Inhibitor Therapy Research Articles

Low-risk febrile neutropenia: does combined chemotherapy/immune checkpoint inhibitor necessitate a change in approach?

Management of patients with low-risk febrile neutropenia in an outpatient setting guided by the MASCC score is proven to be safe and effective. Most patients on ambulatory low-risk febrile neutropenia pathways are undergoing treatment for breast cancer. Recent data has shown benefit of the addition of immune checkpoint inhibitor therapy to cytotoxic chemotherapy in the neoadjuvant setting for patients with early triple-negative breast cancer. We examined whether the addition of ICI therapy altered the clinical severity of febrile neutropenia in this cohort and the ability to manage these patients in an ambulatory setting. An observational analysis was performed at a specialist oncology hospital in the North West of England. We compared patients with triple negative breast cancer presenting with febrile neutropenia following treatment with PC-EC/pembrolizumab to those treated with PC-EC in the neoadjuvant setting. In the study periods, 152 patients received PC-EC and 151 PC-EC/Pembro. Twenty-five patients presented with FN in the PC-EC/Pembro group compared to 16 in those receiving PC-EC (16% vs 11%, p > 0.05). Patients with febrile neutropenia treated with PC-EC/Pembro had more severe clinical presentations as assessed by the MASCC score (18 vs 24; p = 0.01), had worse physiological parameters (NEWS2 at presentation 3 vs 2; p = 0.023) and had a longer length of hospital stay (median 5days vs 0days; p = 0.044). There were no deaths at 30 or 90days in either cohort. Triple-negative breast cancer patients receiving neoadjuvant pembrolizumab in addition to PC-EC appear to have more severe presentations with febrile neutropenia. This may necessitate greater caution in pathways for ambulatory management for this cohort.

Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial

BackgroundOlutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy.MethodsAdult patients with mIDH1R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety.ResultsSixty-seven patients with R/R mIDH1R132 AML received combination OLU + AZA. Median age was 66 years (range 28–82) and 54% were male. Most patients (83%) had 2 + prior regimens, including a hypomethylating agent in 40%, IDH1 inhibitor therapy in 31% (olutasidenib in 24%), and hematopoietic stem cell transplant in 10%. Cytogenetic risk was intermediate in 72%, poor in 18% and unknown in 10%. CR/CRh was achieved in 21/67 (31%; 95% CI 21–44) patients, with a median duration of 14.7 months (95% CI 4.6-not reached). CR was achieved in 18/67 (27%; 95% CI 17–39) patients, with median duration of 20.3 months (95% CI 3.7-not reached). Overall response (partial remission or better) was achieved in 34/67 (51%; 95% CI 38–63) patients. Median overall survival was 12.9 months (95% CI 18.7–19.3). In a subset analysis excluding patients who had prior OLU exposure (N = 51), CR/CRh was achieved in 19/51 (37%; 95% CI 24–52) patients, CR was achieved in 16/51 (31%; 95% CI 19–46), and overall response was achieved in 30/51 (59%; 95% CI 44–72). In patients who achieved CR/CRh and were transfusion-dependent at baseline, transfusion independence (RBC and platelets) was achieved in 64% (7/11) and 57% (4/7) of patients, respectively. The most common Grade 3 or 4 adverse events (> 20% patients) were decreased platelet count (37%), red blood cell count (25%), and neutrophil count (24%). Six patients (9%) experienced differentiation syndrome. Four (6%) discontinued treatment due to an adverse event.ConclusionsOlutasidenib plus azacitidine induced high response rates and durable remissions with a tolerable side effect profile in patients with R/R AML with diverse treatment histories. The results represent another therapeutic option for patients with mIDH1 AML who may benefit from a targeted therapy.Trial registrationNCT02719574.

Prenatally Diagnosed Cardiac Tumors and Tuberous Sclerosis Complex: A Single-Center Experience

Background/Objectives: Cardiac rhabdomyoma (CR), the most frequently occurring fetal cardiac tumor, is often an early marker of tuberous sclerosis complex (TSC). This study evaluates outcomes of fetuses with prenatally diagnosed cardiac tumors managed at a single tertiary center. Methods: Medical records of fetuses diagnosed with cardiac tumors between 2009 and 2024 were retrospectively reviewed. Results: Sixteen cases were identified, with a median follow-up of 6.7 years. TSC was confirmed in 14 cases (88%). Multiple tumors were observed in 13 cases (81%), while 3 cases (19%) had solitary tumors (19%). Both non-TSC cases involved solitary tumors. Cardiac complications (arrhythmias, conduction disorders, and hemodynamic abnormalities) occurred in 38% of cases prenatally and 69% postnatally, with larger tumor diameters significantly associated with complications (p = 0.02). No fetal hydrops or mortality occurred; however, one child died at age five due to a seizure. Postnatal tumor regression occurred in 56% of cases and complete regression in 38% by a median age of 2.3 years (range: 0.6–4.4). One tumor remained stable. Brain MRI revealed TSC-related changes in all TSC-affected patients except one, who had a developmental brain anomaly. Most TSC patients experienced epilepsy (71%) and developmental delays. Conclusion: While CRs are typically benign and regress spontaneously, their strong association with TSC highlights the importance of early diagnosis and family counseling. TSC-related epilepsy and psychomotor delays significantly impair the quality of life. Early mTOR inhibitor therapy offers promise in mitigating TSC-related complications and improving outcomes.

PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer

BackgroundProgrammed cell death ligand 1 (PD-L1) expression on immune cells is correlated with the efficacy of immune checkpoint inhibitor (ICI) therapy in various types of cancer. Platelets are important components of the tumour microenvironment (TME) and are widely involved in the development of many types of cancer including colorectal cancer (CRC). However, the role of PD-L1 positive platelets in ICI therapy for CRC remains unknown. We hypothesized that PD-L1 positive platelets trigger and sustain CRC immunosuppression.MethodsThe functional depletion effects of PD-L1 positive platelets on TME and immune cells were measured via western blotting, immunofluorescence staining, qRT-PCR, ELISpot and flow cytometry. In vivo, CD274 knockout (KO), CD8a KO, platelet-specific KO (PF4-Cre-Hsp90b1flox/flox) mouse models and a subcutaneous tumour model treated with aspirin and PD-L1 mAb were established in C57BL/6 N mice.ResultsWe found that PD-L1 positive platelets are correlated with a poor prognosis, CD8 + T cell exhaustion and serve as a novel noninvasive biomarker for predicting immunotherapy efficacy in patients with CRC. The transfer of PD-L1 from tumour cells to platelets in the TME depends on direct cell contact via the fibronectin-1/GPIbα/integrin α5β1 pathway. In turn, platelets can also induce PD-L1 expression on cancer cells. Animal experiments revealed that antiplatelet pharmacological agents and genetic knockout of platelets potentiated the antitumour effect of the PD-L1 mAb treatment in a CD8 + T cell dependent manner.ConclusionsOur data suggest that PD-L1 positive platelets suppress CD8 + T cell immunity. Clinical combination treatment with ICIs and antiplatelet agents may be an effective therapeutic strategy for treating CRC.

Mixed radiation with different doses induces CCL17 to recruit CD8+T cell to exert anti-tumor effects in non-small cell lung cancer

BackgroundDifferent doses of radiotherapy (RT) exert diverse effects on tumor immunity, although the precise irradiation method remains unknown. This study sought to elucidate the influence of combining different doses of RT with immune checkpoint inhibitors (ICIs) on the infiltration of CD8+T cells within tumors, thereby augmenting the anti-tumor response.MethodsConstructing a mouse model featuring bilateral lung cancer tumors subjected to high and low dose irradiation, the analysis of RNA transcriptome sequencing data and immunohistochemical validation for tumors exposed to various dosages guided the selection of the optimal low-dose irradiation scheme. Subsequently, upon the integration of immune checkpoint inhibitors (ICIs) therapy, the infiltration of immune cells within the tumor was ascertained via immunohistochemistry (IHC) and flow cytometry (FCM). Finally, through bioinformatics analysis and experimental verification, potential strategies to bolster the anti-tumor immune response were investigated.ResultsIn comparison to the administration of 20Gy alone to the primary tumor, supplementing with 6Gy directed at the abscopal tumor produces a more pronounced abscopal response. The synergy of 20Gy, 6Gy, and ICIs markedly boosts the efficiency of ICIs. According to the findings from IHC and FCM studies, the triple therapy group exhibits a heightened infiltration of immune cells into the tumor, largely attributable to the augmented expression of CCL17 within the tumor under these irradiation regimens, which subsequently draws CD8+ T cells to infiltrate the tumor site, exerting cytotoxic effects.ConclusionOur study shows that the combined application of 20Gy and 6Gy can enhance the infiltration of tumor CD8+T cells in mice and improve the effectiveness of immunotherapy.

Deficient Mismatch Repair and BRAF Mutations in Metastatic Colorectal Cancer in the South Island of New Zealand.

Manatū Hauora, the Ministry of Health of New Zealand (NZ), published minimum standards for molecular testing of colorectal cancers (CRCs) in June 2018. These included mismatch repair (MMR) testing at diagnosis and BRAFV600E mutation analysis on newly diagnosed stage IV CRCs. This study aimed to determine the proportion of patients with CRC in the South Island of NZ with metastatic deficient mismatch repair (dMMR) CRC, the proportion of metastatic CRCs and dMMR CRCs that have a BRAFV600E mutation, and audit testing for BRAF mutations and appropriate referral to genetics services. People from the South Island with histologically diagnosed colorectal adenocarcinoma between July 1, 2018, and June 30, 2019, were identified by the National Cancer Registry. Data points extracted from the electronic medical record included staging, MMR status, BRAF mutation testing, and genetics referral. A total of 845 patients met the inclusion criteria; 166 of 845 (19.6%) had dMMR CRC, and of these 130 (78%) had BRAF mutation, 256 patients developed metastatic disease by data cut-off, 20 (7.8%) had dMMR, and 41 (22.2%) had BRAF mutation. When indicated, 275 of 330 (83.3%) were tested for BRAF mutation and 32 of 45 (71.1%) referred to genetics. Compared with other populations, South Island CRC patients had higher rates of dMMR and BRAF mutation. Less than 10% of patients (n = 20) had metastatic dMMR CRC. These patients could be considered candidates for immune checkpoint inhibitor therapy, a small number that would not significantly burden the NZ health system if funded. The vast majority of dMMR CRC was sporadic. Rates of testing could be improved.

Androgen Receptor Pathway Inhibitor Therapy for Advanced Prostate Cancer

The open-label randomized phase 2 LACOG0415 trial evaluated 3 treatment strategies for patients with advanced castration-sensitive prostate cancer (CSPC): androgen deprivation therapy (ADT) plus abiraterone acetate and prednisone (AAP), apalutamide (APA) alone, or APA plus AAP. To investigate the association of ADT plus AAP, APA alone, or APA plus AAP with health-related quality of life (HRQOL) in patients with advanced CSPC in the LACOG0415 trial. The LACOG0415 randomized clinical trial comprised 128 patients with advanced CSPC who were randomized (1:1:1) to 1 of 3 treatment arms from October 16, 2017, to April 23, 2019. Statistical analysis was conducted from March to September 2022. Patients were randomized (1:1:1) to 1 of 3 treatment arms: ADT plus AAP, APA alone, or APA plus AAP. Health-related quality of life was evaluated using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, including its subscales, completed at baseline and every 4 weeks until week 25. FACT-P scores range from 0 to 156, and higher scores indicate better HRQOL. Mean changes in score from baseline to week 25 were adjusted by baseline score and were calculated to evaluate whether there was a difference according to the treatment arm using a mixed-effect model for repeated measures. Time to deterioration was estimated by Kaplan-Meier curves and compared by stratified log-rank test. Analysis was performed on an intention-to-treat basis. A total of 128 patients with advanced CSPC were randomized to receive ADT plus AAP (n = 42; median age, 69.8 years [IQR, 58.9-71.6 years]), APA alone (n = 42; median age, 69.5 years [IQR, 59.8-72.6 years]), or APA plus AAP (n = 44; median age, 71.0 years [IQR, 63.0-72.3 years]). Metastatic disease was present in 95 patients (74.2%), high-risk biochemical recurrence disease in 22 (17.2%), and locally advanced disease in 11 (8.6%). There was no significant difference in baseline mean (SD) FACT-P total scores and subscales among the 3 treatment arms (FACT-P total score: ADT plus AAP arm, 118.5 [24.3]; APA alone arm, 116.1 [23.9]; AAP plus APA arm, 114.9 [18.1]; P = .69). Health-related quality of life was maintained during treatment period, and there were no statistically significant differences at 25 weeks in mean (SD) FACT-P total scores or subscales between treatment arms (FACT-P total score: ADT plus AAP arm, 122.3 [20.4]; APA alone arm, 119.5 [16.4]; AAP plus APA arm, 119.9 [20.3]). The APA alone and AAP plus APA arms were not associated with meaningful improvements in HRQOL compared with the ADT plus AAP arm, except in time to deterioration of the emotional well-being score, which was more favorable in the APA alone arm (reference arm: ADT plus AAP arm; APA alone arm: hazard ratio, 0.37 [0.15-0.85]; P = .02; ADT plus AAP arm: hazard ratio, 0.56 [0.26-1.19]; P = .13). Limitations include short follow-up period and the absence of other questionnaires to capture differences between therapies. In this prespecified secondary analysis of a randomized clinical trial of ADT plus AAP, APA alone, or APA plus AAP for patients with advanced CSPC, HRQOL was not statistically different between treatments with APA alone or APA plus AAP as compared with ADT plus AAP. Larger studies with longer follow-up and more specific questionnaires are needed to further evaluate HRQOL with these treatment strategies. ClinicalTrials.gov Identifier: NCT02867020.

Emerging Trends in Neuroblastoma Diagnosis, Therapeutics, and Research.

This review explores the current understanding and recent advancements in neuroblastoma, one of the most common extracranial solid pediatric cancers, accounting for ~ 15% of childhood cancer-related mortality. The hallmarks of NBL, including angiogenesis, metastasis, apoptosis resistance, cell cycle dysregulation, drug resistance, and responses to hypoxia and ROS, underscore its complex biology. The tumor microenvironment's significance in disease progression is acknowledged in this study, along with the pivotal role of cancer stem cells in sustaining tumor growth and heterogeneity. A number of molecular signatures are being studied in order to better understand the disease, with many of them serving as targets for the development of new therapeutics. This includes inhibitor therapies for NBL patients, which notably concentrate on ALK signaling, MDM2, PI3K/Akt/mTOR, Wnt, and RAS-MAPK pathways, along with regulators of epigenetic mechanisms. Additionally, this study offers an extensive understanding of the molecular therapies used, such as monoclonal antibodies and CAR-T therapy, focused on both preclinical and clinical studies. Radiation therapy's evolving role and the promise of stem cell transplantation-mediated interventions underscore the dynamic landscape of NBL treatment. This study has also emphasized the recent progress in the field of diagnosis, encompassing the adoption of artificial intelligence and liquid biopsy as a non-intrusive approach for early detection and ongoing monitoring of NBL. Furthermore, the integration of innovative treatment approaches such as CRISPR-Cas9, and cancer stem cell therapy has also been emphasized in this review.

The Potential Role of sPD-L1 as a Predictive Biomarker in EGFR-Positive Non-Small-Cell Lung Cancer

Background/Objectives: A significant breakthrough in non-small-cell lung cancer (NSCLC) treatment has occurred with the introduction of targeted therapies and immunotherapy. However, not all patients treated with these therapies would respond to treatment, and patients who respond to treatment would acquire resistance at some time point. This is why we need new biomarkers that can predict response to therapy. The aim of this study was to investigate whether soluble programmed cell death-ligand 1 (sPD-L1) could be a predictive biomarker in patients with epidermal growth factor receptor (EGFR)-positive NSCLC. Materials and Methods: Blood samples from 35 patients with EGFR-mutated (EGFRmut) adenocarcinoma who achieved disease control with EGFR tyrosine kinase inhibitor (EGFR TKI) therapy were collected for sPD-L1 analysis. We analyzed sPD-L1 concentrations in 30 healthy middle-aged subjects, as a control population, to determine the reference range. Adenocarcinoma patients were divided into two groups, i.e., a group with low sPD-L1 (≤182.5 ng/L) and a group with high sPD-L1 (>182.5 ng/L). Results: We found that progression-free survival (PFS) was 18 months, 95% CI (11.1–24.9), for patients with low sPD-L1 and 25 months, 95% CI (8.3–41.7), for patients with high sPD-L1. There was no statistically significant difference in PFS between the groups (p = 0.100). Overall survival (OS) was 34.4 months, 95% CI (26.6–42.2), for patients with low sPD-L1 and 84.1 months, 95% CI (50.6–117.6), for patients with high sPD-L1; there was also no statistically significant difference between the groups (p = 0.114). Conclusion: In our study, we found that patients with high sPD-L1 had numerically better PFS and OS, but this has no statistical significance. Further studies with a larger number of patients are needed to evaluate the role of sPD-L1 as a predictive biomarker in patients with EGFRmut NSCLC.

Unusually indolent CML: a stable non-responder without complete cytogenetic remission for 30 years including 17 years on tyrosine kinase inhibitor therapy

Unusually indolent CML: a stable non-responder without complete cytogenetic remission for 30 years including 17 years on tyrosine kinase inhibitor therapy

A Case of Euglycemic Diabetic Ketoacidosis in a Patient with Diabetic Foot Syndrome.

Euglycemic Diabetic ketoacidosis (E-DKA) is a life-threatening emergency characterized by ketonemia and metabolic acidosis in presence of relatively normal glycemic values. In recent years it has been associated with some predisposing conditions including sodium-glucose transporter 2 inhibitors (SGLT2-i) therapy, widely used in high-risk cardiovascular patients. We report the case of a 78-year-old diabetic woman treated with dapagliflozin, affected by critical limb threatening ischemia and septic osteoarthritis of interphalangeal joint of first right toe. At admission blood exams allowed diagnosis of E-DKA associated to acute kidney failure. The occurrence of the condition was probably due to foot infection acting on a trigger on a SGLT2-i predisposition. We treated the patient according to guidelines' indications achieving the resolution of the metabolic derangement. After the control of acute condition and return of metabolic parameters within the normal range, the patient underwent revascularization procedure and surgical debridement eventually obtaining complete healing of foot lesion.

A Conjugated Oligomer with Drug Efflux Pump Inhibition and Photodynamic Therapy for Synergistically Combating Resistant Bacteria.

High expression of drug efflux pump makes antibiotics ineffective against bacteria, leading to drug-resistant strains and even the emergence of "superbugs". Herein, we design and synthesize a dual functional o-nitrobenzene (NB)-modified conjugated oligo-polyfluorene vinylene (OPFV) photosensitizer, OPFV-NB, which can depress efflux pump activity and also possesses photodynamic therapy (PDT) for synergistically overcoming drug-resistant bacteria. Upon light irradiation, the OPFV-NB can produce aldehyde active groups to covalently bind outer membrane proteins, such as tolerant colicin (TolC), blocking drug efflux of bacteria. The minimum inhibitory concentration of antibiotic model chloramphenicol (CHL) is reduced about 64 times, significantly resensitizing drug-resistant bacteria to antibiotics. Also, the probe can produce highly efficient reactive oxygen species (ROS) under light irradiation. Consequently, the unimolecular OPFV-NB-based system demonstrates insusceptibility to antibiotic resistance while maintaining significant antimicrobial effects (100%) against drug-resistant bacteria. More importantly, in vivo assays corroborate that the combined system greatly accelerates wound healing by eradicating the bacterial population, dampening inflammation, and promoting angiogenesis. Overall, the OPFV-NB not only counteracts antibiotic resistance but also holds tremendous PDT efficiency, which provides a promising therapeutic strategy for combating drug-resistant bacteria and treating bacteria-infected wounds.

Effect of daily alcohol intake on sex hormone levels among postmenopausal breast cancer survivors on aromatase inhibitor therapy: a randomized controlled crossover pilot study

BackgroundAlcohol intake is associated with a higher risk of estrogen receptor-positive (ER+) breast cancer (BC), presumably through its confirmed ability to increase sex hormone levels. Whether consuming alcohol within the recommended limit of one serving per day increases sex hormone levels among postmenopausal women taking aromatase inhibitors (AI) to inhibit estrogen production remains unknown. Therefore, we compared sex hormone levels following white wine to levels following white grape juice among ER + BC survivors taking AIs.MethodsIn this 10-week randomized controlled two-period crossover trial conducted from September 2022 to July 2023 among 20 postmenopausal women on AIs, we examined within-person changes in sex hormone levels following 3 weeks of 5 ounces of white wine daily versus 3 weeks of 6 ounces of white grape juice daily, with each drinking period preceded by two-week washouts and drinking period sequence allocated by randomization.ResultsAll 20 participants completed the trial. Compared to daily grape juice, daily wine led to decreases in total estradiol (11.1%, 95%confidence interval[CI] -49.8%,57.2%), free estradiol index (0.7%, 95%CI -2%,0.7%), and free estradiol concentration (7.7%, 95%CI -48%, 63.9%) but increases in estrone (13.8%, 95%CI -9.5%,43.1%), dehydroepiandrosterone sulfate (DHEAS; 11.4%, 95%CI -3.3%,28.4%), and testosterone (12.6%, 95%CI -0.8%,27.7%) and decreased sex hormone-binding globulin (SHBG; -2.7%, 95%CI -21.9%,21.2%).ConclusionsFive ounces of white wine daily did not lead to statistically significant increases in estradiol, but it led to changes in other sex hormones suggesting higher BC risk. Whether this level of alcohol intake diminishes AI effectiveness warrants further investigation.Trials RegistrationClinicaltrials.gov NCT05423730 registered June 14, 2022.

Immunotherapy on ICU: a narrative review.

Patients with cancer account for 15% of all admissions to critical care and so an understanding of the pathophysiology and anticipated complications of specialist treatment is essential for the intensive care clinician. The development of chimeric antigen receptor T-cell therapy for haematological malignancies and immune checkpoint inhibitors for solid organ tumours has led to significant improvements in the prognosis of those patients whose tumours respond. This review is intended to provide the non-specialist with an understanding of the current concepts in pathophysiology, diagnosis and management of complications due to chimeric antigen receptor T-cell therapy and immune checkpoint inhibitors for malignant disease. We performed searches of electronic databases to identify relevant peer-reviewed publications in the literature. Basic science; clinical trials; cohort studies; systematic reviews; meta-analyses; and guidelines were eligible for inclusion. Abstracts were screened to identify publications relevant to immune effector cell toxicities of chimeric antigen receptor T-cell therapy and immune-related adverse events of immune checkpoint inhibitors. While the pathophysiology for toxicities due to chimeric antigen receptor T-cells and immune checkpoint inhibitors remains incompletely understood, targeted drug therapies have been successfully implemented for toxicities such as cytokine release syndrome. Corticosteroids remain an important component of pharmacological management. The diagnosis of toxicities remains largely clinical, and a high index of suspicion should remain for infective complications. Management of toxicities should be undertaken in conjunction with the patient's primary oncologist. Despite significant advances in the development of targeted immunotherapy, the mechanism of action for the resultant toxicities remains poorly understood and limits the development of predictive models, diagnostic biomarkers and highly effective treatment options. Further research is needed to identify treatment regimens which minimise the use of corticosteroids in chimeric antigen receptor T-cell and immune checkpoint inhibitor-associated toxicities.

Cardiotoxicity and peri-operative considerations in immune checkpoint inhibitor and chimeric antigen receptor T-cell therapy: a narrative review.

Immunotherapy has transformed cancer treatment, particularly with immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy. Despite their efficacy, these therapies can induce cardiotoxicity, presenting significant clinical challenges. Immune checkpoint inhibitors can cause myocarditis; pericarditis; arrhythmias; and myocardial infarction through immune-mediated inflammation. Chimeric antigen receptor T-cell therapy may result in cardiovascular complications due to cytokine release syndrome, including myocardial dysfunction, endothelial damage and arrhythmias. We used PubMed, Embase and Google Scholar to search for peer-reviewed articles in September 2024 without setting any date limits. Our selection criteria encompassed studies focusing on cardiotoxicity related to immune checkpoint inhibitors or chimeric antigen receptor T-cell therapy, comprising original research, meta-analyses, clinical trials and review articles. The findings were reported narratively. Early diagnosis of cardiotoxicity is critical but challenging due to non-specific symptoms. Diagnostic tools include ECG; cardiac biomarkers; echocardiography; cardiac magnetic resonance imaging; and endomyocardial biopsy. However, no single tool is definitive. High-dose corticosteroids are the first-line treatment for immune checkpoint inhibitor-induced myocarditis, with additional immunosuppressive therapies for refractory cases. Standard heart failure management protocols should be followed in cases of heart failure. Tocilizumab and corticosteroids are utilised for chimeric antigen receptor T-cell therapy-induced cytokine release syndrome, alongside supportive care, including fluid resuscitation and vasopressors for severe cases. As the use of immunotherapy expands, understanding the mechanisms, risk factors and management strategies for cardiotoxicity is increasingly important. Collaborative efforts among oncologists, cardiologists and anaesthetists are essential to mitigate these risks, especially in peri-operative settings. Ongoing research is vital to improve the safe and effective use of immunotherapeutic drugs while minimising cardiovascular adverse effects.

Understanding the role of the gut microbiome in solid tumor responses to immune checkpoint inhibitors for personalized therapeutic strategies: a review

Immunotherapy, especially immune checkpoint inhibitor (ICI) therapy, has yielded remarkable outcomes for some patients with solid cancers, but others do not respond to these treatments. Recent research has identified the gut microbiota as a key modulator of immune responses, suggesting that its composition is closely linked to responses to ICI therapy in cancer treatment. As a result, the gut microbiome is gaining attention as a potential biomarker for predicting individual responses to ICI therapy and as a target for enhancing treatment efficacy. In this review, we discuss key findings from human observational studies assessing the effect of antibiotic use prior to ICI therapy on outcomes and identifying specific gut bacteria associated with favorable and unfavorable responses. Moreover, we review studies investigating the possibility of patient outcome prediction using machine learning models based on gut microbiome data before starting ICI therapy and clinical trials exploring whether gut microbiota modulation, for example via fecal microbiota transplantation or live biotherapeutic products, can improve results of ICI therapy in patients with cancer. We also briefly discuss the mechanisms through which the gut microbial-derived products influence immunotherapy effectiveness. Further research is necessary to fully understand the complex interactions between the host, gut microbiota, and immunotherapy and to develop personalized strategies that optimize responses to ICI therapy.

High‑intensity focused ultrasound thermal ablation boosts the efficacy of immune checkpoint inhibitors in advanced cancers with liver metastases: A single‑center retrospective cohort study.

High-intensity focused ultrasound thermal ablation (HIFU) is a novel non-invasive technique in the treatment of liver metastases (LIM) that allows focal destruction and is not affected by dose limits. This retrospective study aimed to explore the efficacy of HIFU in improving survival and the safety of the method in newly diagnosed patients with cancer with LIM who received first-line immune checkpoint inhibitor (ICI) therapy. Between January 2018 and December 2023, data from 438 newly diagnosed patients with cancer and LIM who were treated at Mianyang Central Hospital (Mianyang, China) were reviewed. A total of 94 patients were enrolled in this study, of whom 28 were diagnosed with lung carcinoma, 36 with gastric carcinoma, 11 with esophageal carcinoma, 7 with cholangiocarcinoma and 12 with other malignancies. The patients were divided into groups depending on whether they underwent HIFU. Progression-free survival (PFS), overall survival (OS) and adverse events (AEs) were compared. Clinicopathological features were analyzed using the chi-squared test. Of the 94 patients, 28 received ICI + HIFU as first-line treatment. After a median follow-up of 13.8 months, the median PFS and OS in the HIFU group were 2.38 times [10.95 vs. 4.60 months, 95% confidence interval (CI): 1.087-3.106, P<0.0001] and 1.84 times (19.6 vs. 10.67 months, 95% CI: 1.087-3.106, P=0.0418), respectively, higher than in the group without HIFU. All-cause AEs and immune-mediated AEs were similar between the groups with and without HIFU. However, the incidence of grade 1-2 immune-mediated AEs, troponin elevation, hepatotoxicity and renal dysfunction were more common in the current patients with LIM than those reported previously for the entire population. No immune-mediated AEs of grade ≥3 occurred in either group. HIFU prolonged the PFS and OS of first-line ICI in newly diagnosed patients with advanced cancer with LIM, with manageable safety and tolerability. The efficacy of HIFU in patients with LIM who plan to undergo ICI treatment warrants further prospective clinical investigation.

Analytical performance of OncoPrism-HNSCC, an RNA-based assay to inform immune checkpoint inhibitor treatment decisions for recurrent/metastatic head and neck squamous cell carcinoma

BackgroundWhile immune checkpoint inhibitor (ICI) therapies can significantly improve outcomes for patients with recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC), only about 15–20% benefit from such treatments. Clinical tests that guide the use of ICIs are therefore critically needed. OncoPrism-HNSCC was developed to address this need. The assay combines next generation RNA sequencing-based immunomodulatory gene expression signatures with machine learning algorithms to generate an OncoPrism score that classifies patients as having low, medium, or high likelihood of disease control in response to ICI treatment. Also, OncoPrism-HNSCC leverages the same FFPE patient tumor RNA used for ICI response prediction to identify rare cases where oncogenic rearrangements in NTRK1/2/3 or ALK genes may occur, and which may indicate the use of potentially highly effective targeted therapies. The clinical performance of OncoPrism-HNSCC has been validated. Here, we report its analytical performance in the presence of potentially confounding sources of variation.MethodsThe assay’s analytical sensitivity was assessed by varying RNA input quantity and quality, observing the effect on ICI response prediction scores. Analytical specificity was tested by spiking increasing percentages of genomic DNA into input RNA. Intra-assay and inter-assay precision were evaluated, and the analytical sensitivity, specificity, and precision of gene fusion detection were assessed. Concordance with orthogonal methods of gene fusion detection was tested on 67 FFPE clinical samples.ResultsVarying RNA inputs as low as four-fold below the nominal input amount had little effect on ICI response prediction scores. RNA quality levels below the test threshold had no significant effect. Genomic DNA spike-ins up to 30% had only a small effect on scores. The pooled standard deviation for multiple operators, reagent lots, batches, and sequencers yielded an overall variance represented by just 0.87% of the score range of the test (0–100). NTRK and ALK gene fusion detection was 100% concordant with orthogonal methods.ConclusionsRobust and reliable analytical performance of the OncoPrism-HNSCC assay supports its clinical use, even in the presence of variation typically encountered in the laboratory setting.

Vitiligo-like hypopigmentation secondary to adjuvant checkpoint inhibitor therapy in patients with resectable stage III melanoma: a cohort from two tertiary hospitals.

Vitiligo-like hypopigmentation induced by immune checkpoint inhibitors (ICIs) has been largely associated with improved survival outcomes in metastatic melanoma. However, its development during adjuvant ICI therapy and its role as a prognostic factor in this setting remain unclear. We aimed to describe ICI-induced vitiligo in a cohort of patients with resected stage III melanoma treated with adjuvant ICI and to identify differences in progression-free survival (PFS) and distant metastasis-free survival (DMFS) between those who developed vitiligo and those who did not. Patients and data were collected from two institutions, both retrospectively and prospectively, from January 2018 to February 2024. Patients were divided into 'vitiligo' and 'non-vitiligo' groups for comparisons. Of 40 patients, 22.5% developed ICI-induced vitiligo [median follow-up: 23 months (1-73)]. Treatments received were nivolumab (70%) and pembrolizumab (30%). Fifty-five percent of the patients completed 1 year of treatment, 37.5% discontinued and 7.5% were still ongoing. Vitiligo and non-vitiligo groups differed in the cause of treatment discontinuation (severe toxicity in vitiligo vs. progression in non-vitiligo, P = 0.005) and the occurrence of progression (none in vitiligo vs. 52% in non-vitiligo, P = 0.001). Survival analyses showed longer PFS in vitiligo group (P = 0.013) and no differences in DMFS (P = 0.111). ICI-induced vitiligo typically affected photo-exposed areas, with a median time to onset of 4 months (1-27). These preliminary results on ICI-induced vitiligo in adjuvant treatment are in agreement with those reported in advanced melanoma treatment, so its development in the adjuvant setting could be a sign of good prognosis as well.

DNA mismatch repair (MMR) genes expression in lung cancer and its correlation with different clinicopathologic parameters.

Lung cancer (LC) is a crucial rapidly developing disease. In Egypt, it is one of the five most frequent cancers. Little is known about the impact of deleted mismatch repair genes and its correlation to clinicopathological characteristics. This study evaluates immunohistochemical expression of the mismatch repair genes (PMS2), (MSH2), (MLH1) & (MSH6) & its correlation with clinicopathologic parameters & prognosis of LC. Age was higher with lost MLH1 & PMS2 but HTN was higher with lost four markers. Smoking was associated with expression of MLH1 & PMS2. A progressive course was associated with lost MSH2 & MSH6. Suprarenal metastasis was associated with lost all markers but bone metastasis was associated with lost MSH2 & MSH6. All the markers were significantly correlated with each other, with perfect correlations between MSH6 & MSH2 and between MLH & PMS2. Median overall survival among cases with lost markers was significantly lower than patients with preserved markers. We recommend evaluation of the four proteins as a biomarker that could guide LC therapy. In-depth biological research is imperative to elucidate the precise roles and mechanisms of these markers. This will advance management strategies and even guide immune checkpoint inhibitor therapy for LC.