed that zebrafish and mammalian toxicity profiles are strikingly similar and the transparency of larval zebrafish permits direct in vivo assessment of drug toxicity including hepatotoxicity in zebrafish. METHODS: Hepatotoxicity of 6 known mammalian hepatotoxic drugs (acetaminophen [APAP], aspirin, tetracycline HCl, sodium valproate, cyclophosphamide and erythromycin) and 2 non-hepatotoxic compounds (sucrose and biotin) were quantitatively assessed in larval zebrafish using three specific phenotypic endpoints of hepatotoxicity: liver degeneration, changes in liver size and yolk sac retention. Zebrafish liver degeneration was originally screened visually, quantified using an image-based morphometric analysis and confirmed by histopathology. RESULTS: All the tested mammalian hepatotoxic drugs induced liver degeneration, reduced liver size and delayed yolk sac absorption in larval zebrafish, whereas the non-hepatotoxic compounds did not have observable adverse effect on zebrafish liver. The overall prediction success rate for hepatotoxic drugs and non-hepatotoxic compounds in zebrafish was 100% (8/8) as compared with mammalian results, suggesting that hepatotoxic drugs in mammals also caused similar hepatotoxicity in zebrafish. DISCUSSION: Larval zebrafish phenotypic assay is a highly predictive animal model for rapidly in vivo assessment of compound hepatotoxicity. This convenient, reproducible animal model saves time and money for drug discovery and can serve as an intermediate step between cell-based evaluation and conventional animal testing of hepatotoxicity.