Prognostic biomarkers associated with immune checkpoint inhibitors in hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC), particularly advanced HCC, has been a serious challenge. Immune checkpoint inhibitors (ICIs) are landmark drugs in the field of cancer therapy in recent years, which have changed the landscape of cancer treatment. In the field of HCC treatment, this class of drugs has shown good therapeutic prospects. For example, atezolizumab in combination with bevacizumab has been approved as first-line treatment for advanced HCC due to significant efficacy. However, sensitivity to ICI therapy varies widely among HCC patients. Therefore, there is an urgent need to search for determinants of resistance/sensitivity to ICIs and to screen biomarkers that can predict the efficacy of ICIs. This manuscript reviews the research progress of prognostic biomarkers associated with ICIs in HCC in order to provide a scientific basis for the development of clinically individualised precision medication regimens.

The progress of research on immune checkpoint inhibitor resistance and reversal strategies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in humans, which is prone to recurrence and metastasis and has a poor prognosis. The occurrence and progression of HCC are closely related to immune elimination, immune homeostasis, and immune escape of the immune system. In recent years, immunotherapy, represented by immune checkpoint inhibitors (ICIs), has shown powerful anti-tumor capabilities in HCC patients. However, there are still some HCC patients who cannot benefit from ICIs treatment due to their innate or acquired drug resistance. Therefore, it is of great practical significance to explore the possible mechanisms of resistance to ICIs in HCC and to use them as a target to design strategies to reverse resistance, to overcome drug resistance in HCC and to improve the prognosis of patients. This article summarizes the possible primary (tumor microenvironment alteration, and signaling pathways, etc.) and acquired (immune checkpoint upregulation) resistance mechanisms in patients with HCC treated with ICIs, and based on this, discusses the status and effectiveness of combination drug strategy to reverse drug resistance, to provide a reference for subsequent related studies and decisions.

Association of Aspirin with Dementia or Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Randomized Trials.

BACKGROUND: At present, the effect of aspirin in preventing dementia or mild cognitive impairment (MCI) is controversial. Clarifying their association is of interest for subsequent relevant clinical trials. METHODS: Four databases (PubMed, Embase, Web of Science, and the Cochrane Library) were searched from inception to May 12, 2023, for randomized controlled trials (RCTs) that explored the effects between aspirin and dementia or MCI. Two reviewers independently extracted and analyzed data using Stata software. Discrepancy was resolved by a third reviewer. The primary outcomes were dementia and MCI. The secondary outcomes were cognitive decline and changes in cognitive scores. RESULTS: Five RCTs with 46,804 participants at randomization were included. For the primary outcomes, low-certainty evidence showed that aspirin was not associated with dementia (odds ratio [OR] = 0.93, 95% confidence interval [CI]: [0.85, 1.03], p > 0.05, I2 = 0%) or MCI (OR = 1.00, 95% CI: [0.88, 1.14], p > 0.05, I2 = 3.3%). For the secondary outcomes, moderate-certainty evidence showed that aspirin was not associated with cognitive decline (OR = 1.02, 95% CI: [0.93, 1.11], p > 0.05, I2 = 0%) and a change in global cognitive score (standard mean difference [SMD] = -0.01, 95% CI: [-0.03, 0.02], p > 0.05, I2 = 0%). Low-certainty evidence showed that aspirin was not associated with a change in verbal learning memory score (SMD = -0.04, 95% CI: [-0.09, 0.01], p > 0.05; I2 = 72.5%). CONCLUSIONS: Low- and moderate-certainty evidence showed that aspirin was not associated with dementia, MCI, cognitive decline, or better cognitive scores. Future research may need to focus more on subtypes of dementia, mainly vascular dementia or other vascular neurocognitive diseases, and assess whether aspirin has long-term clinical benefits in a large sample of patients with dementia or MCI.

Efficacy and safety of FDA-approved IDH inhibitors in the treatment of IDH mutated acute myeloid leukemia: a systematic review and meta-analysis.

OBJECTIVE: To systematically evaluate the efficacy and safety of FDA-approved isocitrate dehydrogenase (IDH) inhibitors in the treatment of IDH-mutated acute myeloid leukemia (AML). METHODS: We used R software to conduct a meta-analysis of prospective clinical trials of IDH inhibitors in the treatment of IDH-mutated AML published in PubMed, Embase, Clinical Trials, Cochrane Library and Web of Science from inception to November 15th, 2022. RESULTS: A total of 1109 IDH-mutated AML patients from 10 articles (11 cohorts) were included in our meta-analysis. The CR rate, ORR rate, 2-year survival (OS) rate and 2-year event-free survival (EFS) rate of newly diagnosed IDH-mutated AML (715 patients) were 47%, 65%, 45% and 29%, respectively. The CR rate, ORR rate, 2-year OS rate, median OS and median EFS of relapsed or refractory (R/R) IDH-mutated AML (394 patients) were 21%, 40%, 15%, 8.21 months and 4.73 months, respectively. Gastrointestinal adverse events were the most frequently occurring all-grade adverse events and hematologic adverse events were the most frequently occurring ≥ grade 3 adverse events. CONCLUSION: IDH inhibitor is a promising treatment for R/R AML patients with IDH mutations. For patients with newly diagnosed IDH-mutated AML, IDH inhibitors may not be optimal therapeutic agents due to low CR rates. The safety of IDH inhibitors is controllable, but physicians should always pay attention to and manage the differentiation syndrome adverse events caused by IDH inhibitors. The above conclusions need more large samples and high-quality RCTs in the future to verify.

Efficacy and safety of long-acting cabotegravir versus oral tenofovir disoproxil fumarate-emtricitabine as HIV pre-exposure prophylaxis: A systematic review and meta-analysis.

WHO guidelines recommend daily oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) for pre-exposure prophylaxis (PrEP) of HIV in people at high risk of HIV infection. However, due to social, psychological and other reasons, the compliance with daily oral TDF-FTC in real life is low. Long-acting cabotegravir is currently the only long-acting drug approved by the U.S. Food and Drug Administration (FDA) for HIV PrEP. Due to the long dosing interval (8 weeks), long-acting cabotegravir has low compliance requirements for people at high risk of HIV infection. We aimed to discuss the feasibility of long-acting cabotegravir to replace TDF-FTC as HIV PrEP based on efficacy and safety analyses. Randomized controlled trials were retrieved, and R software was used for meta-analysis after data extraction. and discussion: Results of the meta-analysis showed that compared with TDF-FTC, long-acting cabotegravir was associated with a lower risk of HIV infection (HR = 0.22, 95% CI: 0.08-0.59, p < 0.01), less decreased creatinine clearance (RR = 0.96, 95% CI: 0.93-0.99, p < 0.01), but more tolerated injection sites adverse events (p < 0.01). No statistically significant differences were found between long-acting cabotegravir and oral placebo in non-injection-related adverse events (creatine phosphokinase, headache, nasopharyngitis, upper respiratory tract infection and gastroenteritis) (p > 0.05). Long-acting cabotegravir has a manageable safety profile and is more effective than TDF-FTC in preventing HIV infection. Interestingly, decreased creatinine clearance occurred less frequently with long-acting cabotegravir than with TDF-FTC. Long-acting cabotegravir is very promising to replace TDF-TFC in the future, which requires more large-sample, high-quality RCTs to verify.

The efficacy and safety of trastuzumab deruxtecan (T-DXd) in HER2-expressing solid tumours: a single-arm meta-analysis.

OBJECTIVE: We performed a meta-analysis to assess the efficacy and safety of T-DXd in the treatment of HER2-expressing solid tumours. METHODS: We systematically searched PubMed, Web of Science, Embase and the Cochrane Library and collected studies published before March 17, 2023, on T-DXd for HER2-expressing tumours for a meta-analysis. We performed a subgroup analysis based on the different cancer types and the doses used. RESULTS: There were 11 studies including 1349 HER2-expressing patients in this meta-analysis. The pooled ORR was 47.91%, and the pooled DCR was 87.01%. The mPFS and mOS combined were 9.63 and 10.71 months, respectively. The most common adverse reactions in grades 1-2 were decreased appetite (49.3%) and vomiting (43.0%). The netropemia (31.2%) and leukopenia (31.2%) were the most common grade 3 and higher adverse reactions. Subgroup analysis showed that breast cancer had the best ORR and DCR, with 66.96 and 96.52%, respectively. CONCLUSIONS: Overall, the efficacy of T-DXd in treating HER2-expressing solid tumours is encouraging, especially breast and non-small cell lung cancers, and has an acceptable safety profile. However, concerns remain about potentially serious treatment adverse events (e.g. interstitial lung disease/pneumonia). More well-designed, large-scale randomized controlled trials are needed to demonstrate our study.

Incidence and risk of hypertension associated with PARP inhibitors in cancer patients: a systematic review and meta-analysis.

OBJECTIVE: To analyze the incidence and risk of hypertension associated with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in cancer patients and provide reference for clinicians. METHODS: We used R software to conduct a meta-analysis of phase II/III randomized controlled trials (RCT) on PARP inhibitors for cancer treatment published in PubMed, Embase, Clinical Trials, Cochrane Library and Web of Science from inception to July 29th, 2022. RESULTS: We included 32 RCTs with 10,654 participants for this meta-analysis. For total PARP inhibitors, the incidence and risk ratio of all-grade hypertension were 12% and 1.22 (95% CI: 0.91-1.65, P = 0.19, I2 = 81%), and the incidence and risk ratio of grade 3-4 hypertension were 4% and 1.24 (95% CI: 0.74-2.08, P = 0.42, I2 = 68%). Compared with the control group, the niraparib group, olaparib 800 mg/day group, and olaparib plus cediranib group increased the risk of any grade and grade 3-4 hypertension, while the veliparib group and rucaparib group did not increase the risk of any grade and grade 3-4 hypertension, and olaparib 200 mg-600 mg/day group (exclude olaparib plus cediranib regime) reduced the risk of any grade and grade 3-4 hypertension. CONCLUSION: Olaparib 200-600 mg/day (excluding olaparib plus cediranib regimen) may be the most suitable PARP inhibitor for cancer patients with high risk of hypertension, followed by veliparib and rucaparib. Niraparib, olaparib 800 mg/day and olaparib combined with cediranib may increase the risk of developing hypertension in cancer patients, clinicians should strengthen the monitoring of blood pressure in cancer patients and give medication in severe cases.

Adverse events of immune checkpoint inhibitors for patients with digestive system cancers: A systematic review and meta-analysis.

Objective: To study the incidence and distribution of adverse events in immune checkpoint inhibitors (ICI) for digestive system cancers and to provide a reference for the safe, rational, and effective use of immune detection site inhibitors. Methods: We searched for articles published in English between January 1, 2010, and May 18, 2022. All clinical trials of ICI-based therapies for digestive system cancers were investigated, including only randomized controlled trials that reported data on the overall incidence of treatment-related adverse events (trAEs) or immune-related adverse reactions (irAEs) or tables. Results: We searched 2048 records, of which 21 studies (7108 patients) were eligible for inclusion. The incidence of ICI trAEs of any grade was 82.7% (95% CI 73.9-90.0), and the incidence of grade 3 or higher trAEs was 27.5% (95% CI 21.3-34.1). The pooled rate of ICI irAEs of any grade was 26.3% (95% CI 11.8-44.0), and the incidence of grade 3 or higher irAEs was 9.4% (95% CI 1.1-24.6). In multivariate analysis, the incidence, characteristics, and distribution of AEs varied by cancer type, combination therapy modality (single/two-drug), and different agent types. Conclusion: Our meta-analysis summarizes AEs associated with ICI in digestive system cancers. The incidence, characteristics, and distribution of AEs vary by cancer type, combination therapy modality, and different agent types. These findings can be considered for the early identification of AEs and provide effective interventions to reduce the severity of these patients. It can provide a clinical reference and may contribute to clinical practice.

Nilotinib in Parkinson's disease: A systematic review and meta-analysis.

Background: Nilotinib, which inhibits cellular Abelson tyrosine kinase, may be an effective treatment for patients with Parkinson's disease (PD). The purpose of this study is to evaluate the outcomes of different doses of nilotinib in patients with PD. Methods: We searched PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Clinical Trials from inception to 7 March 2022 to identify all randomized controlled trials (RCTs) of nilotinib reporting outcomes of interest in patients with PD. Outcomes included tolerability, efficacy, safety, and CSF biomarker levels. Review manager 5.4 software was used to analyze all data. Results: Three RCTs with a total of 163 patients were included. No significant difference was found between 150 mg nilotinib or 300 mg nilotinib and placebo in terms of tolerability, adverse events, or HVA levels. 300 mg nilotinib showed significantly higher Movement Disorder Society Unified Parkinson's Disease Rating Scale III (MDS-UPDRS III) scores [SMD = 0.52, 95%CI = (0.12, 0.92), P = 0.01] and 3,4-dihydroxyphenylacetic acid (DOPAC) levels [SMD = 0.52, 95%CI = (0.12, 0.92), P = 0.01], and lower α-synuclein levels [SMD = -2.16, 95%CI = (-3.38, -1.84), P < 0.00001] compared with placebo. And compared with 150 mg nilotinib, 300 mg nilotinib showed significantly lower α-synuclein levels [SMD = -1.16, 95%CI = (-1.70, -0.61), P < 0.0001]. Conclusions: Although our study demonstrated favorable tolerability and safety of different doses of nilotinib, and improvement in part of CSF biomarker levels of 300 mg nilotinib, the poor efficacy on motor outcomes indicated that nilotinib had no advantages in the clinic.