Update in Immunotherapy for Advanced Non-Small Cell Lung Cancer: Optimizing Treatment Sequencing and Identifying the Best Choices.

The introduction of immunotherapy has brought about a paradigm shift in the management of advanced non-small cell lung cancer (NSCLC). It has not only significantly improved the prognosis of patients but has also become a cornerstone of treatment, particularly in those without oncogenic driver mutations. Immune checkpoint inhibitors (ICIs) play a crucial role in the treatment of lung cancer and can be classified into two main groups: Anti-cytotoxic T lymphocyte antigen-4 (Anti-CTLA-4) and anti-T-cell receptor programmed cell death-1 or its ligand (Anti-PD-1 and Anti-PD-L1). Certainly, the landscape of approved first line immunotherapeutic approaches has expanded to encompass monotherapy, immunotherapy-exclusive protocols, and combinations with chemotherapy. The complexity of decision-making in this realm arises due to the absence of direct prospective comparisons. However, a thorough analysis of the long-term efficacy and safety data derived from pivotal clinical trials can offer valuable insights into optimizing treatment for different patient subsets. Moreover, ongoing research is investigating emerging biomarkers and innovative therapeutic strategies that could potentially refine the current treatment approach even further. In this comprehensive review, our aim is to highlight the latest advances in immunotherapy for advanced NSCLC, including the mechanisms of action, efficacy, safety profiles, and clinical significance of ICI.

Comprehensive analysis of tumor mutation burden and immune microenvironment in prostate cancer.

PURPOSE: Prostate adenocarcinoma (PRAD) is a high incidence of malignant tumor of the urinary system and the second most common male cancer in the world. Immune checkpoint inhibitor (ICIS) therapy is becoming a new hope for cancer treatment. METHODS: To realize the possibility of PRAD patients benefiting from ICIS treatment, we analyzed the mutation spectrum of all PRAD patients, calculated the TMB of each PRAD patient, and divided the patients into high TMB group and low TMB group. Differentially expressed genes (DEGs) between the two groups were identified and path analysis was carried out. The immune cell infiltration of each PRAD patient was evaluated and survival analysis was performed to explore the effect of immune cell infiltration on the prognosis. RESULTS: We found that high TMB was associated with better survival outcomes, with higher TMB scores in young patients, T2 and N0 patients. 28 hub genes were screened by the overlap between 229 DEGs and immune-related genes. T cells CD8 and CD4 memory activated in the high TMB group were higher than those in the low TMB group, while Mast cells resting in the low TMB group were higher than that in the high TMB group. High neutrophil infiltration is associated with poor prognosis in patients with PRAD. Finally, from the immune genes used to construct the prognostic risk model of TMB, it is found that CHP2 and NRG1 are independent prognostic factors of PRAD. CONCLUSIONS: This study provides new insights into the immune microenvironment and potential immunotherapy of PRAD.

Cardiovascular toxicity following immune checkpoint inhibitors: A systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors may be associated with multiple immune-related toxicities. Cardiovascular adverse effects are underreported in clinical trials. METHODS: We conducted a systematic review and meta-analysis to evaluate cardiovascular adverse effects incidence among patients with solid tumors receiving immune checkpoint inhibitors in randomized clinical trials and the relative risk of presenting these effects compared to placebo or best supportive care. The search was conducted through MEDLINE, Embase, and Scopus databases from January 1st, 2010 until July 1st, 2020. Outcomes were reported following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. RESULTS: 57 randomized clinical trials including 12,118 patients were included. All grade CV AEs incidence rate was 8.32% (95% CI = 6.35%-10.53%). When only grade 3-5 CV AEs were considered, ICIs were significantly associated with increased risk than placebo or BSC (RR = 1.36; 95% CI = 1.06-1.73; p = 0.01). CONCLUSION: This meta-analysis corroborates the hypothesis of increased CV risk related to immune checkpoint inhibitors.

Investigation on potential biomarkers of hyperprogressive disease (HPD) triggered by immune checkpoint inhibitors (ICIs).

PURPOSE: This project aimed to survey the clinical characteristics and survivals of hyperprogressive disease (HPD) mediated by immune checkpoint inhibitors (ICIs) in an attempt to explore the potential predictors. METHODS: After searching PubMed, MEDLINE, Google Scholar and Cochrane Library databases, 12 studies incorporating 1766 individuals were enrolled. The data were analyzed with Review manager 5.3 software. RESULTS: The results revealed HPD correlated with previous metastatic sites > 2 (OR = 1.86, 95% CI 1.33-2.59, P = 0.0003), liver metastasis (OR = 3.35, 95% CI 2.09-5.35, P < 0.00001), Royal Marsden Hospital (RMH) score ≥ 2 (OR = 2.80, 95% CI 1.85-4.23, P < 0.00001), higher ECOG PS (OR = 1.60, 95% CI 1.13-2.27, P = 0.008) and LDH > upper limits of normal (ULN) (OR = 2.32, 95% CI 1.51-3.58, P = 0.0001). Instead, HPD was unrelated to gender, age, smoking status, PD-L1 expression, therapy, neutrophil-to-lymphocyte ratio, the histology, the status of EGFR, ALK and KRAS in non-small cell lung cancer and HER-2 expression in advanced gastric cancer. Moreover, HPD was evidently correlated with a shorter OS (HR = 2.92, 95% CI 1.79-4.76, P < 0.0001) and PFS (HR = 3.62, 95% CI 2.79-4.68, P < 0.00001). The same phenomena existed in stratified studies based on study regions and tumor types. CONCLUSIONS: This study demonstrated that HPD was related to the number of prior metastatic sites > 2, liver metastasis, RMH score ≥ 2, higher ECOG PS score and LDH > ULN. Moreover, HPD was correlated with a poor OS and PFS in patients following ICI therapy.

The optimal immune checkpoint inhibitors combined with chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) plus chemotherapy (CT) have strikingly expanded the therapeutic landscape for advanced non-small cell lung cancer (NSCLC), but little is known about which is superior. We performed a meta-analysis that compared the efficacy and safety of PD-1 inhibitor + CT with PD-L1 inhibitor + CT. METHODS: PubMed, Embase, Web of Science, Cochrane Library, and major international scientific meetings were searched for relevant randomized controlled trials (RCTs), and the indirect analysis was performed for PD-1 + CT vs PD-L1 + CT. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (TRAEs). RESULTS: 8 phase III RCTs with 4253 patients comparing PD-1/PD-L1 + CT in NSCLC were included. The PD-1 + CT led to notably longer OS most in low/negative expression of PD-L1 for NSCLC patients compared with PD-L1 + CT. In terms of Grade 3-5 TRAEs, the results showed that PD-1 + CT and PD-L1 + CT exclusively increased the risk of adverse incidence than CT alone, especially for PD-L1 + CT (p < 0.00001). For subgroups including female, young patients, patients with nonsmoker, and EGFR/ALK wild-type, PD-1 + CT was associated with prolonged OS (p < 0.05). Meanwhile, for no liver metastasis of NSCLC patients, we found obviously OS advantage for patients treated with PD-1 + CT compared to PD-L1 + CT. CONCLUSIONS: ICIs + CT seemed to be more effective first-line regimen and PD-1 + CT could be recommended as the first-rank therapy for advanced NSCLC patients with low/negative expression of PD-L1. However, we should be particularly vigilant about the occurrence of the Grade 3-5 TRAEs.

Chlorotic spots on Clerodendrum, a disease caused by a nuclear type of Brevipalpus (Acari:Tenuipalpidae) transmitted virus

Chlorotic spots have been observed in plants of Clerodendrum x speciosum growing in residential gardens and parks in Piracicaba, SP, Brazil. Thin sections of diseased tissues revealed characteristic cytopathic effects of the nuclear type of the Brevipalpus (Acari: Tenuipalpidae) mite-transmitted viruses (BTrV). Brevipalpus mites, identified as B. phoenicis, infesting symptomatic C. x speciosum plants transmitted the pathogen to healthy C. x speciosum and to C. thomsonae, Gomphrena globosa, Hibiscus cannabinus, H. coccineus, H. schizopetalus, Salvia leucantha, Spathiphyllum wallasi and Tetragonia expansa causing chlorotic spots on their leaves. Mechanical inoculation using leaf extracts from infected C. x speciosum resulted in chlorotic spots on inoculated C. x speciosum, Chenopodium quinoa, C. amaranticolor, G. globosa, H. cannabinus, H. coccineus and T. expansa leaves. C. amaranticolor and C. quinoa kept at 28 - 30°C became systemically infected. The same cytopathic effects caused by the nuclear type of BTrV were seen in tissues from all infected test plants by electron microscopy. The virus was purified from systemically infected leaves of C. amaranticolor and C. quinoa. A polyclonal antiserum obtained from an immunized rabbit presented a strong reaction with the homologous antigen in ELISA tests. The results suggest that this chlorotic spot disease of C. x speciosum is caused by a new species of the nuclear type of BTrV, tentatively named Clerodendrum chlorotic spot virus (ClCSV).

Manchas cloróticas e necróticas foram observadas em folhas de várias plantas de coração-sangrento (Clerodendrum x speciosum) cultivadas em parques e jardins em Piracicaba, SP, associadas à infestação pelo ácaro tenuipalpídeo Brevipalpus phoenicis. Exames preliminares de secções de tecido das manchas cloróticas ao microscópio eletrônico revelaram a ocorrência de efeitos citopáticos característicos dos induzidos pelos vírus do tipo nuclear, transmitido por ácaros Brevipalpus (VTB). Brevipalpus phoenicis coletados de C. x speciosum sintomático e transferidos para plantas sadias de C. x speciosum reproduziram as lesões. O ácaro também transmitiu o patógeno para C. thomsonae, Gomphrena globosa, Hibiscus cannabinus, H. coccineus, H. schizopetalus, Salvia leucantha, Spathiphyllum wallasi e Tetragonia expansa, as quais exibiram manchas cloróticas e/ou necróticas. O vírus também foi transmitido mecanicamente para Chenopodium amaranticolor, C. quinoa, G. globosa, H. cannabinus, H. coccineus e T. expansa, além de C. x speciosum. Plantas de C. amaranticolor e C. quinoa mantidas a 28 - 30ºC desenvolveram infecção sistêmica. Em todos os tecidos sintomáticos das plantas-teste inoculadas, examinados ao microscópio eletrônico, foram encontrados efeitos citopáticos do tipo nuclear causado por VTB. O vírus foi purificado a partir de folhas com infecção sistêmica de C. amaranticolor e C. quinoa. Injeções de preparações purificadas em coelho geraram um anti-soro policlonal que reagiu especificamente com o antígeno homólogo em teste de ELISA. As evidências obtidas indicam que as manchas cloróticas do Clerodendrum estão associadas a um VTB do tipo nuclear, tentativamente denominado de vírus da mancha clorótica do Clerodendrum (Clerodendrum chlorotic spot virus- ClCSV).

Chlorotic spots on Clerodendrum, a disease caused by a nuclear type of Brevipalpus (Acari:Tenuipalpidae) transmitted virus

Chlorotic spots have been observed in plants of Clerodendrum x speciosum growing in residential gardens and parks in Piracicaba, SP, Brazil. Thin sections of diseased tissues revealed characteristic cytopathic effects of the nuclear type of the Brevipalpus (Acari: Tenuipalpidae) mite-transmitted viruses (BTrV). Brevipalpus mites, identified as B. phoenicis, infesting symptomatic C. x speciosum plants transmitted the pathogen to healthy C. x speciosum and to C. thomsonae, Gomphrena globosa, Hibiscus cannabinus, H. coccineus, H. schizopetalus, Salvia leucantha, Spathiphyllum wallasi and Tetragonia expansa causing chlorotic spots on their leaves. Mechanical inoculation using leaf extracts from infected C. x speciosum resulted in chlorotic spots on inoculated C. x speciosum, Chenopodium quinoa, C. amaranticolor, G. globosa, H. cannabinus, H. coccineus and T. expansa leaves. C. amaranticolor and C. quinoa kept at 28 - 30°C became systemically infected. The same cytopathic effects caused by the nuclear type of BTrV were seen in tissues from all infected test plants by electron microscopy. The virus was purified from systemically infected leaves of C. amaranticolor and C. quinoa. A polyclonal antiserum obtained from an immunized rabbit presented a strong reaction with the homologous antigen in ELISA tests. The results suggest that this chlorotic spot disease of C. x speciosum is caused by a new species of the nuclear type of BTrV, tentatively named Clerodendrum chlorotic spot virus (ClCSV).

Manchas cloróticas e necróticas foram observadas em folhas de várias plantas de coração-sangrento (Clerodendrum x speciosum) cultivadas em parques e jardins em Piracicaba, SP, associadas à infestação pelo ácaro tenuipalpídeo Brevipalpus phoenicis. Exames preliminares de secções de tecido das manchas cloróticas ao microscópio eletrônico revelaram a ocorrência de efeitos citopáticos característicos dos induzidos pelos vírus do tipo nuclear, transmitido por ácaros Brevipalpus (VTB). Brevipalpus phoenicis coletados de C. x speciosum sintomático e transferidos para plantas sadias de C. x speciosum reproduziram as lesões. O ácaro também transmitiu o patógeno para C. thomsonae, Gomphrena globosa, Hibiscus cannabinus, H. coccineus, H. schizopetalus, Salvia leucantha, Spathiphyllum wallasi e Tetragonia expansa, as quais exibiram manchas cloróticas e/ou necróticas. O vírus também foi transmitido mecanicamente para Chenopodium amaranticolor, C. quinoa, G. globosa, H. cannabinus, H. coccineus e T. expansa, além de C. x speciosum. Plantas de C. amaranticolor e C. quinoa mantidas a 28 - 30ºC desenvolveram infecção sistêmica. Em todos os tecidos sintomáticos das plantas-teste inoculadas, examinados ao microscópio eletrônico, foram encontrados efeitos citopáticos do tipo nuclear causado por VTB. O vírus foi purificado a partir de folhas com infecção sistêmica de C. amaranticolor e C. quinoa. Injeções de preparações purificadas em coelho geraram um anti-soro policlonal que reagiu especificamente com o antígeno homólogo em teste de ELISA. As evidências obtidas indicam que as manchas cloróticas do Clerodendrum estão associadas a um VTB do tipo nuclear, tentativamente denominado de vírus da mancha clorótica do Clerodendrum (Clerodendrum chlorotic spot virus- ClCSV).

Ensaio de combate ao ácaro da leprose de citros Brevipalpus phoenicis (Geijskes, 1939) com novo juvenóide e outros acaricidas

A field test was carried out on adult orange trees sprayed with flucycloxuron, propargite and bromopropilate to check their efficiency in controlling leprosis mite. Treatments used were: A) check; B) flucycloxuron, 10g; C) flucycloxuron, 15g; D) flucycloxuron, 20g; E) flucycloxuron, 30g; F) propargite, 72g; G) bromopropilate, 37,5g. Quantities indicated are grams of active ingredients per 100 liters of water. Control evaluations were made 2 days before and 7, 20, 34 and 50 days after spraying. Treatments of propargite and bromopropilate turned out to be the most efficient. Treatments B, C, D, E were not efficient at all.

Foi montado um ensaio visando conhecer a eficiência do flucicloxurom (juvenóide constituído de benzoil-fenil-uréia substituída), do propargite e do bromopropilato, no combate ao acaro da leprose (Brevipalpus phoenicis Geijskes, 1939). Os produtos foram empregados nas seguintes dosagens: A) testemunha; B) flucicloxurom, 10g; C) flucicloxurom, 15g; D) flucicloxurom, 20g; E) flucicloxurom, 30g; F) propargite, 72g; G) bromopropilato, 37,5g (tratamento padrão), sendo os valores supracitados quantidade de ingrediente ativo por 100 litros de calda. Foram aplicados 6 litros de calda por laranjeira, com pulverizador motorizado costal. Foram feitas 5 avaliações do combate: uma prévia (02 dias antes da pulverização) e quatro outras (07, 20, 34 e 50 dias pós-aplicação). A partir dos resultados obtidos, conclui-se que os tratamentos mais eficientes foram o propargite e o bromopropilato.

Ensaio de combate ao ácaro da leprose de citros Brevipalpus phoenicis (Geijskes, 1939) com novo juvenóide e outros acaricidas

A field test was carried out on adult orange trees sprayed with flucycloxuron, propargite and bromopropilate to check their efficiency in controlling leprosis mite. Treatments used were: A) check; B) flucycloxuron, 10g; C) flucycloxuron, 15g; D) flucycloxuron, 20g; E) flucycloxuron, 30g; F) propargite, 72g; G) bromopropilate, 37,5g. Quantities indicated are grams of active ingredients per 100 liters of water. Control evaluations were made 2 days before and 7, 20, 34 and 50 days after spraying. Treatments of propargite and bromopropilate turned out to be the most efficient. Treatments B, C, D, E were not efficient at all.

Foi montado um ensaio visando conhecer a eficiência do flucicloxurom (juvenóide constituído de benzoil-fenil-uréia substituída), do propargite e do bromopropilato, no combate ao acaro da leprose (Brevipalpus phoenicis Geijskes, 1939). Os produtos foram empregados nas seguintes dosagens: A) testemunha; B) flucicloxurom, 10g; C) flucicloxurom, 15g; D) flucicloxurom, 20g; E) flucicloxurom, 30g; F) propargite, 72g; G) bromopropilato, 37,5g (tratamento padrão), sendo os valores supracitados quantidade de ingrediente ativo por 100 litros de calda. Foram aplicados 6 litros de calda por laranjeira, com pulverizador motorizado costal. Foram feitas 5 avaliações do combate: uma prévia (02 dias antes da pulverização) e quatro outras (07, 20, 34 e 50 dias pós-aplicação). A partir dos resultados obtidos, conclui-se que os tratamentos mais eficientes foram o propargite e o bromopropilato.