Hydration with Mannitol and Dextrose May Promote Cisplatin-Induced Nephrotoxicity: Test of Five Protocols of Hydration during Cisplatin Therapy in Rat Models

Backgrounds. Cisplatin (CP) still is a novel choice for solid tumor therapy, but it is accompanied with the side effect of nephrotoxicity. Hydration may reduce the risk of CP-induced nephrotoxicity, while the issue is still challenging. In this study, five types of hydration protocols including saline, mannitol, dextrose saline, saline plus furosemide, and saline plus mannitol were examined in both sexes of rats during CP therapy. Methods. Seventy-six male and female Wistar rats in 14 groups of experiments were subjected to CP therapy, and five types of hydration protocols were implemented, and the induced nephrotoxicity was evaluated via biochemical markers, kidney function parameters, and pathology investigation. Results. Male and female rats had different responses to hydration protocol types. The higher mortality rate was seen in female rats that received mannitol or dextrose hydration types. In addition, the serum levels of blood urea nitrogen (BUN) and creatinine (Cr) and sodium excretion fraction (ENa%) increased and the clearance of Cr (ClCr) decreased significantly ( P < 0.05 ) in female rats hydrated with saline plus furosemide or mannitol plus saline-treated groups. The worsened condition in male rats is observed in the mannitol hydration group with a significant decrease of ClCr and significant increase of serum BUN and Cr and ENa% ( P < 0.05 ). The higher kidney tissue damage score (KTDS) in the mentioned groups verified the findings. Conclusion. Hydration with mannitol or dextrose promotes the risk of nephrotoxicity during CP therapy with more intensity on the female.

Incidence of hepatitis associated with addition of immune checkpoint blockade to conventional solid tumor therapy: A meta-analysis of phase 3 randomized clinical trials.

2645 Background: Immune checkpoint blockade (ICB) has emerged as a promising treatment strategy for many solid tumors. Although safe for many patients, ICB causes immune-related adverse events (irAEs) including hepatitis, which may result in morbidity and treatment disruption. Severe hepatitis requires immunosuppression, including corticosteroids and mycophenolate mofetil. We conducted a meta-analysis of clinical trials to investigate the effect of adding ICB to conventional solid tumor therapy on the incidence of hepatitis. Methods: Phase 3 randomized clinical trials (RCTs) comparing ICB and conventional therapy to conventional therapy alone were chosen by database search on PubMed, Embase, Web of Science, and Cochrane Library. The odds ratios [OR] of any-grade and grade ≥3 hepatitis, elevated aspartate aminotransferase (AST), and elevated alanine aminotransferase (ALT) were calculated. Meta-analysis was conducted to determine the incidence of hepatitis, elevated AST, and elevated ALT among patients receiving ICB and those receiving conventional therapy alone. Subgroup analysis based on the mechanism of ICB (Cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] inhibitor, programmed cell death protein 1 [PD-1] inhibitor, and programmed death-ligand 1 [PD-L1] inhibitor) was also conducted. Results: A total of 29 randomized controlled trials (RCTs) enrolling 18,829 participants were analyzed. Incidence of hepatitis was derived from 24 RCTs enrolling 15,183 patients, and incidence of grade ≥3 hepatitis was derived from 22 RCTs enrolling 13,846 patients. Incidence of elevated AST was extracted from 18 RCTs, and incidence of elevated ALT was extracted from 20 RCTs. Addition of ICB to conventional therapy was associated with an increase in incidence of any-grade hepatitis (OR 2.54, 95% confidence interval [CI] 1.82-3.55) and grade ≥3 hepatitis (OR 4.22, 95% CI 2.51-7.11). The addition of ICB was also associated with an increase in incidence of elevated AST (any grade: OR 2.19, 95% CI 1.59-3.03; grade ≥3: OR 3.18, 95% CI 1.85-5.48) and elevated ALT (any grade: OR 2.08, 95% CI 1.47-2.92; grade ≥3: OR 2.41, 95% CI 1.40-4.14). Subgroup analysis based on the mechanism of ICB demonstrated increased incidence of grade ≥3 hepatitis associated with CTLA-4 inhibitor, PD-1 inhibitor, and PD-L1 inhibitor therapy (OR 2.78, 95% CI 1.26-6.14; OR 6.30, 95% CI 2.23-17.78; OR 4.73, 95% CI 1.83-12.23, respectively). No significant difference of heterogeneity was observed among subgroups ( I2= 0%, p = 0.43). Conclusions: Addition of ICB to conventional solid tumor therapy was associated with increased incidence of any-grade and severe hepatitis, and elevations of AST and ALT, regardless of the mechanism of ICB. Clinicians should weigh the risk of liver toxicity when considering addition of ICB therapy in patients with solid tumors.

Targeting Solid Tumors With BTK Inhibitors

The repurposing of FDA-approved Bruton’s tyrosine kinase (BTK) inhibitors as therapeutic agents for solid tumors may offer renewed hope for chemotherapy-resistant cancer patients. Here we review the emerging evidence regarding the clinical potential of BTK inhibitors in solid tumor therapy. The use of BTK inhibitors may through lead optimization and translational research lead to the development of new and effective combination regimens for metastatic and/or therapy-refractory solid tumor patients.

An NIR-Fluorophore-Based Theranostic for Selective Initiation of Tumor Pyroptosis-Induced Immunotherapy

Pyroptosis is an inflammatory form of programmed cell death that can effectively eliminate malignant cells and boost anticancer immunity. However, most of the current pyroptosis inducers lack cell selectivity, which may cause severe side effects for cancer therapy. In this work, for the first time, we discovered that the commonly used near-infrared (NIR) fluorogenic hemicyanine (CyNH2) induces pyrolysis to kill cancer cells and boost antitumor immunity. Cancer cells overexpressing the NAD(P)H: quinone oxidoreductase isozyme 1 (NQO1)-responsive theranostic (NCyNH2) were designed for selective cell pyroptosis and were nonfluorescent with low toxicity before activation. In the presence of NQO1, the fluorescence of CyNH2 was restored and could selectively initiate pyroptosis of cancer cells and further lead to systemic antitumor immunity activation for solid tumor therapy. Thus, this fluorogenic NIR dye may represent a novel theranostic agent for the selective initiation of tumor pyroptosis.

A Tunable Temperature-Responsive and Tough Platform for Controlled Drug Delivery

Localized intelligent drug delivery systems (IDDSs) are promising platforms for solid tumor therapy with lower toxicity to physiological systems and improved curative effect due to efficiently controlled site-specific delivery of...

Palladium Cube with Pt Shell Deposition for Localized Surface Plasmon Resonance Enhanced Photodynamic and Photothermal Therapy of Hypoxic Tumor

Multifunctional phototherapy nanoagents for imaging-guided synergistic photothermal therapy (PTT) and photodynamic therapy (PDT) are highly desirable in the field of solid tumor therapy. Nevertheless, the tumor microenvironment (TME) inherently charactered...

Allogeneic Hematopoietic Stem Cell Transplantation Overcomes the Poor Prognosis in MLL-Rearranged Solid Tumor Therapy Related-Acute Myeloid Leukemia

BACKGROUND: MLL rearrangement is very common in solid tumor therapy-related acute myeloid leukemia (t-AML). This study investigated the prognosis of MLL t-AML. METHODS: Patients with solid tumor t-AML and MLL de novo AML were enrolled in this retrospective study. The patients were divided into 3 groups: non-MLL t-AML(n=41), MLL t-AML(n=18) and MLL de novo AML(n=98). RESULTS: Of the 157 patients enrolled, 150 patients underwent anti-leukemia therapy. The complete remission (CR) rate was 83.3%, 85.5% and 86.2%(P=0.251), respectively, in MLL t-AML, non-MLL t-AML and MLL AML groups. The 3-years overall survival (OS) was 37.5%, 21.5% and 20.4% (P=0.046). The 3-years leukemia-free survival (LFS) was 28.0%, 32.2% and 22.7% (P=0.031), and the incidence of relapse was 30.0%, 50.4% and 53.5% (P=0.382), respectively, in the three groups. Multivariate analysis revealed that MLL t-AML was a risk factor while allo-HSCT a protective factor for relapse, LFS, and OS (P=0.005, P&lt;0.001 and P&lt;0.001) (P&lt;0.001, P&lt;0.001 and P=0.002, respectively). The 3-years OS was 0%, 17.9% and 0%(P=0.038), LFS was 0%, 23.1% and 0%(P=0.017), and relapse was 100%, 53.1% and 74.4% (P=0.001), respectively among three groups in patients undergoing chemotherapy alone, while OS was 64.3%, 52.7% and 40.7% (P=0.713), LFS was 60.0%, 48.8% and 37.0% (P=0.934), and relapse was 25.0%, 47.4% and 47.5% (P=0.872), respectively, among these group in the patients undergoing allo-HSCT. Intriguingly, MLL t-AML was no longer risk factor for relapse and LFS (P=0.882 and P=0.484, respectively), while it became a favorable factor for OS (P=0.011) in the patients undergoing allo-HSCT CONCLUSIONS: MLL t-AML had poor prognosis compared with non-MLL t-AML and MLL de novo AML,, but allo-HSCT might overcome the poor prognosis of MLL t-AML. Disclosures Liu: Nanfang Hospital, Southern Medical University: Research Funding.