Search Results (1,312)

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies. Full article

Objectives: Pediatric nasopharyngeal carcinoma (NPC) is rare and often presents at an advanced stage. Although multimodal treatment can achieve favorable survival, long-term survivors may experience substantial treatment-related morbidity. We aimed to evaluate survival outcomes according to stage and metastatic status and to characterize late toxicity in a 20-year single-center pediatric NPC series. Methods. We retrospectively reviewed 24 pediatric patients diagnosed with NPC between 2003 and 2023. Histology was classified according to WHO criteria, and tumors were staged using the AJCC TNM system. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan–Meier method. Survival distributions were compared using the log-rank test. Late treatment-related toxicities documented during follow-up were recorded descriptively. Results: Twenty-four patients with WHO type III NPC were included. Fourteen patients had stage III disease and 10 had stage IV disease; three had distant metastasis at diagnosis. The median follow-up duration was 50.5 months. At last follow-up, 19 patients were alive and five had died. The estimated 5- and 10-year OS rates were both 72.7%, and the corresponding EFS rates were both 63.7%. Stage IV disease and metastatic presentation were associated with inferior OS. Dysphagia, malnutrition, xerostomia, fibrosis, hypothyroidism, and deafness were the most frequently recorded adverse health effects. Conclusions: This 20-year single-center experience shows that AJCC stage and metastatic status remain key determinants of survival in pediatric NPC. The high burden of late treatment-related complications highlights the importance of integrating long-term multidisciplinary survivorship surveillance into the care of pediatric NPC survivors. Full article

(1) Background: Reactive oxygen species (ROS) act as physiological signaling mediators but contribute to oxidative damage, cellular dysfunction, and age-related disease when redox homeostasis fails. Forkhead box O4 (FOXO4) has emerged as a redox-sensitive regulator linking stress adaptation, antioxidant defense, and cellular senescence. This structured narrative review critically evaluates which redox- and aging-related conclusions are supported directly for FOXO4 and which remain inferred from other FOXO isoforms. (2) Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched from inception to May 2026; Google Scholar was used only for supplementary citation tracking and did not contribute a separate platform-level count. Of 420 records, 300 remained after deduplication, 110 full texts were assessed, and 89 publications were retained. FOXO4-related evidence was classified as directly FOXO4-specific (n = 18), FOXO-family/conserved (n = 24), or extrapolated predominantly from FOXO1/FOXO3/DAF-16 (n = 20); 27 contextual publications on redox biology, senescence, disease, and NRF2 were tracked separately. (3) Results: The strongest FOXO4-specific evidence supports three mechanistic axes: cysteine-dependent redox sensing, stress-regulated nuclear trafficking and coactivator engagement through transportin-1 and p300/CBP, and FOXO4–p53-mediated survival of senescent cells. By contrast, direct FOXO4 regulation of commonly cited antioxidant targets, including SOD2, catalase, sestrins, and GADD45, remains insufficiently demonstrated and is inferred mainly from FOXO3 or broader FOXO-family studies. FOXO4-DRI has shown senolytic activity in preclinical models, including vascular endothelium, but has not been clinically validated. (4) Conclusions: FOXO4 is a redox-responsive transcriptional regulator with well-supported roles in cysteine-based signaling and senescent-cell survival, whereas its target-gene-level antioxidant program remains incompletely resolved. Clinical translation of FOXO4–p53 disruption requires isoform- and tissue-specific validation, pharmacokinetic and delivery studies, long-term toxicology, and explicit assessment of p53-dependent tumor surveillance. Full article

Background/Objectives: Non-muscle invasive bladder cancer (NMIBC) is characterized by high recurrence rates despite appropriate treatment and surveillance. Identifying inexpensive and readily available biomarkers capable of improving risk stratification remains an important clinical challenge. The platelet-to-lymphocyte ratio (PLR), a marker of systemic inflammation, has emerged as a potential prognostic indicator in several malignancies. This study aimed to evaluate the association between preoperative PLR, tumor recurrence, and recurrence-free survival (RFS) in NMIBC patients treated with intravesical Bacillus Calmette–Guérin (BCG) or thermochemotherapy. Methods: This retrospective study included 153 patients diagnosed with NMIBC between January 2020 and January 2024. All patients underwent transurethral resection of bladder tumor (TURBT) followed by intravesical BCG (n = 123) or thermochemotherapy (n = 30). Preoperative PLR was calculated from complete blood counts obtained before surgery. Receiver operating characteristic (ROC) analysis was used to determine the optimal PLR cut-off value. Recurrence-free survival was evaluated using Kaplan–Meier survival analysis and Cox proportional hazards regression models. Results: During a mean follow-up period of approximately 19 months, recurrence was observed in 35.8% of patients treated with BCG and 30% of those treated with thermochemotherapy. ROC analysis demonstrated good discriminatory ability for recurrence prediction (AUC = 0.831, 95% CI: 0.761–0.901, p < 0.001) and identified an optimal PLR threshold of 120. Patients with elevated PLR values demonstrated higher recurrence rates and shorter recurrence-free survival. Kaplan–Meier analysis revealed a clear separation of survival curves according to PLR status. In multivariable Cox regression analysis, PLR > 120 remained independently associated with recurrence-free survival in the BCG group (HR = 2.703, 95% CI: 1.118–6.534, p = 0.027), whereas only a borderline association was observed in the thermochemotherapy group (HR = 23.265, 95% CI: 0.952–568.336, p = 0.054). Conclusions: Elevated preoperative PLR was associated with recurrence and recurrence-free survival in patients with NMIBC. The prognostic value of PLR appeared to be more pronounced in patients receiving intravesical BCG therapy. Given its low cost, accessibility, and ease of calculation, PLR may serve as a useful adjunctive biomarker for clinical risk stratification when used alongside established clinicopathological prognostic factors. Further prospective multicenter studies are required to validate these findings. Full article

Background and Clinical Significance: Cutaneous squamous cell carcinoma (CSCC) is a common non-melanoma skin cancer, and while most cases are curable, a small proportion progresses to locally advanced or metastatic disease. As neoadjuvant immunotherapy with PD-1 inhibitors such as cemiplimab becomes more widely adopted, understanding real-world patterns of response remains essential. Case Presentation: We report a case of a man in his 50s with a large, locally advanced CSCC of the left hand in whom neoadjuvant cemiplimab was chosen to reduce tumor burden and preserve hand function when margin-negative resection was unlikely. The patient received four cycles of cemiplimab and demonstrated marked clinical improvement followed by complete pathological response at the primary site upon wide local excision. However, metastatic involvement of the epitrochlear and axillary lymph nodes was identified at surgery despite initial benign imaging. Postoperative PET/CT showed no additional disease, and the patient subsequently underwent axillary dissection and adjuvant cemiplimab with good functional recovery. Conclusions: This case highlights the potential for neoadjuvant cemiplimab to achieve substantial local tumor control and functional preservation while emphasizing the need for careful nodal assessment and ongoing surveillance in patients with very-high-risk CSCC. In cases where baseline cross-sectional staging is not performed, pre-existing occult nodal disease cannot be excluded. Full article

Neurofibromatosis type 1 (NF1) is a genetic tumor predisposition syndrome characterized by a substantial risk of developing peripheral nerve sheath tumors, including malignant peripheral nerve sheath tumors (MPNSTs), which occur in 8–13% of patients. Approximately 50% arise from plexiform neurofibromas (PNs) and 40% develop de novo, making them a major cause of premature mortality. Current clinical management is limited by the intrinsic shortcomings of standard imaging modalities: magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT), and tissue biopsy in distinguishing benign PNs from early malignant transformation, which remains a major clinical challenge. This progression follows a stepwise molecular continuum marked by cumulative genetic alterations and widespread epigenetic dysregulation. In this setting, liquid biopsy has emerged as a promising non-invasive approach to help fill these diagnostic gaps by enabling real-time molecular monitoring through the analysis of circulating tumor DNA (ctDNA) and other blood-based biomarkers. This review examines the current evidence supporting liquid biopsy applications in NF1 management, including early detection of MPNST, discrimination between benign and malignant lesions, mutational profiling for therapeutic targeting, and disease monitoring before and during treatment. We also discuss the current evidence on fragmentomics, methylomics and driver mutation profiling as tools to distinguish PNs from MPNSTs. Recent evidence suggests that liquid biopsy may help detect molecular changes associated with malignant transformation before clear clinical signs emerge, potentially opening an important window for intervention and supporting a shift towards a more molecularly informed surveillance model. Finally, this review considers the possible extension of liquid biopsy to other tumor types, including NF1-deficient breast cancer, and outlines a future management framework aimed at improving early diagnosis and personalized therapeutic intervention in this high-risk population. Full article

Background/Objectives: Breast cancer is the most commonly diagnosed malignancy among women, with hormone receptor-positive tumors representing the majority of cases. Increasing survival rates have shifted attention toward long-term complications, including the risk of secondary malignancies. Emerging evidence suggests a potential association between breast cancer and gastrointestinal (GI) neoplasia. This study aimed to evaluate the role of colonoscopic and upper gastrointestinal endoscopic monitoring in patients with ER/PR-positive breast cancer and to assess its potential value in the early detection of digestive lesions. Methods: We conducted a prospective observational study including 186 female patients with histologically confirmed ER/PR-positive breast cancer. A total of 95 patients underwent colonoscopy, and 91 patients underwent upper gastrointestinal endoscopy. Clinical, demographic, and risk factor data were collected. A structured questionnaire was used to assess gastrointestinal symptoms. Endoscopic findings, lesion characteristics, and histopathological results were recorded. Bowel preparation quality was assessed using the Boston Bowel Preparation Scale. Results: Colonoscopy identified polyps and other lesions, with the majority located in the rectum and descending colon. A total of 12 biopsies were performed, revealing 1 malignant lesion, 2 borderline lesions, and the remainder benign. Upper gastrointestinal endoscopy showed gastritis as the most frequent finding, followed by gastric ulcers and polyps, while most patients had normal endoscopic results. Overall, 72% of patients presented at least one risk factor for digestive malignancy. Following treatment, most patients reported improvement in gastrointestinal symptoms. Conclusions: Patients with ER/PR-positive breast cancer may present a higher prevalence of gastrointestinal lesions, potentially related to shared risk factors and the systemic effects of endocrine therapy. Targeted, symptom-oriented endoscopic evaluation may facilitate early detection of premalignant and malignant digestive conditions. A multidisciplinary, risk-adapted surveillance approach should be considered to improve patient outcomes. Further large-scale studies are required to establish evidence-based screening strategies in this population. Full article

Background: Cancer-associated thrombosis is a major complication in pancreatic cancer; however, its true burden and prognostic significance remain unclear, largely owing to under-detection of asymptomatic events. In addition, the clinical relevance of cancer-related hypercoagulability and neutrophil extracellular traps (NETs), which may link thrombosis and tumor biology, has not been adequately evaluated in advanced pancreatic cancer. Methods: In this prospective study, newly diagnosed patients with unresectable pancreatic ductal adenocarcinoma underwent systematic screening for venous thromboembolism (VTE) at baseline, followed by longitudinal surveillance. Circulating coagulation markers and NET-related biomarkers were analyzed. Associations among VTE, hypercoagulability, NET-related biomarkers, and overall survival (OS) were evaluated. Results: Among 134 patients, VTE was detected at diagnosis in 28.4%, with the majority being asymptomatic. Hypercoagulability and NET-related biomarkers were significantly associated with VTE occurrence. Patients with baseline VTE (6.2 vs. 12.1 months, p = 0.002) and hypercoagulability (7.7 vs. 15.2 months, p = 0.002) demonstrated shorter OS. In multivariate analysis, hypercoagulability, but not baseline VTE, remained independently associated with inferior OS (hazard ratio 2.03, 95% confidence interval 1.27–3.27). Notably, the adverse prognostic impact of hypercoagulability was consistently observed across nearly all predefined clinical subgroups. Furthermore, a reduction in or normalization of D-dimer levels following anticoagulant therapy was associated with prolonged survival. Conclusions: Hypercoagulability, rather than overt thrombotic events, independently predicts survival outcomes in advanced pancreatic cancer. These findings support a biology-driven approach to thrombosis assessment and indicate that monitoring and therapeutic modulation of hypercoagulability may improve risk stratification and clinical management in this population. Full article

Background: Cutaneous squamous cell carcinoma (cSCC) is commonly regarded as a sporadic malignancy primarily driven by ultraviolet exposure. However, the occurrence of multiple, aggressive tumors at a relatively young age suggests the presence of underlying genetic susceptibility. The role of germline variants affecting extracellular matrix organization, pigmentation pathways, and tumor metabolism in aggressive cSCC remains incompletely understood. Case Presentation: We describe a 53-year-old patient with a long-standing history of multiple aggressive cutaneous squamous cell carcinomas involving the scalp and facial regions, characterized by recurrent and multifocal disease. A comprehensive diagnostic approach was undertaken, including histopathological examination, fluorescence confocal microscopy, high-frequency cutaneous ultrasound, and genetic analysis using whole-exome sequencing (WES). Results: Histopathology confirmed high-risk features consistent with aggressive cSCC. Cutaneous ultrasound and fluorescence confocal microscopy provided complementary, non-invasive insights into tumor depth, architecture, and invasive patterns. Whole-exome sequencing identified a heterozygous truncating variant in COL6A3 (NM_004369.4:c.5645C>A, p.Ser1882Ter), classified as likely pathogenic according to ACMG criteria. Additionally, two heterozygous variants of uncertain significance were detected in TYR (NM_000372.5:c.1569C>A, p.Ser523Arg) and FH (NM_000143.4:c.1237-5_1237-4insTCTCCCTCCCTC). Although individually inconclusive, the combined germline genetic background may have contributed to the patient’s aggressive and multifocal cutaneous phenotype. Discussion: This case report supports a potential role of extracellular matrix remodeling, pigmentation-related susceptibility, and metabolic dysregulation in cutaneous carcinogenesis and tumor aggressiveness. This case illustrates how integrating WES with advanced non-invasive imaging techniques can enhance the understanding of biologically aggressive cSCC. Conclusions: This report highlights a unique case of multifocal aggressive cSCC characterized by a distinct germline genetic profile identified by WES and multimodal imaging assessment. Comprehensive molecular and imaging evaluation may be beneficial in selected patients with atypical or aggressive cutaneous squamous cell carcinoma, with implications for personalized surveillance and management. Full article

Background: MGMT-methylated glioblastomas respond well to temozolomide-based standard of care (Stupp protocol), demonstrate longer survival as compared to unmethylated tumors, and carry an increased risk of pseudo-progression. Establishing time to first true progression can serve as a non-invasive clinical reference point to distinguish true from pseudo-progression. Objective: To define the time to first true progression in patients with MGMT-methylated glioblastoma who were treated with the standard of care/Stupp protocol. Methods: We conducted a retrospective analysis from our institutional database of MGMT-methylated glioblastoma patients from 2018–2024. Time to first progression was measured from initial surgery to first true progression, as determined by a multidisciplinary team based on radiographic imaging review and/or pathology. Results: Fifteen patients met eligibility criteria. Median time to first progression of MGMT-methylated glioblastoma patients who received standard of care was twenty-one months. 40% of patients remained progression-free beyond thirty-six months after their initial surgery. Conclusions: Most patients with MGMT-methylated glioblastomas do not develop true progression within the first year and a half post-operatively. Therefore, MRI changes on surveillance scans should be carefully interpreted within this time frame. Expected timeline for true progression, alongside advanced radiographic imaging techniques and knowledge of treatment-specific pseudo-progression risk, may improve diagnostic accuracy. Full article

Background/Objectives: Duodenal epithelial neoplasms are rare; however, the widespread use of surveillance endoscopy and advances in endoscopic imaging technology have increased their incidental detection. Owing to their rarity, the clinicopathological characteristics and natural course of duodenal epithelial neoplasms have not been thoroughly investigated. In this study, we aimed to clarify the genomic profile and clinicopathological characteristics of duodenal epithelial neoplasms. Methods: A total of 158 patients with duodenal epithelial neoplasms were enrolled. Comprehensive genomic profiling and immunohistochemical staining were performed. Immunophenotypes were categorized as gastric type (G-type), gastrointestinal type (GI-type), or intestinal type (I-type). The detection rate of potentially actionable genomic alterations and a high tumor mutational burden (TMB-H ≥ 10 Muts/Mb) were evaluated and compared across tumor types. Results: The median size of adenocarcinomas was larger than that of adenomas (p = 0.002). The age at diagnosis of G-type tumors was higher than that for the other two tumor types (p < 0.001). The median size of I-type tumors was smaller than that of the other two tumor types (p = 0.019). Compared with the other two types, G-type tumors were predominantly located in the superior region (p < 0.001), were macroscopic Type I (p = 0.002), and had significantly higher genomic alteration rates for KRAS (p < 0.001), GNAS (p < 0.001), CDKN2A (p = 0.004), and MDM2 (p < 0.001). Eighteen patients showed TMB-H. Conclusions: TMB-H was observed in >10% duodenal tumors. Additionally, the pathogenesis of G-type duodenal tumors differs from that of other immunophenotypic tumors. These findings could help in understanding the genomic profiles of duodenal tumors and in selecting treatment options. Full article

Background: Papillary thyroid carcinoma (PTC) is typically associated with an excellent prognosis, and distant metastases are uncommon. When present, metastases most frequently involve the lungs and bones, while intra-abdominal dissemination is exceedingly rare and poorly characterized. The optimal management of such atypical metastatic patterns, particularly the role of surgery, remains undefined. Case Presentation: A 69-year-old female presented eight years after total thyroidectomy, cervical lymph node dissection, and radioactive iodine therapy for PTC with progressive abdominal pain, nausea, vomiting, and painful abdominal wall and bilateral inguinal masses. Imaging demonstrated extensive metastatic disease involving the anterior abdominal wall, gastrohepatic ligament, pelvis, retroperitoneum, diaphragm, urinary bladder, uterus, and inguinal lymph nodes, which was confirmed on biopsy as metastatic PTC. Serum thyroglobulin was markedly elevated at 473 µg/L. Given the bulky, symptomatic, and progressive disease refractory to prior radioactive iodine therapy, a multidisciplinary tumor board recommended cytoreductive surgery with palliative intent. The patient underwent resection of eleven major metastatic deposits over five hours without intraoperative complications, achieving complete macroscopic clearance of intra-abdominal disease. Histopathology confirmed metastatic PTC in all specimens. Postoperative serum thyroglobulin declined to 107 µg/L following surgery and adjuvant radioactive iodine therapy, and the patient reported complete resolution of abdominal symptoms at follow-up. Conclusions: This case highlights the potential role of cytoreductive surgery as a palliative strategy in carefully selected patients with advanced intra-abdominal metastatic PTC. Such rare presentations underscore the importance of long-term surveillance and multidisciplinary decision-making. Further case accumulation is needed to better define optimal management strategies and patient selection criteria in this setting. Full article

Obesity is increasingly recognized as a complex systemic disorder rather than a simple consequence of excess energy intake and fat accumulation. This review presents a systems biology framework that examines how obesity-driven disruption of inter-organ communication networks contributes to chronic disease susceptibility, with particular emphasis on colorectal cancer (CRC). Disrupted signaling among the brain, adipose tissue, liver, skeletal muscle, gut, and immune system generates maladaptive feedback loops that promote chronic metabolic inflammation (metaflammation), loss of physiological resilience, and progressive metabolic dysfunction. Within this framework, obesity is redefined as a network disease characterized by neuroendocrine dysregulation, adipose tissue remodeling, immune dysfunction, impaired organ crosstalk, and alterations in the gut microbiome. A central feature of this dysregulation is persistent low-grade inflammation driven by immune-metabolic reprogramming and sustained activation of inflammatory pathways. Obesity-associated metaflammation is further linked to accelerated biological aging through mechanisms involving cellular senescence, mitochondrial dysfunction, oxidative stress, and impaired metabolic resilience. These interconnected processes create a tumor-promoting environment by enhancing oncogenic signaling, disrupting intestinal barrier integrity, altering microbial and metabolic signaling, impairing immune surveillance, and promoting epithelial dysfunction, thereby increasing susceptibility to CRC. The review also examines how behavioral, circadian, environmental, and socioeconomic factors influence metabolic health and cancer risk. Finally, emerging translational opportunities, including biomarker-guided risk stratification, precision prevention, metabolic network restoration, and integrative lifestyle and pharmacological interventions, are discussed. Collectively, this review reframes obesity as a whole-body regulatory disorder and provides an integrated conceptual framework linking metabolism, inflammation, aging, and colorectal carcinogenesis to inform future prevention and therapeutic strategies. Full article

Background/Objectives: Tumor-infiltrating lymphocyte (TIL) therapy is an important option for patients with metastatic melanoma progressing after standard systemic therapy, but real-world data on treatment delivery, toxicity monitoring, and immune recovery remain limited. We evaluated clinical outcomes, treatment tolerance, immune reconstitution, and cardiac biomarker dynamics across three Mayo Clinic sites. Methods: We retrospectively analyzed adults with metastatic melanoma who received lymphodepleting chemotherapy followed by TIL infusion and high-dose interleukin-2 (IL-2) between April 2024 and December 2025. Clinical outcomes, treatment delivery, and adverse events were assessed. Longitudinal immune monitoring included CD4 and CD8 T-cell counts, CD4:CD8 ratio, and immunoglobulin G (IgG) at baseline and follow-up. In a prespecified cardiac sub-cohort, high-sensitivity troponin (hs-Tn) was measured during IL-2 administration to evaluate associations with cardiac events and IL-2 interruption. Results: Thirty-six patients underwent TIL infusion. The objective response rate was 50.0%, including complete responses in 13.9%, and the disease control rate was 72.2%. Median progression-free survival was 3.61 months, and median overall survival was 12.94 months. M1d disease was associated with inferior overall survival on univariable analysis (HR 6.55, 95% CI 2.03–21.17; p = 0.002), with attenuation after multivariable adjustment. Receipt of ≥3 IL-2 doses was associated with longer overall survival on univariable analysis (HR 0.20, 95% CI 0.06–0.64; p = 0.007), but this association also attenuated after adjustment. Longitudinal immune monitoring demonstrated persistent CD4 lymphopenia through 6 months, sustained inversion of the CD4:CD8 ratio, and declining IgG at months 3 and 6. In the cardiac sub-cohort (24 patients; 87 IL-2 doses), post-dose hs-Tn ≥15 ng/L was associated with clinically significant cardiac events (OR 9.6, 95% CI 1.5–60.6; p = 0.016) and IL-2 interruption (OR 3.4, 95% CI 1.1–10.7; p = 0.036). For cardiac events, hs-Tn ≥15 ng/L had 100% sensitivity and 100% negative predictive value. Conclusions: In routine practice, TIL therapy was feasible and active in metastatic melanoma. M1d disease identified a subgroup with poor survival, peri-dose hs-Tn showed promise as a tool to support safer IL-2 delivery, and prolonged CD4 suppression with IgG decline suggests that recovery after TIL therapy extends beyond initial hematologic reconstitution. These findings support prospective validation of biomarker-guided IL-2 monitoring and extended post-treatment immune surveillance. Full article

Background/Objectives: Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with a 40% recurrence rate. However, reliable biomarkers for early recurrence detection or treatment guidance are lacking, especially for virus-negative tumors. Circulating tumor DNA (ctDNA), a fragment of tumor-derived cell-free DNA in blood, has emerged across multiple cancers as a minimally invasive precision biomarker to detect minimal residual disease (MRD); predict recurrence; and monitor treatment response. This review’s objective was to summarize recent advances in ctDNA as a tool for therapeutic decision-making in MCC, contextualized by findings in other malignancies. Methods: A comprehensive literature review was performed, focusing on studies published between 2016 and 2026 that evaluate ctDNA in MCC and other cancers. Key prospective trials, observational studies, and case reports were identified through PubMed and relevant conference proceedings. Data on ctDNA assay methods (tumor-informed vs. tumor-agnostic), clinical sensitivity, lead time for recurrence detection, and predictive value for therapy response were extracted and synthesized. Results: Across cancers such as colorectal, lung, and melanoma, ctDNA positivity after curative treatment predicts relapse months in advance of imaging and can guide adjuvant therapy decisions. In MCC, recent studies demonstrate that ctDNA levels correlate with MCC tumor burden and exhibit high sensitivity and specificity for clinically evident disease. Stage I-III MCC patients who were ctDNA-positive within four months of treatment had a 7.4-fold higher recurrence risk within the subsequent 12–18 months of follow-up. Serial ctDNA monitoring may enable earlier intervention in otherwise asymptomatic ctDNA-positive MCC cases, helping distinguish responders from non-responders. Conclusions: ctDNA is an emerging precision biomarker that offers significant prognostic and surveillance utility in MCC. It enables earlier detection of recurrence, potentially allowing treatment to begin before clinical disease manifests. It also helps stratify patients by risk and treatment response, informing personalized surveillance intensity and therapeutic choices. Integrating ctDNA monitoring into MCC management could improve outcomes by guiding timely interventions, although prospective trials are needed to confirm that ctDNA-guided decisions translate to improved patient survival. Formal cost-effectiveness analyses have not yet been conducted and represent an important area for future investigation. Full article