George Zarkavelis

Background: Circulating tumor DNA (ctDNA) has emerged as a potential marker of minimal residual disease (MRD) after resection of colorectal liver metastases (CRLM), but its prognostic value and possible role in guiding postoperative management remain uncertain. This systematic review evaluated the available evidence on ctDNA for predicting recurrence and survival after CRLM resection, with particular attention to perioperative and serial ctDNA measurements and their potential value in guiding adjuvant treatment. Methods: PubMed/MEDLINE, Scopus, and the Cochrane Library were searched from inception to 21 July 2026 for studies evaluating ctDNA in patients undergoing resection of CRLM. Prospective and retrospective cohort studies and relevant randomized trial sub-studies were eligible. The primary outcome was the association between ctDNA status and recurrence, while secondary outcomes included recurrence-free survival (RFS), disease-free survival (DFS), overall survival (OS), serial ctDNA dynamics, and the potential predictive value of ctDNA for adjuvant chemotherapy. Risk of bias was assessed using the QUIPS tool. Findings were synthesized narratively, with an additional exploratory random-effects meta-analysis of early postoperative tissue-informed ctDNA positivity and RFS/DFS. Unadjusted and adjusted HRs were pooled separately. Results: Twenty-eight studies published between 2018 and 2026 were included, representing 2079 unique patients after accounting for overlapping cohorts. In six studies, postoperative ctDNA positivity was associated with poorer RFS/DFS (pooled unadjusted HR 5.15, 95% CI 3.65–7.27; I² = 0%). Five studies provided adjusted estimates (pooled HR 4.95, 95% CI 2.45–10.01; I² = 60.5%). Serial monitoring provided additional prognostic information: persistent ctDNA positivity or conversion from negative to positive during follow-up was associated with poor outcomes, whereas ctDNA clearance was generally associated with a lower risk of recurrence. ctDNA could precede radiological recurrence by approximately 2.5 to >20 months, although detection was less reliable in patients with small-volume pulmonary recurrence. In contrast, the prognostic value of preoperative ctDNA was less consistent and appeared to depend on assay methodology, quantitative ctDNA burden, and previous systemic treatment. Observational studies reported associations between postoperative MRD status and outcomes following adjuvant chemotherapy, but non-randomized treatment allocation and potential time-related bias limit conclusions about treatment benefit. Considerable variation in assay platforms and postoperative sampling schedules remained across studies. Conclusions: Postoperative ctDNA positivity is associated with poorer recurrence-related outcomes after CRLM resection. However, the moderate-to-high risk of bias and differences between studies limit confidence in the evidence. The predictive value of ctDNA for adjuvant chemotherapy benefit remains unproven. Prospective randomized trials are needed to determine whether ctDNA-guided management improves patient outcomes.

Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker for detecting minimal residual disease (MRD) and predicting recurrence after curative treatment, yet evidence in esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric cancer has largely been examined within individual tumor types. In this scoping review, we mapped this evidence across all three malignancies and clarified key methodological and clinical considerations. Following the PRISMA-ScR guidelines, we searched PubMed, Scopus, and the Cochrane Library (3 April 2026) for studies linking ctDNA to disease-free, recurrence-free, or overall survival after curative-intent treatment. Twenty-seven studies (1746 patients; 10 ESCC, 4 EAC, 8 gastric, and 5 mixed) were included. Across every tumor type, postoperative ctDNA MRD was the most informative timepoint, with independent multivariable hazard ratios for disease-free, recurrence-free, or event-free survival of 2.8 to 21.8, whereas preoperative ctDNA was seldom prognostic. Serial monitoring further improved performance and flagged recurrence 78 to 278 days before imaging. Tumor-informed assays showed higher sensitivity than tumor-agnostic ones (80% vs. 35%), though direct comparisons were limited; correction for clonal hematopoiesis was essential for tumor-agnostic assays, and blood-based assays performed poorly in diffuse-type and peritoneal disease. Postoperative ctDNA MRD is a consistent, independent prognostic biomarker across upper gastrointestinal cancers that adds prognostic information beyond conventional staging and pathological response, supporting prospective interventional trials of ctDNA-guided management.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by enhancing the immune response against tumors. However, they can cause immune-related adverse events (irAEs), including rare but potentially fatal myocarditis. We describe a 71-year-old man with stage IIIA lung adenocarcinoma treated with adjuvant pembrolizumab who developed severe ICI-associated myocarditis. Despite early diagnosis, treatment with intensive immunosuppression and mechanical support, he suffered fatal cardiac complications. A systematic review of the literature up to May 2025 identified 44 cases of ICI-associated myocarditis. Data on clinical features, diagnostics, treatment, and outcomes were extracted and analyzed. Most cases involved older patients with lung cancer treated with pembrolizumab or nivolumab. Onset varied from days to years after therapy initiation. Presentations included dyspnea, chest pain, arrhythmias, and elevated cardiac biomarkers. The biopsy showed T-cell and macrophage infiltration. High-dose corticosteroids were the primary treatment; additional immunosuppressants were used in cases that were refractory. Mortality was 45%, mainly due to cardiac failure and sepsis. Discussion: ICI-associated myocarditis arises from immune dysregulation affecting cardiac tissue, potentially involving shared antigens and systemic inflammation. Early detection and aggressive immunosuppression are crucial but often insufficient, resulting in high mortality. This underscores the urgent need for a better understanding of pathogenesis and the development of effective management strategies to improve patient outcomes. Finally, a multidisciplinary approach is important to improve outcomes in ICI-associated myocarditis.

Immune-mediated necrotizing myopathy (IMNM), a type of inflammatory myopathy, is associated with anti-SRP or anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) antibodies, with statin use potentially inducing statin-associated IMNM (SAIMNM) due to HMGCR targeting. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may offer a safer alternative for lipid-lowering in these patients. This study aims to describe the clinical characteristics of SAIMNM patients and evaluate the safety of PCSK9 inhibitors after myositis onset. We present the clinical characteristics of five SAIMNM patients and evaluate the safety of PCSK9 inhibitors in these cases. Additionally, we conducted a literature review using four different databases (Medline/PubMed, Scopus, Cochrane and DOAJ) to summarize the available data on IMNM. While numerous articles discussed statin-induced myositis, we selected only those studies that addressed the treatment of dyslipidemia after the management of IMNM. All five patients were women, with four having a history of statin use. One statin-naïve patient was positive for anti-SRP antibodies, while the others had anti-HMGCR antibodies. After a mean follow-up of 18.2 months, creatine phosphokinase (CPK) levels dropped from 1028.6 IU/L to 135 IU/L, and LDL cholesterol levels decreased from 206.2 mg/dL to 87.2 mg/dL. All patients were treated with steroids (with a gradual dosage reduction), and four of the five received second line immunosuppressive therapy, such as intravenous immunoglobulin, methotrexate, azathioprine, and mycophenolate mofetil. No disease recurrence occurred after starting PCSK9 inhibitors. A review of seven studies (15 patients) showed a mean CPK of 1531.9 IU/L. 40% received steroids and another immunosuppressant. Statin rechallenge caused relapse in two cases, but PCSK9 inhibitors were well tolerated, with only one patient needing additional immunosuppression. Additionally, ezetimibe and bempedoic acid were used successfully in some patients. Finally, lipid levels appeared to be lower after treatment with PCSK9 inhibitors. Administration of PCSK9 inhibitors appears to be an effective and safe option for the treatment of dyslipidaemia in patients with IMNM.

Background: Immune checkpoint inhibitors (ICIs) are increasingly included in management guidelines for various types of cancer. However, immune-related adverse events (irAEs) are an inevitable consequence of these therapies. Some of these side effects, such as pneumonitis, can be particularly serious. Additionally, the combination of ICIs with radiotherapy (RT) may further increase the risk of pneumonitis. Objective: The aim of this systematic review is to examine all available studies on pneumonitis following the use of ICIs and RT to assess its appearance and severity. Methods: We systematically searched four different databases (PubMed, Scopus, Cochrane, and DOAJ) to identify all relevant studies within our scope. Additionally, we reviewed the references of the studies we found, as well as those of other systematic reviews and meta-analyses. We assessed the risk of bias using the Cochrane Risk of Bias Tool version 2 for randomized controlled trials and the RTI Risk of Bias Item Bank for non-randomized trials. Finally, we extracted relevant data into an Excel file and presented them in tables throughout this study. Results: A total of 58 articles met our inclusion criteria, comprising 4889 patients across multiple studies and nine case reports. Due to significant heterogeneity in study methodologies and data reporting, a cumulative statistical analysis was not performed. The included studies were published between 2017 and 2025. The incidence of pneumonitis varied, with retrospective studies showing higher rates compared to randomized and non-randomized controlled trials. Case reports described a range of pneumonitis presentations, treatments, and outcomes, with corticosteroids being the primary treatment. Conclusions: The incidence of pneumonitis varied, with retrospective studies showing the highest rates compared to other study designs. Early detection and management of pneumonitis in patients receiving RT and/or ICIs are crucial for improving outcomes. Identifying high-risk patients through predictive models, radiomics, and biomarkers may help tailor treatment strategies and minimize toxicity. Further research is needed to establish the most appropriate diagnostic criteria, optimize management approaches, and refine advanced imaging and biomarker-based risk stratification to improve patient care. Interdisciplinary collaboration is essential for reducing the risk of pneumonitis and improving patient outcomes.

Immune checkpoint inhibitors (ICIs) play a crucial role in treating various cancers. While ICIs are invaluable in the fight against different cancers, they also pose the risk of immune-related adverse events (irAEs), which can range widely in symptoms and severity. Rheumatologic complications, including digital ischemia, are among the irAEs. While rare, they require early detection for effective management. The aim of the study is to present a case report on digital ischemia related to immunotherapy and to conduct a literature review on relevant cases. We present a case involving a patient from our oncology department who developed, pericarditis, digital ischemia and anti-centromere antibodies during immunotherapy with pembrolizumab for non-small cell lung cancer (NSCLC). We collaborated with our rheumatology department to initiate treatment, including corticosteroids, iloprost, and mycophenolate mofetil. Through the follow-up, the patient showed clinical improvement. A literature review identified only 10 relevant articles, highlighting the rarity of digital ischemia as an irAE. Corticosteroids and vasodilators were commonly used treatments, with amputation unavoidable in 40% of cases. IrAEs are becoming more common due to the widespread use of ICIs. For this reason, it is crucial to diagnose and treat rare IrAEs, such as digital ischemia, as early as possible to improve outcomes.

Immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 inhibitors, have become the standard of care for many cancer types. However, they induce immune-related adverse events (irAEs), including neurotoxicity and hypophysitis. The incidence and outcomes of neurotoxicity and hypophysitis in patients treated with immune checkpoint inhibitors are not well established. We conducted a retrospective study of 812 patients with solid cancers who received immune checkpoint inhibitors at the University General Hospital of Ioannina between January 2018 and January 2023. We assessed demographic and clinical data, including the severity of symptoms, treatment regimen, other irAEs, resolution type and time, and death. Two patients experienced neurotoxicity and two hypophysitis. All four patients required inpatient administration and received corticosteroids or/and hormone replacement. Three patients responded to the initial therapy, experiencing full recovery, while one patient was corticosteroid-resistant, and immunoglobin G was administered. Two patients never received immunotherapy after their toxicity due to the severity of symptoms; one patient continued monotherapy with nivolumab, changing from combination therapy with ipilimumab–nivolumab, while the fourth patient continued his initial treatment with nivolumab. Our study suggests that the incidence of neurotoxicity and hypophysitis in patients treated with immune checkpoint inhibitors is low, but careful monitoring and prompt treatment with corticosteroids are necessary for effective management.

Tumor-infiltrating lymphocytes (TILs) contribute to breast cancer (BC) prognosis. We investigated the prognostic impact of CD8+ TILs in patients with early breast cancer treated with adjuvant chemotherapy in a large observational clinical trial. Along with a 10 year follow-up, considering the efficacy and safety, we report the results of the translational part of our study. We examined the patients’ tumors for total (t), stromal (s), and intratumoral (i) CD8 lymphocyte density (counts/mm²) on tissue-microarray cores. The impact of CD8+ TILs counts on DFS and OS, and its correlation with breast cancer subtypes and standard clinicopathological parameters, were investigated, along with efficacy and safety data. Among the 928 eligible patients, 627 had available CD8+ data. Of which, 24.9% had a high expression of sCD8, iCD8, and total CD8, which were correlated with higher Ki67, TILs density, ER/PgR negativity, and higher histological grade. The 5year DFS and OS rates were 86.1% and 91.4%, respectively. Patients with high iCD8 and tCD8 had longer DFS and OS compared to those with low counts/mm² (DFS: HR = 0.58, p = 0.011 and HR = 0.65, p = 0.034 and OS: HR = 0.63, p = 0.043 and HR = 0.58, p = 0.020, respectively). Upon adjustment for clinicopathological parameters, iCD8 and tCD8 retained their favorable prognostic significance for DFS and OS, whereas high sCD8 was only prognostic for DFS. Menopausal status, tumor size, and nodal status retained their prognostic significance in all examined multivariate models. CD8+ TILs, and especially their intratumoral subset, represent a potential favorable prognostic factor in early BC.

The detection of actionable mutations in tumor tissue is a prerequisite for treatment customization in patients with metastatic colorectal cancer (mCRC). Analysis of circulating tumor DNA (ctDNA) for the identification of such mutations in patients’ plasma is an attractive alternative to invasive tissue biopsies. Despite having the high analytical sensitivity required for ctDNA analysis, digital polymerase chain reaction (dPCR) technologies can only detect a very limited number of hotspot mutations, whilst a broader mutation panel is currently needed for clinical decision making. Recent advances in next-generation sequencing (NGS) have led to high-sensitivity platforms that allow screening of multiple genes at a single assay. Our goal was to develop a small, cost- and time-effective NGS gene panel that could be easily integrated in the day-to-day clinical routine in the management of patients with mCRC. We designed a targeted panel comprising hotspots in six clinically relevant genes (KRAS, NRAS, MET, BRAF, ERBB2 and EGFR) and validated it in a total of 68 samples from 30 patients at diagnosis, first and second disease progression. Results from our NGS panel were compared against plasma testing with BEAMing dPCR regarding the RAS gene status. The overall percent of agreement was 83.6%, with a positive and negative percent agreement of 74.3% and 96.2%, respectively. Further comparison of plasma NGS with standard tissue testing used in the clinic showed an overall percent agreement of 86.7% for RAS status, with a positive and negative percent agreement of 81.2% and 92.8%, respectively. Thus, our study strongly supports the validity and efficiency of an affordable targeted NGS panel for the detection of clinically relevant mutations in patients with mCRC.

Gastric cancer is the fifth most common neoplasm worldwide with high rates of mortality. Afatinib, a low molecular, irreversible potent inhibitor of ErbB trans-membrane receptor family, has shown p...