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Background: Stage III surgically resected melanoma is a disease at high risk of recurrence. Immune checkpoint inhibitors (ICIs) and the target therapy with BRAF and MEK inhibitors significantly changed the outcome of patients with metastatic melanoma and several studies have also shown their benefit in the adjuvant setting for the delay of recurrence in stage III melanoma patients. Hyperprogression disease was observed as a possible adverse response to immunotherapy in the metastatic setting, suggesting that some patients could face additional risk of progression with ICIs, although no consensus was found for the correct definition of this event. Case presentation: We describe here two cases of rapid multiorgan metastatization during adjuvant immunotherapy in patients with stage III resected melanoma. Even though it would be not accurate to define this syndrome as hyperprogression because of apparent absence of the initial disease in the adjuvant setting, we observed in these two cases the same very rapid progression after first administration of adjuvant ICIs that resulted in death of patients within two months from the starting of treatment. Both patients had NRAS mutated melanoma. Conclusion: There is an urgent need for a better understanding of the causes of these fatal outcomes and for the identification of biomarkers that would allow to select the patients before offering theman adjuvant treatment, reducing the risk of hyperprogression. Fromthese cases, we suggest that it could be useful a particular attention in proposing ICI adjuvant treatment based on the molecular profile. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant and adjuvant immunotherapies for cancer have evolved through a series of remarkable and critical research advances; however, addressing their similarities and differences is imperative in clinical practice. Therefore, this study aimed to examine their similarities and differences from the perspective of informatics analysis. Methods: This cross-sectional study retrospectively analyzed extensive relevant studies published between 2014 and 2023 using stringent search criteria, excluding nonpeer-reviewed and non-English documents. The main outcome variables are publication volume, citation volume, connection strength, occurrence frequency, relevance percentage, and development percentage. Furthermore, an integrated comparative analysis was conducted using unsupervised hierarchical clustering, spatiotemporal analysis, regression statistics, and Walktrap algorithm analysis. Results: This analysis included 1373 relevant studies. Advancements in neoadjuvant and adjuvant immunotherapies have been promising over the last decade, with an annual growth rate of 25.18 vs. 6.52% and global collaboration (International Co-authorships) of 19.93 vs. 19.84%. Respectively, five dominant research clusters were identified through unsupervised hierarchical clustering based on machine learning, among which Cluster 4 (Balance of neoadjuvant immunotherapy efficacy and safety) and Cluster 2 (Adjuvant immunotherapy clinical trials) [Average Publication Year (APY): 2021.70 ± 0.70 vs. 2017.54 ± 4.59] are emerging research populations. Burst and regression curve analyses uncovered domain pivotal research signatures, including microsatellite instability (R2=0.7500, P=0.0025) and biomarkers (R2=0.6505, P=0.0086) in neoadjuvant scenarios, and the tumor microenvironment (R2=0.5571, P=0.0209) in adjuvant scenarios. The Walktrap algorithm further revealed that 'neoadjuvant immunotherapy, nonsmall cell lung cancer (NSCLC), immune checkpoint inhibitors, melanoma' and 'adjuvant immunotherapy, melanoma, hepatocellular carcinoma, dendritic cells' (Relevance Percentage: 100 vs. 100%, Development Percentage: 37.5 vs. 17.1%) are extremely relevant to this field but remain underdeveloped, highlighting the need for further investigation. Conclusion: This study identified pivotal research signatures and provided substantial predictions for neoadjuvant and adjuvant cancer immunotherapies. In addition, comprehensive quantitative comparisons revealed a notable shift in focus within this field, with neoadjuvant immunotherapy taking precedence over adjuvant immunotherapy after 2020; such a qualitative finding facilitate proper decision-making for subsequent research and mitigate the wastage of healthcare resources. [ABSTRACT FROM AUTHOR]

Simple Summary: Esophageal cancer is a severe disease with a high mortality rate. Recent advancements in treatments have improved outcomes, but survival rates remain low. This study investigates the use of immunotherapy, a treatment that helps the immune system fight cancer, in combination with standard chemoradiation and surgery for patients with locally advanced esophageal cancer. By analyzing data from the National Cancer Database, we found that patients who received adjuvant immunotherapy had better survival rates than those who did not receive immunotherapy or who received neoadjuvant immunotherapy. These findings suggest that adjuvant immunotherapy could be a beneficial addition to existing treatment protocols, and further research is needed to confirm these results and optimize patient outcomes. Background: The current National Comprehensive Cancer Network advises neoadjuvant chemoradiotherapy followed by surgery for locally advanced cases of esophageal cancer. The role of immunotherapy in this context is under heavy investigation. Methods: Patients with esophageal adenocarcinoma were identified in the National Cancer Database (NCDB) from 2004 to 2019. Three groups were generated as follows: (a) no immunotherapy, (b) neoadjuvant immunotherapy, and (c) adjuvant immunotherapy. Overall survival was evaluated using the Kaplan–Meier method and Cox proportional hazard analysis, adjusting for previously described risk factors for mortality. Results: Of the total 14,244 patients diagnosed with esophageal adenocarcinoma who received neoadjuvant chemoradiation, 14,065 patients did not receive immunotherapy, 110 received neoadjuvant immunotherapy, and 69 received adjuvant immunotherapy. When adjusting for established risk factors, adjuvant immunotherapy was associated with significantly improved survival compared to no immunotherapy and neoadjuvant immunotherapy during a median follow-up period of 35.2 months. No difference was noted among patients who received no immunotherapy vs. neoadjuvant immunotherapy in the same model. Conclusions: In this retrospective analysis of the NCDB, receiving adjuvant immunotherapy offered a significant survival advantage compared to no immunotherapy and neoadjuvant immunotherapy in the treatment of esophageal adenocarcinoma. The addition of neoadjuvant immunotherapy to patients treated with neoadjuvant chemoradiation did not improve survival in this cohort. Further studies are warranted to investigate the long-term outcomes of immunotherapy in esophageal cancer. [ABSTRACT FROM AUTHOR]

Significant advancements have been made in the treatment of cutaneous melanoma over the past decade, particularly with the effectiveness of immune checkpoint inhibitors (ICIs) in advanced and adjuvant stages. However, the efficacy of ICIs for non-Caucasian populations and the rare clinical subtypes acral melanoma (AM) and mucosal melanoma (MM), has gradually been recognized to be lower in the advanced setting than cutaneous melanoma, suggesting that the use of ICIs in treating AM and MM need careful consideration in terms of ethnic and disease-specific factors to optimize outcomes in the adjuvant and neoadjuvant setting. However, the efficacy of adjuvant and neoadjuvant ICIs for AM and MM remains unclear. Therefore, in this review, we discussed the latest study updates on adjuvant and neoadjuvant therapies for AM and MM, focusing on anti-PD-1 antibody-based therapies. Our findings revealed that the efficacy of adjuvant and neoadjuvant therapy with anti-programmed death-1 receptor (anti-PD-1) antibody-based therapies for cutaneous melanoma is promising; however, their effectiveness varies according to ethnicity and melanoma subtype. There are several ongoing clinical trials on adjuvant and neoadjuvant therapies targeting AM or MM, which will provide the future perspectives of the strategy in the adjuvant and neoadjuvant settings for these rare melanoma subtypes.

BackgroundStage III surgically resected melanoma is a disease at high risk of recurrence. Immune checkpoint inhibitors (ICIs) and the target therapy with BRAF and MEK inhibitors significantly changed the outcome of patients with metastatic melanoma and several studies have also shown their benefit in the adjuvant setting for the delay of recurrence in stage III melanoma patients. Hyperprogression disease was observed as a possible adverse response to immunotherapy in the metastatic setting, suggesting that some patients could face additional risk of progression with ICIs, although no consensus was found for the correct definition of this event.Case presentationWe describe here two cases of rapid multiorgan metastatization during adjuvant immunotherapy in patients with stage III resected melanoma. Even though it would be not accurate to define this syndrome as hyperprogression because of apparent absence of the initial disease in the adjuvant setting, we observed in these two cases the same very rapid progression after first administration of adjuvant ICIs that resulted in death of patients within two months from the starting of treatment. Both patients had NRAS mutated melanoma.ConclusionThere is an urgent need for a better understanding of the causes of these fatal outcomes and for the identification of biomarkers that would allow to select the patients before offering them an adjuvant treatment, reducing the risk of hyperprogression. From these cases, we suggest that it could be useful a particular attention in proposing ICI adjuvant treatment based on the molecular profile.

Introduction: For locally advanced, inoperable esophageal cancer, concurrent chemoradiotherapy (CCRT) becomes the norm. Combining immunotherapy with radiotherapy has been shown to improve efficacy. Circulating tumor DNA (ctDNA) is a strong predictor of effectiveness and tumor recurrence and is indicative of minimal residual disease (MRD). Patients with inoperable stage II-III esophageal squamous cell carcinoma (ESCC) are enrolled in the ECMRD-001 trial to evaluate changes in MRD status before and after CCRT combined with immunotherapy and adjuvant immunotherapy following neoadjuvant immunochemotherapy. Methods and analysis: The ECMRD-001 trial is a prospective cohort study. Eligible patients will receive radical concurrent chemoradiotherapy combined with immunotherapy after neoadjuvant immunochemotherapy, followed by adjuvant immunotherapy for at least one year. Follow-up will be up to three years. MRD-related blood and tissue samples and T-cell immunohistobank related blood and tissue samples collected before, during and after treatment and follow-up will be grouped into sample collection time points. The relationship between MRD status at different time points and treatment efficacy is the primary outcome. Correlation between MRD status and immune microenvironment, radiotherapy dose, and tumor recurrence are the secondary outcomes. Examination of ctDNA mutations is the exploratory outcome. Discussion: ctDNA-based MRD may be a potential predictive marker for the efficacy and tumor recurrence of inoperable ESCC patients. Elevated ctDNA-MRD may predict tumor recurrence earlier than imaging. ctDNA-based MRD analysis and ctDNA-based MRD guided diagnosis and treatment should be implemented into clinical practice to improve efficacy and reduce tumor recurrence of inoperable stage II-III ESCC. [ABSTRACT FROM AUTHOR]

Esophageal cancer is the sixth most common cancer worldwide. Approximately 50% of patients have locally advanced disease. The CROSS and NEOCRTEC5010 trials have demonstrated that neoadjuvant chemoradiotherapy followed by surgery is the standard treatment for patients with resectable disease. However, a pathological complete response is frequently not achieved, and most patients have a poor prognosis. The CheckMate 577 trial demonstrates that nivolumab adjuvant therapy improves disease-free survival in patents without a pathological complete response. However, there are still numerous clinical questions of concern that remain controversial based on the results of the subgroup analysis. In this review, we aim to offer constructive suggestions addressing the clinical concerns raised in the CheckMate 577 trial. [ABSTRACT FROM AUTHOR]

No adjuvant treatment has been established for patients who remain at high risk of recurrence and incidental pathologic lymph node metastasis for esophageal squamous cell carcinoma (ESCC). In this open-label, multicenter, phase III, randomized controlled trial, ESCC patients who did not achieve pathologic complete response after neoadjuvant chemotherapy plus surgery and clinical T1–2 N0 patients with incidental pathologic lymph node metastasis following initial surgery were randomized at a 2:1 ratio to receive either a sintilimab regimen or observational management (NCT05495152). The primary end point was disease-free survival for all randomized patients. The results of this randomized controlled trial addressed controversy regarding the survival benefits of adjuvant sintilimab treatment for patients with resected locally advanced ESCC. Clinical Trial Registration: NCT05495152 (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Primary malignant melanoma of the parotid gland (PGMM) is extremely rare, with a poor prognosis. Surgery is the main treatment option followed by adjuvant treatments such as radiotherapy, but which adjuvant treatment to be optimal is still controversial. In this case, a 63-year-old male PGMM patient was first misdiagnosed as a “myoepithelial tumor” and then treated with surgery, postoperative immunotherapy (sintilimab), chemotherapy, and radiotherapy successfully. The progression free survival was more than 19 months without signs of metastasis or recurrence to date. To our best knowledge, this is the first report of postoperative immunotherapy combined with chemotherapy and radiotherapy for PGMM. Our case indicated that combination therapy including surgery, adjuvant immunotherapy (sintilimab) combined with chemotherapy and radiotherapy may be a potential treatment option for PGMM, which needs further research.

Abstract Background Adjuvant therapies such as radiation therapy, chemotherapy, and immunotherapy are usually given after cancer surgery to improve the survival of cancer patients. However, despite advances in several adjuvant therapies, they are still limited in the prevention of recurrences. Methods We evaluated the immunological effects of RNA-based adjuvants in a murine melanoma model. Single-stranded RNA (ssRNA) were constructed based on the cricket paralysis virus (CrPV) internal ribosome entry site (IRES). Populations of immune cells in bone marrow cells and lymph node cells following immunization with CrPVIRES-ssRNA were determined using flow cytometry. Activated cytokine levels were measured using ELISA and ELISpot. The tumor protection efficacy of CrPVIRES-ssRNA was analyzed based on any reduction in tumor size or weight, and overall survival. Results CrPVIRES-ssRNA treatment stimulated antigen-presenting cells in the drain lymph nodes associated with activated antigen-specific dendritic cells. Next, we evaluated the expression of CD40, CD86, and XCR1, showing that immunization with CrPVIRES-ssRNA enhanced antigen presentation by CD8a+ conventional dendritic cell 1 (cDC1), as well as activated antigen-specific CD8 T cells. In addition, CrPVIRES-ssRNA treatment markedly increased the frequency of antigen-specific CD8 T cells and interferon-gamma (IFN-γ) producing cells, which promoted immune responses and reduced tumor burden in melanoma-bearing mice. Conclusions This study provides evidence that the CrPVIRES-ssRNA adjuvant has potential for use in therapeutic cancer vaccines. Moreover, CrPVIRES-ssRNA possesses protective effects on various cancer cell models.

Simple Summary: Immune checkpoint inhibitors (ICIs) are being increasingly used after primary treatment of early-stage tumors to treat any residual disease and prevent recurrence. Herein, we provide a comprehensive review of pivotal clinical studies demonstrating efficacy and safety outcomes when ICIs are utilized after surgery in patients with melanoma, urothelial cancer, renal cell carcinoma, lung cancer, gastroesophageal cancer, and hepatobiliary malignancies. In addition, we highlight the potential role of these agents within the emerging field of transplant oncology. To guide the selection of eligible patients for ICIs, we outline approved and emerging biomarkers that may predict benefit from use of these agents and help monitor response, especially in the absence of visible disease on imaging. Furthermore, we provide real-world considerations with regards to tolerability and cost-effectiveness of these agents and necessary future directions that should be explored to increase the survival outcomes associated with the use of ICIs after surgery. The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk–benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice. [ABSTRACT FROM AUTHOR]

Spontaneous remission (SR) of local recurrence after adjuvant immunotherapy has rarely been reported, and the underlying mechanism is poorly understood. Herein, we reported a patient with stage cT2aN2M0 squamous cell lung carcinoma who received neoadjuvant and adjuvant treatment with nivolumab plus chemotherapy. The patient experienced a late relapse in the subcarinal lymph node seven months after the last dosage of treatment but achieved SR in the next three months without additional antitumor therapy. The complete response lasted for eleven months and counting. Notably, high copies of pathogenic microorganisms were detected in the patient's bronchoalveolar lavage fluid along with the recurrence but disappeared after SR. The patient also experienced a lymph node puncture-induced fever but had no other symptoms. A longitudinal analysis of infiltrated immune cells in the recurrent lymph node was performed by multiplex immunofluorescence and whole transcriptome sequencing, which revealed that CD8+ T cells were recruited during the initial relapse, specifically in the stromal area, then migrated into the tumor tissue, and continued to increase after elimination of tumor cells. Meanwhile, the initial recruitment of CD8+ T cells was coupled with a higher proportion of B cells, and the abundant neutrophil population was synchronous with the infiltration of CD8+ T cells into tumor cells. This is the first report on an Non-small cell lung cancer (NSCLC) patient with a late relapse after adjuvant immune checkpoint inhibitor (ICI) therapy who achieved SR. Our case highlights the complexity and plasticity of antitumor immunity and is expected to help find efficient strategies against the resistance of ICI treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Localized renal cell carcinoma is primarily treated surgically by resection. Some patients carry criteria for a high risk of tumour recurrence, for which postoperative immunotherapy is approved and currently used. The receptor CXCR3 differentiates anti-tumour T cells, which are known to be significantly increased in patients at high risk of tumor recurrence. The aim of our study therefore was to evaluate occurrence of CXCR3 in tissue samples, to analyse its expression in higher tumor grades and stages and to interpret the results to designate CXCR3 as a potential marker for predicting recurrence in renal cell carcinoma after primary surgical resection. Background: Surgery is the standard treatment in localized renal cell carcinoma (RCC). Pembrolizumab is now approved for adjuvant therapy in high-risk patients. However, inhomogeneity of studies gives ambiguity which patient benefit most from adjuvant therapy. A high infiltration of CD8+ T cells is known to be linked with poor prognosis in RCC. CXCR3 is a key player of CD8+ T cell differentiation and infiltration. We aimed to evaluate CXCR3 as a potential marker for predicting recurrence. Methods: CXCR3 and immune cell subsets (CD4, CD8, CD68 and FoXP3) were measured on RCC samples by multiplex immunofluorescence (mIF) staining. Cellular localization of CXCR3 was evaluated using single-cell RNA analysis on a publicly available dataset. Results: Tumor samples of 42 RCC patients were analyzed, from which 59.5% were classified as clear-cell RCC and of which 20 had recurrence. Single-cell RNA analysis revealed that CXCR3 was predominantly expressed in intratumoral T cells and dendritic cells. CXCR3 expression was higher in advanced tumors stages (p = 0.0044) and grade (p = 0.0518), correlating significantly with a higher CD8+ T cell expression (p < 0.001). Patients with CXCR3high RCCs had also a significant shorter RFS compared to CXCR3low (median: 78 vs. 147 months, p = 0.0213). In addition, also tumor stage pT3/4 (p < 0.0001) as well as grade G3/4 (p = 0.0008) negatively influenced RFS. Conclusion: CXCR3high cell density was associated with high T cell infiltration and advanced tumor stage, worsening RFS in surgically resected RCC patients. Beside its prognostic value, CXCR3 might be a predictive biomarker to guide therapy decision for adjuvant therapy in localized RCC. [ABSTRACT FROM AUTHOR]

Background: Wide variation exists globally in the treatment and outcomes of stage III patients with non–small cell lung cancer (NSCLC). We conducted an up-to-date patterns of care analysis in the state of Victoria, Australia, with a particular focus on the proportion of patients receiving treatment with radical intent, treatment trends over time, and survival. Materials and Methods: Stage III patients with NSCLC were identified in the Victorian Lung Cancer Registry and categorized by treatment received and treatment intent. Logistic regression was used to explore factors predictive of receipt of radical treatment and the treatment trends over time. Cox regression was used to explore variables associated with overall survival (OS). Covariates evaluated included age, sex, ECOG performance status, smoking status, year of diagnosis, Australian born, Aboriginal or Torres Strait Islander status, socioeconomic status, rurality, public/private status of notifying institution, and multidisciplinary meeting discussion. Results: A total of 1396 patients were diagnosed between 2012 and 2019 and received treatment with radical intent 67%, palliative intent 23%, unknown intent 5% and no treatment 5%. Radical intent treatment was less likely if patients were >75 years, ECOG ≥1, had T3-4 or N3 disease or resided rurally. Surgery use decreased over time, while concurrent chemoradiotherapy and immunotherapy use increased. Median OS was 38.0, 11.1, and 4.4 months following radical treatment, palliative treatment or no treatment, respectively. Conclusion: Almost a third of stage III patients with NSCLC still do not receive radical treatment. Strategies to facilitate radical treatment and better support decision making between increasing multimodality options are required. Variations exist in the treatment and outcomes for patients with stage III non–small cell lung cancer. This article reports an up-to-date patterns of care analysis focusing on the proportion of patients receiving treatment with radical intent, treatment trends over time, and survival. [ABSTRACT FROM AUTHOR]

Currently, chemotherapy is the standard adjuvant treatment for early-stage non-small cell lung cancer (NSCLC). However, adjuvant cisplatin-based chemotherapy after surgery has been shown to improve 5-year survival rates by only 4−5%. Immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC, there is a growing interest in the role of immunotherapy in early-stage NSCLC. Here, we summarize the rationale for adjuvant immunotherapy, including the postoperative immunosuppressive environment and immunological effects of platinum chemotherapy. Many ongoing clinical trials and the related progress in adjuvant immunotherapy in early-stage resectable NSCLC are discussed. Furthermore, we highlight several unresolved challenges, including markers predictive of treatment benefit, the efficacy of treatment for some oncogene-addicted tumors, the optimal combination therapy, the duration of adjuvant immunotherapy, and optimal selection between neoadjuvant and adjuvant immunotherapy. Early findings in some clinical trials are promising, and updated overall survival results will be useful for validating the current role of adjuvant immunotherapy, particularly in the context of perioperative strategy. [ABSTRACT FROM AUTHOR]

Randomized clinical trials demonstrated a recurrence-free survival benefit with adjuvant anti-programmed death-1 (anti-PD1) inhibitors of resected stage IIB-IV melanoma. However, no improvement in overall survival has been observed thus far. Furthermore, there are no predictive markers for immunotherapy response in melanoma, therefore adjuvant treatment is offered to all comers based exclusively on the pathological and clinical stages. Additionally, one year of treatment duration and the risk of chronic immune-related adverse effects may negatively impact patients´ quality of life. In this review, we will try to answer whether the currently available data on adjuvant anti-PD1 therapy of stage IIB-IV resected melanoma is sufficient to make this strategy available to all patients. We will also discuss the economic impact of this therapy on healthcare system budgets. Recent studies suggest that the high cost of cancer drugs may affect access to these agents globally by raising questions of sustainability for patients and society. [Display omitted] • Recurrence-free survival (RFS) benefit with adjuvant anti-PD1 immunotherapy (IT) has been shown for stage IIB-IV melanoma. • Lack of overall survival (OS) benefit raises concerns about the long-term efficacy of this strategy. • RFS is not a strong surrogate for OS in the context of adjuvant IT. • Other major concerns include overtreatment, chronic immune-related adverse events, and the high cost of anti-PD1 IT. • Individualized decision-making is crucial before incorporating adjuvant IT as standard treatment for melanoma patients. [ABSTRACT FROM AUTHOR]

Abstract Objective To evaluate the effect of postoperative pathological findings related to the eligibility of adjuvant immunotherapy on oncologic outcomes in patients with localized and locally advanced muscle‐invasive bladder carcinoma (MIBC) and upper tract urothelial carcinoma (UTUC). Patients and methods We retrospectively evaluated 1082 patients treated with radical cystectomy (n = 597) and nephroureterectomy (n = 485) between January 2000 and April 2021. Patients were divided into two groups: pT3‐4 or pN+ without neoadjuvant chemotherapy and ypT2‐4 or pN+ treated with neoadjuvant chemotherapy (trial‐eligible group) or others (trial‐ineligible group). The primary outcome was the effect of trial eligibility for adjuvant immunotherapy on disease‐free survival (DFS) and overall survival (OS). Secondary outcomes included the additional effect of lymphovascular invasion (LVI) status to the clinical trial criteria on prognosis and a risk model development. Results The median ages of the patients were 69 and 72 years in the MIBC and UTUC groups, respectively. Fifty‐two percent of patients met the trial inclusion criteria. Trial eligibility was significantly associated with poor DFS and OS among patients with MIBC and UTUC. LVI‐positive status was significantly associated with poor prognosis among patients in the trial‐eligible group. A very high risk (LVI+ or pN+ among the pT3‐4 or ypT2‐4) was significantly associated with poor prognosis. Conclusion A total of 52% of patients were eligible for adjuvant immunotherapy. Trial eligibility was significantly associated with a poor prognosis. LVI+ and pN+ may play a key role in candidate selection for adjuvant immunotherapy.

Tissue-resident memory T (TRM) cells have emerged as key players in the immune control of melanoma. These specialized cells are identified by expression of tissue retention markers such as CD69, CD103 and CD49a with downregulation of egress molecules such as Sphingosine-1-Phosphate Receptor-1 (S1PR1) and the lymphoid homing receptor, CD62L. TRM have been shown to be integral in controlling infections such as herpes simplex virus (HSV), lymphocytic choriomeningitis virus (LCMV) and influenza. More recently, robust pre-clinical models have also demonstrated TRM are able to maintain melanoma in a dormant state without progression to macroscopic disease reminiscent of their ability to control viral infections. The discovery of the role these cells play in anti-melanoma immunity has coincided with the advent of immune checkpoint inhibitor (ICI) therapy which has revolutionized the treatment of cancers. ICIs that target programmed death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) have led to substantial improvements in outcomes for patients with metastatic melanoma and have been rapidly employed to reduce recurrences in the resected stage III setting. While ICIs mediate anti-tumor activity via CD8+ T cells, the specific subsets that facilitate this response is unclear. TRM invariably exhibit high expression of immune checkpoints such as PD-1, CTLA-4 and lymphocyte activating gene-3 (LAG-3) which strongly implicates this CD8+ T cell subset as a crucial mediator of ICI activity. In this review, we present pre-clinical and translational studies that highlight the critical role of TRM in both immune control of primary melanoma and as a key CD8+ T cell subset that mediates anti-tumor activity of ICIs for the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Background: Adjuvant therapies such as radiation therapy, chemotherapy, and immunotherapy are usually given after cancer surgery to improve the survival of cancer patients. However, despite advances in several adjuvant therapies, they are still limited in the prevention of recurrences.Methods: We evaluated the immunological effects of RNA-based adjuvants in a murine melanoma model. Single-stranded RNA (ssRNA) were constructed based on the cricket paralysis virus (CrPV) internal ribosome entry site (IRES). Populations of immune cells in bone marrow cells and lymph node cells following immunization with CrPVIRES-ssRNA were determined using flow cytometry. Activated cytokine levels were measured using ELISA and ELISpot. The tumor protection efficacy of CrPVIRES-ssRNA was analyzed based on any reduction in tumor size or weight, and overall survival.Results: CrPVIRES-ssRNA treatment stimulated antigen-presenting cells in the drain lymph nodes associated with activated antigen-specific dendritic cells. Next, we evaluated the expression of CD40, CD86, and XCR1, showing that immunization with CrPVIRES-ssRNA enhanced antigen presentation by CD8a+ conventional dendritic cell 1 (cDC1), as well as activated antigen-specific CD8 T cells. In addition, CrPVIRES-ssRNA treatment markedly increased the frequency of antigen-specific CD8 T cells and interferon-gamma (IFN-γ) producing cells, which promoted immune responses and reduced tumor burden in melanoma-bearing mice.Conclusions: This study provides evidence that the CrPVIRES-ssRNA adjuvant has potential for use in therapeutic cancer vaccines. Moreover, CrPVIRES-ssRNA possesses protective effects on various cancer cell models. [ABSTRACT FROM AUTHOR]

Background: A series of randomized controlled trials (RCTs) have demonstrated the promising prospect of immunotherapy in operable non-small cell lung cancer (NSCLC) and further changed the clinical practice. However, current studies still yet to answer which immunotherapy mode is the optimal strategy, and there is currently a lack of direct comparison between neoadjuvant immunochemotherapy and perioperative immunotherapy ("sandwich mode", including neoadjuvant immunochemotherapy and adjuvant immunotherapy). Thus, we conducted a network meta-analysis (NMA) to evaluate the efficacy between neoadjuvant immunochemotherapy and perioperative immunotherapy., Methods: We performed a Bayesian NMA (PROSPERO registration number: CRD42024495955) by retrieving relevant eligible studies from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences until December 31, 2023. Phase II or III RCTs that evaluated the efficacy of different strategies of immunotherapy in operable NSCLC, including neoadjuvant immunochemotherapy and perioperative immunotherapy ("sandwich mode"), were retrieved for analysis. The patients were grouped into neoadjuvant chemotherapy alone (arm A), neoadjuvant immunotherapy plus chemotherapy (arm B); neoadjuvant immunotherapy plus chemotherapy followed by surgery and adjuvant immunotherapy (arm C), respectively. The endpoint was event-free survival (EFS) in different subgroups., Results: Seven studies of 2,934 patients were selected for this NMA finally. Compared with neoadjuvant chemotherapy, both neoadjuvant immunochemotherapy [hazard ratio (HR) 0.61, 95% confidence interval (CI): 0.36-0.98] and perioperative immunotherapy (HR 0.56, 95% CI: 0.42-0.71) significantly improved the EFS in intention-to-treat population, but there was no statistical difference between these two treatments (HR 1.1, 95% CI: 0.62-1.9). There was no statistical difference between perioperative immunotherapy and neoadjuvant immunochemotherapy in all subgroup analysis of EFS. However, in patients with non-squamous disease, programmed cell death-ligand 1 (PD-L1) expression more than 50%, or stage III disease, both neoadjuvant immunotherapy [(HR 0.50, 95% CI: 0.26-0.97), (HR 0.24, 95% CI: 0.061-0.96), (HR 0.50, 95% CI: 0.39-0.63)] and perioperative immunotherapy [(HR 0.64, 95% CI: 0.46-0.87), (HR 0.40, 95% CI: 0.21-0.71), (HR 0.54, 95% CI: 0.34-0.85)] improved EFS significantly compared with neoadjuvant chemotherapy., Conclusions: Both neoadjuvant immunochemotherapy and perioperative immunotherapy significantly increased EFS compared with neoadjuvant chemotherapy. There is no evidence that perioperative immunotherapy is better than neoadjuvant immunochemotherapy in EFS. Patients with non-squamous disease, PD-L1 expression more than 50%, or stage III disease can try the neoadjuvant immunochemotherapy mode., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-287/coif). All authors report that this study was supported by the Youth Project of the Natural Science Foundation of Guangdong Province (No. 2022A1515110399), and the National Key R&D Program of China (No. 2022YFE0133100). The authors have no other conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Melanoma is a malignant tumor that develops from the melanocyte-containing epithelial lining of mucosal membranes. This case report highlights a patient who presented with an asymptomatic decrease in hemoglobin (HGB), which necessitated an upper gastrointestinal (GI) endoscopy that identified a necrotic ulcerating lesion on the greater curvature of the stomach, which was confirmed to be a primary malignant gastric melanoma upon biopsy. The multidisciplinary team (MDT) subsequently recommended subtotal gastrectomy with D2 lymphadenectomy. After subsequent surgical intervention, the tumor was successfully removed with clear margins. A successful multidisciplinary approach led to favorable postoperative outcomes, highlighting the importance of timely diagnosis and management of rare presentations of melanoma., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Institutional Review Board (IRB) of An-Najah National University issued approval NA. The IRB of An-Najah National University waives approvals for case reports and asks for only an informed consent form from the patient. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Barqawi et al.)

Tissue-resident memory T (TRM) cells have emerged as key players in the immune control of melanoma. These specialized cells are identified by expression of tissue retention markers such as CD69, CD103 and CD49a with downregulation of egress molecules such as Sphingosine-1-Phosphate Receptor-1 (S1PR1) and the lymphoid homing receptor, CD62L. TRM have been shown to be integral in controlling infections such as herpes simplex virus (HSV), lymphocytic choriomeningitis virus (LCMV) and influenza. More recently, robust pre-clinical models have also demonstrated TRM are able to maintain melanoma in a dormant state without progression to macroscopic disease reminiscent of their ability to control viral infections. The discovery of the role these cells play in anti-melanoma immunity has coincided with the advent of immune checkpoint inhibitor (ICI) therapy which has revolutionized the treatment of cancers. ICIs that target programmed death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) have led to substantial improvements in outcomes for patients with metastatic melanoma and have been rapidly employed to reduce recurrences in the resected stage III setting. While ICIs mediate anti-tumor activity via CD8+ T cells, the specific subsets that facilitate this response is unclear. TRM invariably exhibit high expression of immune checkpoints such as PD-1, CTLA-4 and lymphocyte activating gene-3 (LAG-3) which strongly implicates this CD8+ T cell subset as a crucial mediator of ICI activity. In this review, we present pre-clinical and translational studies that highlight the critical role of TRM in both immune control of primary melanoma and as a key CD8+ T cell subset that mediates anti-tumor activity of ICIs for the treatment of melanoma.

Objectives: Even though postoperative chemotherapy can eliminate residual tumor cells in patients with colorectal cancer (CRC), severe adversity, weakened immunity and drug resistance are still problems. Adjuvant cytokine‐induced killer (CIK) cell therapy is an alternative to CRC patients after surgery. The present study investigated the efficacy of adjuvant CIK cell therapy combined with chemotherapy in postoperative CRC patients. Methods: This retrospective analysis included 137 postoperative CRC patients, including 71 who received adjuvant chemotherapy alone (control group) and 66 who received adjuvant immunotherapy based on CIK cells combined with chemotherapy (CIT group). Results: Long‐term follow‐up study indicated that overall survival (OS) and progression‐free survival (PFS) were significantly longer in the CIT group than in the control group. Subgroup analyses showed that CIT treatment significantly improved OS and PFS of CRC patients classified as stage II and N0 stage and in patients with primary tumors in the rectum. Increasing the number of CIK infusions resulted in better prognosis. CRC patients aged < 65 years were found to benefit more from CIT‐based therapy than patients aged ≥ 65 years. A retrospective case–control study indicated that the primary tumor expression of signalling lymphocytes activating molecule family 7 (SLAMF7) was associated with increased efficacy of CIT treatment. Conclusions: Adjuvant CIT therapy was an effective therapeutic strategy for postoperative CRC patients prolonging OS and PFS. Patient age, tumor stage and expression of SLAMF7 may be potential indicators of the efficacy of CIT therapy. [ABSTRACT FROM AUTHOR]

Abstract Objectives Even though postoperative chemotherapy can eliminate residual tumor cells in patients with colorectal cancer (CRC), severe adversity, weakened immunity and drug resistance are still problems. Adjuvant cytokine‐induced killer (CIK) cell therapy is an alternative to CRC patients after surgery. The present study investigated the efficacy of adjuvant CIK cell therapy combined with chemotherapy in postoperative CRC patients. Methods This retrospective analysis included 137 postoperative CRC patients, including 71 who received adjuvant chemotherapy alone (control group) and 66 who received adjuvant immunotherapy based on CIK cells combined with chemotherapy (CIT group). Results Long‐term follow‐up study indicated that overall survival (OS) and progression‐free survival (PFS) were significantly longer in the CIT group than in the control group. Subgroup analyses showed that CIT treatment significantly improved OS and PFS of CRC patients classified as stage II and N0 stage and in patients with primary tumors in the rectum. Increasing the number of CIK infusions resulted in better prognosis. CRC patients aged

Background: Adjuvant treatment of malignant melanoma has improved the outcomes for patients. However, real-world data on efficacy and safety are limited. We investigated outcomes of melanoma patients treated with adjuvant immune checkpoint inhibitors (ICI) in the Ghent University Hospital., Methods: Patients with melanoma (stage III-IV), who received at least one cycle of ICI as adjuvant treatment between 2018 and 2021 were included in this retrospective cohort study. Primary outcomes were recurrence-free (RFS) and overall survival (OS). Other outcomes of interest were relapse patterns and safety., Results: 59 patients were included, with a median follow-up of 36 months. Disease recurrence or death of any cause was observed in 25/59 (42.4%) of the patients. The median RFS was 56.0 months (95%CI 36.1-75.9 months). At 48 months, RFS and OS were 55.9% and 84%, respectively. 9/23 (39%) recurrences were locoregional and 14/23 (60.9%) patients developed distant metastasis as first recurrence, including 2 (3.4%) with brain metastasis. Median time to recurrence was 9 months (range 2-56 months). 35/59 (59.3%) completed one year of adjuvant treatment, 12/59 (20.3%) stopped because of recurrence and 10/59 (16.9% because of toxicity. Immune-related adverse events wereseen in 29/59 (49.4%) patients, 10/59 (16.9%) developed grade 3-4 toxicity., Conclusion: This study confirms the real-world efficacy and safety of adjuvant ICI for melanoma, achieving RFS and OS comparableto the pivotal clinical trials. About 40% of patients develop arelapse, mainly during the adjuvant treatment. The outcomes ofpatients progressing during adjuvant ICI are poor, emphasizing the need of prospective and real-world studies on optimal management after progression on (neo)adjuvant treatment.

An editorial is presented on Hepatectomy and radiofrequency ablation (RFA) being established as curative therapies for hepatocellular carcinoma (HCC). Topics include repeated treatments with RFA, hepatectomy, and transarterial chemoembolization deteriorating liver function in many patients; and treatment causing the tumor for releasing tumor-associated antigens and antigen-presenting cells presenting the antigens to CD8+ T cells.

Abstract Background Several randomized controlled trials have shown that adjuvant immunotherapy with autologous cytokine-induced killer (CIK) cells prolongs recurrence-free survival (RFS) after curative treatment for hepatocellular carcinoma (HCC). We investigated the efficacy of adjuvant immunotherapy with activated CIK cells in real-world clinical practice. Methods A total of 59 patients who had undergone curative surgical resection or radiofrequency ablation for stage I or II HCC, and subsequently received adjuvant CIK cell immunotherapy at two large-volume centers in Korea were retrospectively included. Propensity score matching with a 1:1 ratio was conducted to avoid possible bias, and 59 pairs of matched control subjects were also generated. The primary endpoint was RFS and the secondary endpoints were overall survival and safety. Results The median follow-up duration was 28.0 months (interquartile range, 22.9–42.3 months). In a univariable analysis, the immunotherapy group showed significantly longer RFS than the control group (hazard ratio [HR], 0.42; 95% CI, 0.22–0.80; log-rank P = 0.006). The median RFS in the control group was 29.8 months, and the immunotherapy group did not reach a median RFS. A multivariable Cox proportional hazard analysis showed that immunotherapy was an independent predictor for HCC recurrence (adjusted HR, 0.38; 95% CI, 0.20–0.73; P = 0.004). The overall incidence of adverse events in the immunotherapy group was 16/59 (27.1%) and no patient experienced a grade 3 or 4 adverse event. Conclusions The adjuvant immunotherapy with autologous CIK cells after curative treatment safely prolonged the RFS of HCC patients in a real-world setting.

Yan Wang,1 Benji Lv,2 Ke Li,3 Anqi Zhang,3 Hong Liu3 1Department of Clinical Laboratory, 2Department of Blood Transfusion, 3Department of Central Laboratory, Liaocheng People’s Hospital, Liaocheng Clinical School of Taishan Medical University, Liaocheng, Shandong Province, China Objective: The aim of this study was to systematically evaluate the efficacy and safety of the combination of dendritic cells and cytokine-induced killer cells (DC–CIK) adjuvant immunotherapy and chemotherapy in the treatment of multiple myeloma (MM).Methods: Clinical trials were gathered by searching Web of Science, PubMed, Embase, Cochrane Library, Wanfang, and CNKI database. Outcome measurements including therapeutic efficacy, prognosis, immune function, and adverse events were extracted and evaluated.Results: A total of 12 trials including 594 MM patients were involved in this study for statistical analysis. Results indicated that compared to chemotherapy alone, the combination of DC–CIK immunotherapy with chemotherapy significantly improved patients’ overall response rate (ORR, odds ratio [OR] =2.77, 95% confidence interval [CI] =1.88–4.10, P

Abstract Background Surgical resection combined with adjuvant chemotherapy is considered as the gold-standard treatment for advanced colorectal cancer patients. These patients have a poor 5-year survival rate of 5% or less. Furthermore, a large dose of chemotherapy can produce adverse side effects and severe toxicity. Therefore, this retrospective study aimed to evaluate the efficacy of dendritic cell-cytokine-induced killer (DC-CIK) cell infusion as an adjuvant therapy in patients with advanced colorectal cancer combined with first-line treatment. Methods A total of 142 patients with stage III/IV colorectal carcinoma who had been treated with first-line therapy were included in this study. Among these patients, 71 patients received first-line treatment only (non-DC-CIK group), while the other 71 patients who had similar demographic and clinical characteristics received a DC-CIK cell infusion combined with first-line treatment (DC-CIK group). These patients were followed up until August 2014. Data were analyzed by Kaplan-Meier and Cox regression. Results Our results showed that the 5-year overall survival (OS) rate for the DC-CIK group versus the non-DC-CIK group was 41.3 versus 19.4% (p = 0.001) and the 5-year progression-free survival (PFS) rate for the DC-CIK group versus the non-DC-CIK group was 57.4 versus 33.6% (p = 0.022). Conclusions Our results showed that patients with advanced colorectal cancer might benefit from DC-CIK immunotherapy combined with first-line therapy by significantly prolonging 5-year OS and PFS.

Background: Checkpoint inhibitors have shown improvement in recurrence-free survival in the post-operative setting for node-positive melanoma and were first approved in late 2015. However, single-agent checkpoint therapies have yet to show benefit to overall survival (OS) for lower-risk stage III cancers. We evaluated the OS benefit of post-operative immunotherapy in the National Cancer Database (NCDB)., Patients and Methods: Patient cases were selected from the NCDB 2020 Participant Use File. Patients diagnosed with stage III cutaneous melanoma between 2016 and 2019 who underwent definitive resection for their melanoma were included. OS between those who received post-operative immunotherapy within 84 days of surgery and those who did not was analyzed by the Kaplan-Meier method. Demographic and clinical characteristics between the two groups were compared via Cox proportional hazard models., Results: 14 978 patients with stage III melanoma were included. Of those, 34.9% (n = 5234) received post-operative immunotherapy and 65.1% (n = 9744) did not. Using the American Joint Committee on Cancer version 8 (AJCCv8) staging, 36-month survival was significantly higher in patients who received post-operative immunotherapy compared to no post-operative systemic therapy in those diagnosed with stage IIIB (88.0% versus 84.7%, P = 0.011), IIIC (75.6% versus 68.1%, P < 0.001), or IIID (59.2% versus 48.4%, P = 0.002). No significant improvement in 36-month survival was seen in patients who received post-operative immunotherapy in patients with stage IIIA disease (93.0% versus 92.2%, P = 0.218)., Conclusions: Post-operative immunotherapy had an OS benefit in patients with AJCCv8 stage IIIB, IIIC, and IIID disease, but had no significant survival benefit for patients with stage IIIA melanomas., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: For locally advanced, inoperable esophageal cancer, concurrent chemoradiotherapy (CCRT) becomes the norm. Combining immunotherapy with radiotherapy has been shown to improve efficacy. Circulating tumor DNA (ctDNA) is a strong predictor of effectiveness and tumor recurrence and is indicative of minimal residual disease (MRD). Patients with inoperable stage II-III esophageal squamous cell carcinoma (ESCC) are enrolled in the ECMRD-001 trial to evaluate changes in MRD status before and after CCRT combined with immunotherapy and adjuvant immunotherapy following neoadjuvant immunochemotherapy., Methods and Analysis: The ECMRD-001 trial is a prospective cohort study. Eligible patients will receive radical concurrent chemoradiotherapy combined with immunotherapy after neoadjuvant immunochemotherapy, followed by adjuvant immunotherapy for at least one year. Follow-up will be up to three years. MRD-related blood and tissue samples and T-cell immunohistobank related blood and tissue samples collected before, during and after treatment and follow-up will be grouped into sample collection time points. The relationship between MRD status at different time points and treatment efficacy is the primary outcome. Correlation between MRD status and immune microenvironment, radiotherapy dose, and tumor recurrence are the secondary outcomes. Examination of ctDNA mutations is the exploratory outcome., Discussion: ctDNA-based MRD may be a potential predictive marker for the efficacy and tumor recurrence of inoperable ESCC patients. Elevated ctDNA-MRD may predict tumor recurrence earlier than imaging. ctDNA-based MRD analysis and ctDNA-based MRD guided diagnosis and treatment should be implemented into clinical practice to improve efficacy and reduce tumor recurrence of inoperable stage II-III ESCC., Trial Registration: The ECMRD-001 study has been registered at ClinicalTrials.gov as NCT05952661 (July 19, 2023), https://classic.clinicaltrials.gov/ct2/show/NCT05952661., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Zhang, Zhao, Song, Deng and Shen.)

Background: Several randomized controlled trials have shown that adjuvant immunotherapy with autologous cytokine-induced killer (CIK) cells prolongs recurrence-free survival (RFS) after curative treatment for hepatocellular carcinoma (HCC). We investigated the efficacy of adjuvant immunotherapy with activated CIK cells in real-world clinical practice.Methods: A total of 59 patients who had undergone curative surgical resection or radiofrequency ablation for stage I or II HCC, and subsequently received adjuvant CIK cell immunotherapy at two large-volume centers in Korea were retrospectively included. Propensity score matching with a 1:1 ratio was conducted to avoid possible bias, and 59 pairs of matched control subjects were also generated. The primary endpoint was RFS and the secondary endpoints were overall survival and safety.Results: The median follow-up duration was 28.0 months (interquartile range, 22.9-42.3 months). In a univariable analysis, the immunotherapy group showed significantly longer RFS than the control group (hazard ratio [HR], 0.42; 95% CI, 0.22-0.80; log-rank P = 0.006). The median RFS in the control group was 29.8 months, and the immunotherapy group did not reach a median RFS. A multivariable Cox proportional hazard analysis showed that immunotherapy was an independent predictor for HCC recurrence (adjusted HR, 0.38; 95% CI, 0.20-0.73; P = 0.004). The overall incidence of adverse events in the immunotherapy group was 16/59 (27.1%) and no patient experienced a grade 3 or 4 adverse event.Conclusions: The adjuvant immunotherapy with autologous CIK cells after curative treatment safely prolonged the RFS of HCC patients in a real-world setting. [ABSTRACT FROM AUTHOR]

Our earlier multicenter randomized controlled trial showed that adjuvant immunotherapy with cytokine-induced killer (CIK) cells resulted in longer recurrence-free survival (RFS) and overall survival (OS) as well in patients who received curative treatment for hepatocellular carcinoma (HCC). In the present study, we determined if the efficacy of CIK cell therapy continued after end of repeated CIK cell injections. We performed a follow-up study of our preceding trial. We included 226 patients: 114 patients in the immunotherapy group (injection of 6.4 × 109 CIK cells, 16 times during 60 weeks) and 112 patients in the control group (no treatment) after potentially curative treatment for HCC. In total, 162 patients (89 of the immunotherapy group and 73 of controls) underwent an extended follow-up for 60 months after randomization of the last patient. The primary endpoint was RFS, and secondary endpoints included OS. During follow-up time of median 68.5 months (interquartile range 45.0-82.2 months), the immunotherapy group continued to show a significantly lower risk of recurrence or death [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.48-0.94; P = 0.009 by one-sided log-rank test]. At 5 years, RFS rate was 44.8% in the immunotherapy group and 33.1% in the control group. The risk of all-cause death was also lower in the immunotherapy group compared to the control group (HR 0.33; 95% CI 0.15-0.76; P = 0.006). In patients who received curative treatment for HCC, the significant improvement in RFS and OS as a result of adjuvant CIK cell immunotherapy lasted over 5 years without boosting. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality worldwide. At late stage of the disease CRC often shows (multiple) metastatic lesions in the peritoneal cavity which cannot be efficiently targeted by systemic chemotherapy. This is one major factor contributing to poor prognosis. Oxaliplatin is one of the most commonly used systemic treatment options for advanced CRC. However, drug resistance – often due to insufficient drug delivery – is still hampering successful treatment. The anticancer activity of oxaliplatin includes besides DNA damage also a strong immunogenic component. Consequently, the aim of this study was to investigate the effect of bacterial ghosts (BGs) as adjuvant immunostimulant on oxaliplatin efficacy. BGs are empty envelopes of gram-negative bacteria with a distinct immune-stimulatory potential. Indeed, we were able to show that the combination of BGs with oxaliplatin treatment had strong synergistic anticancer activity against the CT26 allograft, resulting in prolonged survival and even a complete remission in this murine model of CRC carcinomatosis. This synergistic effect was based on an enhanced induction of immunogenic cell death and activation of an efficient T-cell response leading to long-term anti-tumor memory effects. Taken together, co-application of BGs strengthens the immunogenic component of the oxaliplatin anticancer response and thus represents a promising natural immune-adjuvant to chemotherapy in advanced CRC.

Background. Electrochemotherapy is a tumour ablation modality, based on electroporation of the cell membrane, allowing non-permeant anticancer drugs to enter the cell, thus augmenting their cytotoxicity by orders of magnitude. In preclinical studies, bleomycin and cisplatin proved to be the most suitable for clinical use. Intravenous administration of cisplatin for electrochemotherapy is still not widely accepted in the clinics, presumably due to its lower antitumor effectiveness, but adjuvant therapy by immunomodulatory or vascular-targeting agents could provide a way for its potentiation. Hence, the aim of the present study was to explore the possibility of adjuvant tumour necrosis factor α (TNF-α) therapy to potentiate antitumor effectiveness of electrochemotherapy with intravenous cisplatin administration in murine sarcoma.

Lung cancer is the most common cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) represents the majority of lung cancer cases, and its standard treatment is primarily surgery. Nonetheless, this type of cancer exhibits an important rate of tumor recurrence. Immune checkpoint inhibitors (ICIs) have demonstrated significant survival benefits in many cancers, especially in early-stage NSCLC. This review considers the latest CheckMate816, IMpower010 and KEYNOTE-091 trials that led to US FDA approvals. The new wave of resectable NSCLC trial results are also summarized. Finally, the latest challenges for these treatment modalities, such as the choice between neoadjuvant and adjuvant use, the accurate identification of biomarkers and the presence of driver mutations such as EGFR, are discussed.

Esophageal cancer is the sixth most common cancer worldwide. Approximately 50% of patients have locally advanced disease. The CROSS and NEOCRTEC5010 trials have demonstrated that neoadjuvant chemoradiotherapy followed by surgery is the standard treatment for patients with resectable disease. However, a pathological complete response is frequently not achieved, and most patients have a poor prognosis. The CheckMate 577 trial demonstrates that nivolumab adjuvant therapy improves disease-free survival in patents without a pathological complete response. However, there are still numerous clinical questions of concern that remain controversial based on the results of the subgroup analysis. In this review, we aim to offer constructive suggestions addressing the clinical concerns raised in the CheckMate 577 trial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lin, Liang, Liu and Pan.)

Our previous phase I/IIA study showed that autologous dendritic cells (DCs) pulsed with tumor-associated antigens are well tolerated in patients with hepatocellular carcinoma (HCC). In this randomized, multicenter, open-label, phase II trial, we investigated the efficacy and safety of this DC-based adjuvant immunotherapy with 156 patients, who treated for HCC with no evidence of residual tumor after standard treatment modalities. Patients were randomly assigned to immunotherapy (n = 77; injection of 3 × 107 DC cells, six times over 14 weeks) or control (n = 79; no treatment). The primary end point was recurrence-free survival (RFS), and the secondary endpoints were immune response and safety. The RFS between the immunotherapy and control groups was not significantly different (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.60–1.56; p = 0.90). However, post-hoc subgroup analyses revealed that DC immunotherapy significantly reduced the risk of tumor recurrence of non-radiofrequency ablation (non-RFA) group patients (n = 83, HR, 0.49; 95% CI, 0.26–0.94; p = 0.03), whereas unexpectedly increased the risk of recurrence in RFA group (n = 61, p = 0.01). Tumor-specific immune responses were significantly enhanced (both p < 0.01) in the immunotherapy group. Baseline serum interleukin (IL)-15 was statistically correlated with RFS prolongation (HR, 0.16; 95% CI, 0.03–1.58; p = 0.001) within the immunotherapy groups. Overall adverse events were more frequent in the immunotherapy group (p < 0.001) but were mainly mild to moderate in severity. In conclusion, adjuvant immunotherapy with DC vaccine reduces the risk of tumor recurrence in HCC patients who underwent standard treatment modalities other than RFA. Baseline IL-15 might be a candidate biomarker for DC-based HCC immunotherapy.

Anti-programmed cell death protein-1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) antibodies have been widely used in cancers. The present study aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors in human cancers. Studies were searched from Cochrane Library, PubMed and Embase databases. Randomized controlled trials (RCTs) that investigated adjuvant therapy with anti-PD-1/PD-L1 agents in solid cancers were eligible for inclusion. As the primary focus of the meta-analysis, clinical outcome measures including overall survival (OS), disease-free survival (DFS), and adverse events (AEs) were analyzed by Stata 15.0 software. A total of six RCTs (n=4,436) met the inclusion criteria. The DFS [hazard ratio (HR)=0.71; 95% confidence interval (CI): 0.63-0.78; P<0.001] and OS (HR=0.66, 95% CI: 0.46-0.86, P<0.001) of patients were significantly prolonged by adjuvant immunotherapy. Subgroup analysis indicated that significantly improved DFS was observed in patients treated with different anti-PD-1/PD-L1 drugs (nivolumab, pembrolizumab, or atezolizumab), as well as in those with different tumors (melanoma, urothelial carcinoma, esophageal or gastroesophageal junction cancer, or renal cell carcinoma), and PD-L1 status [negative (<1%) or positive (≥1%)]. However, PD-1/PD-L1 inhibitors was associated with increased ≥ grade 3 treatment-related AEs (odds ratio=1.63; 95% CI: 1.20-2.21; P=0.002). The available evidence suggests that adjuvant therapy with PD-1/PD-L1 inhibitors provided more survival benefit than placebo for patients with cancer, with increased grade 3 or higher AEs. Prospero registration no. CRD42021290654. [ABSTRACT FROM AUTHOR]

Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-897/coif). The authors have no conflicts of interest to declare.

Rationale: Resistance to 5-fluorouracil (5-FU) chemotherapy remains the main barrier to effective clinical outcomes for patients with colorectal cancer (CRC). A better understanding of the detailed mechanisms underlying 5-FU resistance is needed to increase survival. Interleukin (IL)-33 is a newly discovered alarmin-like molecule that exerts pro- and anti-tumorigenic effects in various cancers. However, the precise role of IL-33 in CRC progression, as well as in the development of 5-FU resistance, remains unclear. Methods: High-quality RNA-sequencing analyses were performed on matched samples from patients with 5-FU-sensitive and 5-FU-resistant CRC. The clinical and biological significance of IL-33, including its effects on both T cells and tumor cells, as well as its relationship with 5-FU chemotherapeutic activity were examined in ex vivo , in vitro and in vivo models of CRC. The molecular mechanisms underlying these processes were explored. Results: IL-33 expressed by tumor cells was a dominant mediator of antitumoral immunity in 5-FU-sensitive patients with CRC. By binding to its ST2 receptor, IL-33 triggered CD4+ (Th1 and Th2) and CD8+ T cell responses by activating annexin A1 downstream signaling cascades. Mechanistically, IL-33 enhanced the sensitivity of CRC cells to 5-FU only in the presence of T cells, which led to the activation of both tumor cell-intrinsic apoptotic and immune killing-related signals, thereby synergizing with 5-FU to induce apoptosis of CRC cells. Moreover, injured CRC cells released more IL-33 and the T cell chemokines CXCL10 and CXCL13, forming a positive feedback loop to further augment T cell responses. Conclusions: Our results identified a previously unrecognized connection between IL-33 and enhanced sensitivity to 5-FU. IL-33 created an immune-active tumor microenvironment by orchestrating antitumoral T cell responses. Thus, IL-33 is a potential predictive biomarker for 5-FU chemosensitivity and favorable prognosis and has potential as a promising adjuvant immunotherapy to improve the clinical benefits of 5-FU-based therapies in the treatment of CRC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Currently, chemotherapy is the standard adjuvant treatment for early-stage non-small cell lung cancer (NSCLC). However, adjuvant cisplatin-based chemotherapy after surgery has been shown to improve 5-year survival rates by only 4-5%. Immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC, there is a growing interest in the role of immunotherapy in early-stage NSCLC. Here, we summarize the rationale for adjuvant immunotherapy, including the postoperative immunosuppressive environment and immunological effects of platinum chemotherapy. Many ongoing clinical trials and the related progress in adjuvant immunotherapy in early-stage resectable NSCLC are discussed. Furthermore, we highlight several unresolved challenges, including markers predictive of treatment benefit, the efficacy of treatment for some oncogene-addicted tumors, the optimal combination therapy, the duration of adjuvant immunotherapy, and optimal selection between neoadjuvant and adjuvant immunotherapy. Early findings in some clinical trials are promising, and updated overall survival results will be useful for validating the current role of adjuvant immunotherapy, particularly in the context of perioperative strategy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tang, Ye, Tang, Su, Xu, Zhong and Liang.)