Search Results (14,183)

Background: Dislocations and fracture-dislocations of the lower cervical spine represent complex injuries with a high risk of neurological damage. Especially in the presence of a confirmed traumatic disc lesion, an anterior surgical approach is described as favoured in the literature. However, studies show that with sufficient reduction technique, even in the presence of a confirmed disc protrusion, posterior stabilization can be considered a safe therapeutic option. The aim of this study is to analyze anterior and posterior treatment of dislocations and fracture-dislocations of the subaxial cervical spine with regard to neurological and radiological outcomes. Methods: In our monocentric cohort study, we investigated the immediate postoperative radiological and neurological outcome depending on the chosen surgical approach and the presence of a disc protrusion. Patients treated at our centre between January 2005 and June 2025 were included. Patients with preoperative complete spinal cord injury were excluded. Neurological status was assessed using the ASIA score preoperatively at admission and postoperatively at discharge or prior to staged surgery. Results: A total of 92 patients were included in the study. Most patients showed an ASIA score C (33.7%). A total of 49 patients (53.3%) were operated anteriorly and 42 patients (45.6%) posteriorly. One patient was primarily stabilized bilaterally. Nine patients initially treated anteriorly had to be secondarily stabilized additionally from posterior. In both groups, neurological deterioration occurred in one case. All other patients remained stable on the ASIA score or improved by at least one point on the scale. Conclusions: The findings provide evidence in favour of a personalized, pathology-oriented approach to lower cervical spine fracture-dislocations rather than selecting the surgical approach based solely on the presence of traumatic disc protrusion. Further prospective studies are needed to validate these observations. Full article

Background/Objectives: Spontaneous intracranial hypotension (SIH) is a functionally limiting condition caused by cerebrospinal fluid leakage. This study aims to evaluate the clinical outcomes of surgical management based on precise leak localization and to describe the characteristics of a surgically treated SIH cohort. Methods: We enrolled 23 patients who underwent surgical treatment for SIH between March 2024 and November 2025. Clinical outcomes included maximum headache severity and total daily upright hours. Radiologic outcomes were evaluated using the Bern score and the resolution of spinal extradural fluid at 2 months postoperatively. Results: The cohort comprised 19 patients (82.6%) with Type 1 and four patients (17.4%) with Type 3 leak. Exploratory subgroup analyses suggested that patients with Type 3 leak were significantly older (mean 65.3 vs. 38.2 years, p < 0.01) with lower thoracic leak (p = 0.02) compared to Type 1 patients. In the 20 patients who completed follow-up, significant improvements were observed in maximum headache intensity (Numeric Rating Scale 4.6 to 1.4, p < 0.01), daily upright time (3 to 12 h, p < 0.01), and Bern score (3.4 to 0.9, p < 0.01). Postoperative rebound headache occurred in 52.2% of patients. Complete resolution of spinal epidural fluid was achieved in 87.5% of Type 1 patients and normalization of the Bern score was achieved in all Type 3 patients. Conclusions: Surgical intervention based on precise leak localization offers substantial clinical and radiological benefits for SIH patients refractory to conservative management. These findings support a treatment-oriented approach based on precise leak localization in patients with SIH. Full article

Background: Predicting long-term outcomes after pulmonary metastasectomy for colorectal cancer remains challenging because existing prognostic methods lack precision. We developed and validated a prognostic scoring system derived from a major international meta-analysis to improve risk stratification and to evaluate the benefit of adjuvant chemotherapy across risk groups. Methods: Using a Japanese registry of 819 patients who underwent lung resection between 2010 and 2019, we constructed a 0–13-point score based on eight variables including tumor size, number, biological markers, and intrathoracic lymph node status, which may require intraoperative or pathological confirmation. Granular data on chemotherapy regimens, timing, and duration were unavailable. Patients were classified as low, intermediate, or high risk. The primary analysis used inverse probability of treatment weighting to adjust for baseline imbalances; however, only 819 of 1657 patients (49.4%) had complete prognostic data, introducing potential selection bias. Results: The score separated patients into three groups with distinct five-year survival rates: 81.1% (low), 67.8% (intermediate), and 59.1% (high). In high-risk patients, chemotherapy was associated with improved overall survival but did not delay recurrence. In low-risk patients, chemotherapy correlated with reduced recurrence-free survival, a finding that persisted after adjustment. Conclusions: This validated scoring system aids individualized surgical decision making by identifying patients unlikely to benefit from routine postoperative chemotherapy. Observed survival advantages in high-risk patients may reflect selection of fitter individuals rather than direct treatment effects, underscoring the need to address selection bias in future trials. Full article

Coronary artery anomalies (CAAs) are a rare but clinically significant group of congenital abnormalities that are associated with myocardial ischaemia, malignant arrhythmias and sudden cardiac death, particularly in young people and athletes. Despite increasing recognition of these conditions and advances in cardiovascular imaging, there are still significant challenges regarding their classification, risk stratification and management, particularly with respect to surgical indications. This review provides a comprehensive overview of the current evidence on the classification, pathophysiology, diagnosis and management of CAAs, with a particular focus on surgical decision-making and contemporary guideline recommendations. A systematic literature search was conducted up to February 2025 using PubMed and Google Scholar. Priority was given to international guidelines, consensus statements, systematic reviews, meta-analyses and large observational studies. CAAs encompass a broad spectrum of anatomical variants and clinical presentations. Among these, anomalies of coronary origin are the most extensively studied. Surgical management is well established for coronary arteries arising from the pulmonary artery, particularly for anomalous left coronary artery from the pulmonary artery (ALCAPA). Substantial advances have also been made in the diagnosis, risk stratification, and treatment of anomalous aortic origin of a coronary artery (AAOCA), which has become a major focus of contemporary guideline recommendations. For patients with AAOCA, surgical correction, including unroofing, coronary reimplantation or coronary artery bypass grafting, is recommended for individuals with symptoms and/or high-risk anatomical features. In contrast, the diagnosis and management of myocardial bridging, coronary artery fistulas, and coronary artery ectasia remain controversial, with considerable variability in the indications for medical, percutaneous, and surgical treatment. The management of CAAs is an evolving field. While there is consensus for a limited number of anomalies, most cases still require individualised decision-making. It is essential to develop standardised diagnostic frameworks, improved risk stratification tools and outcome-based management criteria. A multidisciplinary, evidence-based approach involving cardiologists, cardiac imagers, interventional cardiologists and cardiac surgeons is crucial in order to optimise patient outcomes and reduce the risk of adverse cardiovascular events, including sudden cardiac death. Full article

Chronic pain is increasingly understood as a multidimensional condition in which, in a substantial subgroup of patients, a protective symptom can evolve into a persistent maladaptive disorder of the nervous system, while in others it may remain closely tied to ongoing mechanical or structural factors. Central sensitization (CS) represents a key mechanism underlying this transition, characterized by enhanced neural responsiveness and impaired endogenous pain inhibition, leading to a dissociation between pain and tissue pathology. The aim of this narrative review is to critically discuss current evidence on CS as a mechanism-based explanation for persistent pain, using lumbar disk herniation (LDH) as a clinical model of the radiological-clinical mismatch, and to discuss its direct implications for identifying sensitized phenotypes, multimodal assessment, and rehabilitation strategies. A total of 77 sources published between 2006 and 2026 were synthesized. These reviewed sources demonstrate that identification of the sensitized phenotype requires a multimodal assessment approach combining self-report measures, such as the Central Sensitization Inventory (CSI), with psychophysical methods including quantitative sensory testing (QST) and conditioned pain modulation (CPM). Cognitive-emotional factors are also critical, as postoperative kinesiophobia affects approximately 38.3% of LDH patients and is associated with increased pain intensity and reduced self-efficacy. Management strategies reported in these publications focus on mechanism-based interventions, particularly pain neuroscience education (PNE) and graded, time-contingent exercise, which aim to modify pain-related cognitions and restore endogenous inhibitory processes. These approaches may be supported by adjunctive therapies, including dry needling (DN), electro-dry needling (EDN), centrally acting pharmacological agents (e.g., serotonin–norepinephrine reuptake inhibitors [SNRIs] and gabapentinoids), and psychologically informed treatments such as cognitive behavioral therapy (CBT). While surgical decompression may reduce CS-related symptoms, preoperative sensitization does not necessarily predict poorer outcomes, highlighting the interaction between peripheral and central mechanisms. Adopting a sensitization-informed perspective may encourage a broader integration of contemporary pain models alongside traditional structural views in lumbar disc herniation clinical care. Full article

Objectives: Catamenial pneumothorax (CP) is a rare but clinically relevant cause of spontaneous pneumothorax (SP) in women and is associated with high recurrence rates. We hypothesized that CP is underrecognized in routine surgical practice due to an incomplete clinical assessment rather than an absence of characteristic intraoperative findings. Methods: We conducted a retrospective single-center analysis of all patients undergoing surgical treatment for pneumothorax between 2000 and 2025. Female patients with SP and no structural lung disease were identified and systematically evaluated for features suggestive of CP. Demographic, clinical, intraoperative, and outcome data were compared between patients with and without CP. Results: Among 4581 surgically treated pneumothoraces, 1253 (27.4%) occurred in women. Of these, 211 cases of SP without structural lung disease were analyzed. CP was identified in 15 cases among 14 patients (7.1%). Patients with CP were older at initial diagnosis (median 39 vs. 32 years; p = 0.0264) and exhibited higher recurrence rates (92.9% vs. 42.4%; p = 0.0003). A temporal association with menstruation was documented in 57.1% of CP cases, while in 35.7% no such assessment had been performed. Intraoperative findings suggestive of thoracic endometriosis were present in 85.7% of CP patients, whereas histological confirmation was achieved in only 14.3%. Conclusions: CP is likely underdiagnosed in surgical cohorts of women with SP. The principal diagnostic limitation appears to be incomplete history-taking rather than lack of intraoperative evidence. Given the high recurrence risk and limited efficacy of surgery alone, systematic assessment of menstrual association and interdisciplinary management are essential to optimize outcomes. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of antiresorptive and antiangiogenic therapies, and identifying specific risk factors for recurrence remains a significant clinical challenge. This study aimed to evaluate the clinical characteristics and independent risk factors for recurrence in a large-scale cohort of MRONJ patients. Methods: This single-center retrospective study analyzed 812 patients diagnosed with MRONJ according to the 2022 AAOMS criteria at Chosun University Dental Hospital between 2020 and 2024. Demographic, clinical, radiographic, and medication-related variables were collected. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors associated with recurrence. Results: The majority of patients were female (89.9%), with a mean age of 72.9 years, and mandibular involvement was most frequent (70.8%). Tooth extraction was the most common local precipitating factor (47.0%). The overall recurrence rate was 10.1%. Multivariate analysis identified bilateral jaw involvement (OR = 4.555, p = 0.006), mandibular ramus involvement (OR = 8.222, p = 0.008), and systemic liver disease (OR = 3.703, p = 0.037) as significant independent risk factors. Conversely, routes of prior antiresorptive medication administration involving intravenous-only or combined oral/intravenous therapy, as well as hyperlipidemia and a history of dental implant surgery, were associated with lower recurrence rates. Conclusions: Anatomical complexity and systemic health status are critical predictors of MRONJ recurrence. Patients presenting with bilateral or mandibular ramus involvement, or with compromised liver function, require more aggressive surgical debridement and individualized treatment planning to reduce the risk of recurrence. Given the small affected subgroups, the effect sizes for mandibular ramus involvement and liver disease should be interpreted with caution. Full article

Background: Para-aortic lymph node involvement is present in approximately 17–24% of women with locally advanced cervical cancer (LACC) and is one of the strongest adverse prognostic factors in this population. Current international guidelines recommend two alternative staging techniques: the International Federation of Gynecology and Obstetrics (FIGO) and European Society of Gynecologic Oncology (ESGO) endorse imaging-based staging as the primary method to define radiation fields, whereas the National Comprehensive Cancer Network (NCCN) lists pre-treatment minimally invasive para-aortic lymphadenectomy as a Category 2B recommendation. Objective: We aimed to review and critically appraise the available evidence on the oncologic impact (progression-free and overall survival) of pre-treatment surgical para-aortic staging compared with clinical imaging-based staging in women with LACC. Methods: We searched MEDLINE (Ovid), Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Scopus from inception to January 2026, complemented by manually searching the reference lists for relevant articles and prior reviews. The review focused on comparative studies of women with LACC of squamous, adenocarcinoma, or adenosquamous histology—operationally defined as FIGO 2009 stages IB2–IVA with pelvic nodal involvement or FIGO 2018 stages IB3–IVA who received definitive-intent radiotherapy with or without concurrent chemotherapy and brachytherapy, and for whom comparative survival outcomes between a surgical-staging arm and an imaging-staging arm were reported. For this manuscript, a narrative review style was planned and reported in line with SANRA (Scale for the Assessment of Narrative Review Articles) quality criteria. Results: Twelve studies were included: two randomized controlled trials and ten observational studies (nine retrospective cohorts and one population-based analysis). Surgical staging consistently increased detection of occult para-aortic disease and led to more frequent use of extended-field radiotherapy (18–44%), but it did not yield a reproducible advantage in terms of progression-free or overall survival over imaging-guided chemoradiation. Conclusions: In LACC, pre-treatment surgical para-aortic staging improves anatomic and prognostic information but has not shown a consistent survival advantage over imaging-based staging combined with contemporary chemoradiation. Current comparative evidence does not support routine surgical staging, and its use still warrants further prospective evaluation in large clinical trials. Until results from ongoing phase III trials are available, surgical staging should be considered an individualized option in highly selected cases within multidisciplinary decision-making at experienced clinical centers. Full article

Cranial cruciate ligament (CrCL) rupture in cats is less common than in dogs, and its optimal treatment remains a subject of debate. This study aimed to evaluate the application of cranial tibial wedge osteotomy (CTWO) as a dynamic stabilization technique in cats with CrCL rupture, describing the technical aspects and clinical outcomes obtained. Five cases with a confirmed diagnosis of CrCL rupture between 2020 and 2024 were included in this study. All patients were treated with CTWO using specific osteosynthesis locking plates designed for use in dogs and a complementary cerclage wire. Radiographic rechecks were performed at 8 and 12 weeks postoperatively, and clinical evaluations were performed 24 h, 8 weeks, 12 weeks, and 6 months postoperatively in every patient. Successful and complete bone healing of the tibial osteotomy was observed in every case. No intraoperative or postoperative complications related to implants or soft tissues were recorded. All cats achieved complete functional recovery without lameness at the last recheck six months after surgery. The technique was performed without significant technical difficulties, providing adequate stability and favorable clinical outcomes in all cases. These preliminary results support the use of CTWO as an effective surgical alternative for the treatment of CrCL rupture in cats. However, further studies with a larger number of cases and a longer follow-up are required to better evaluate its clinical application, outcomes, and influence on osteoarthritis progression in the long term. Full article

The annual congress of the Italian Association of Plastic Aesthetic Surgery (AICPE), with more than 700 members, represents one of the most relevant conference meetings in Europe relating to Aesthetic Plastic Surgery due to the number of participants and due to the faculty of invited speakers chosen for their renowned scientific value. The 13th meeting was held in Rome (Italy) from 10 to 12 April 2026. Key focus areas of the scientific program concerned breast (reduction, lifting supported or not by mesh, implant surfaces, augmentation), face and neck (lifting, blepharoplasty, malar implants, feminization), body (abdominoplasty and torsoplasty, post-partum and ex-obesity surgery, body and limb contouring, complication treatments) and nose surgery combined with medical innovations in energy devices, threads and aesthetic medicine procedures. Special attention was also given to the theme of the therapeutic role of aesthetic surgery, which is increasingly becoming an integral part of a clinical pathway useful for restoring the patient’s psycho-physical balance. Presented here is a report of the abstracts accepted due to their innovative or cutting-edge content that were selected to be given as oral presentations during the congress sessions. The 2nd edition of the Saccomanno memorial award for the best abstract presented by a young surgeon has been organized with the endorsement of Surgical Techniques Development by MDPI. Full article

Background/Objectives: This study aimed to evaluate the gingival crevicular fluid (GCF) levels of fractalkine/CX3CL1 and CX3CR1 in patients with gingivitis and periodontitis before and after non-surgical periodontal therapy. Methods: A total of 90 individuals comprising 30 with stage 3 periodontitis, 30 with gingivitis, and 30 periodontally healthy, were enrolled in the study. Gingivitis and periodontitis patients underwent non-surgical periodontal treatment. GCF samples were collected at baseline and at 1 and 3 months after treatment. CX3CL1 and CX3CR1 were measured by an ELISA analysis. Results: GCF CX3CL1 and CX3CR1 were significantly elevated in patients with periodontitis and gingivitis compared to healthy controls (p < 0.001). The periodontitis patients also showed higher GCF levels of CX3CL1 and CX3CR1 than those with gingivitis (p < 0.001). Significant decreases in GCF CX3CL1 and CX3CR1 were detected at 1 month after periodontal treatment compared to baseline values in both the gingivitis and periodontitis patients (p < 0.001). Moreover, the periodontitis patients exhibited significant decreases in both CX3CL1 and CX3CR1 levels at 3 months post-treatment compared to 1 month (p < 0.001), whereas no significant changes were observed between the two time points in the gingivitis patients (p > 0.05). Conclusions: Our findings suggest that the CX3CL1–CX3CR1 axis might contribute to the inflammatory processes of periodontal diseases and may represent a treatment-responsive component of the local host response. Full article

Background: Dedicated artificial intelligence (AI) systems for fracture detection already exist, yet general-purpose multimodal models are increasingly accessible to clinicians despite not being developed or formally validated as medical devices. Their behavior in focused orthopedic imaging tasks remains insufficiently characterized. Purpose: To characterize how two accessible general-purpose multimodal models interpret AP pelvis radiographs with hip fractures, focusing on context dependence, overconfidence, and complementary error patterns within a surgically confirmed positive-only cohort. This was a behavioral characterization study of a fracture-positive cohort, not a diagnostic accuracy evaluation. Methods: In April 2026, we retrospectively studied 214 surgically confirmed hip fractures on AP pelvis radiographs using two general-purpose multimodal models under six prompting conditions. In runs A–D, the models were explicitly told that a hip fracture was present and were asked to classify it; in runs E–F, they were not told whether a hip fracture was present. Each image was rerun de novo in a separate chat session through vendor APIs using a fixed base prompt and no image preprocessing. We recorded hip-fracture detection, correct laterality, coarse fracture pattern, intracapsular displacement, AO/OTA grading, subtrochanteric identification, and self-reported confidence. Because the cohort contained hip fractures only, we report fracture-detection rates and classification performance within a positive-only cohort rather than full diagnostic-accuracy metrics. Results: Using the more conservative endpoint of hip-fracture detection with correct laterality, GPT-5.4 was correct in 79.0% and 86.4% of cases in runs E and F, whereas Gemini was correct in 80.4% and 93.5%, respectively. When outputs from both models were combined, this endpoint reached 89.7% in run E and 96.7% in run F, indicating complementary rather than redundant error patterns. Incorrect laterality cues markedly degraded performance, from 90.7% to 66.4% in GPT-5.4 and from 97.7% to 57.0% in Gemini. Performance remained limited for treatment-relevant subtyping, particularly AO/OTA grading and subtrochanteric identification. Both models frequently remained highly confident when wrong, and self-reported confidence did not reliably distinguish correct from incorrect outputs. Conclusions: Accessible general-purpose multimodal models showed partial capability for coarse hip-fracture interpretation, but they remained context-sensitive, unreliable for treatment-relevant subtyping, and highly confident even when incorrect. Their complementary error patterns are hypothesis-generating rather than evidence of clinical readiness. On the basis of these findings, we do not support unvalidated or uncontrolled clinical use of such models. As access to these tools expands, explicit usage boundaries, minimum performance expectations, repeated local revalidation, and sustained human oversight become increasingly necessary. Full article

Background: Spinopelvic dissociation secondary to sacral fracture–dislocation is a rare but severe injury, most often resulting from high-energy trauma. Management remains challenging, particularly in adolescents, and the optimal choice between open and percutaneous fixation is still debated. Methods: We present two adolescent cases of traumatic sacral fracture–dislocation with spinopelvic dissociation, one treated with percutaneous fixation and one with open lumbopelvic stabilization both with the use of navigation. The systematic literature review included 29 published studies. Together with the present two-patient case series, the overall analysis comprised 30 studies/series and 739 patients. Data on demographics, mechanisms of injury, neurological involvement, treatment strategies, and outcomes were extracted and analyzed. Results: Case 1 (18 years) was managed with closed reduction and percutaneous fixation, achieving complete neurological and functional recovery at 6 months. Case 2 (14 years) underwent open reduction, decompression, and lumbopelvic fixation, with favorable radiological outcomes but residual sphincter dysfunction at follow-up. In the literature, the weighted mean age was 40.6 years (range 5–91), with 48.6% presenting neurological deficits, most frequently cauda equina syndrome. Surgical management was performed in nearly all cases, with mean time to fixation ranging from 3.6 to 8.6 days. Open techniques were predominantly used in patients with severe displacement or neurological compromise, whereas percutaneous fixation was associated with reduced surgical morbidity and satisfactory neurological recovery in selected patients. Permanent bladder and bowel dysfunction persisted in up to 33% of cases. Conclusions: Spinopelvic dissociation following sacral fracture–dislocation remains a rare and highly unstable injury with frequent neurological impairment. Early surgical stabilization may be beneficial when the patient’s clinical condition permits, and the choice between open and percutaneous fixation should be individualized according to fracture morphology, neurological status, and the need for direct decompression. Our adolescent cases highlight both the potential for complete recovery and the risk of residual dysfunction, reflecting the complexity of these injuries. Full article

Background and Objectives: Seroma formation is the most common postoperative complication following mastectomy and axillary dissection, negatively affecting wound healing and delaying adjuvant therapy. Despite numerous surgical and pharmacological approaches, no universally effective strategies have been established. This study aimed to comparatively evaluate the effects of porcine dermal collagen (PDC), tranexamic acid (TXA), and thymoquinone (TQ) on seroma formation and tissue repair. Materials and Methods: A randomized controlled experimental study was conducted using 40 female Wistar albino rats that underwent modified radical mastectomy and axillary dissection. All surgical and postoperative procedures were performed in accordance with the institutional animal welfare and ethical guidelines, including postoperative analgesic administration. The animals were divided into four groups: control, PDC, TXA, and TQ (n = 10 each). Seroma volume was measured on postoperative day 14. Histopathological evaluation, immunohistochemical analysis (FGF2, VEGF, TGF-β1, p53), and quantitative real-time PCR were performed to assess tissue remodeling and molecular responses. Results: All treatment groups demonstrated a significant reduction in seroma volume compared to the control group, with the most pronounced decrease observed in the TQ and TXA groups (p < 0.0001), while PDC showed a moderate effect (p < 0.01). Histopathological analysis revealed increased collagen deposition and fibrin formation in the PDC and TQ groups, whereas TXA exhibited a more limited remodeling profile than the others. Immunohistochemical and molecular analyses showed significant upregulation of VEGF across all groups, with broader and more consistent increases in the PDC and TQ groups. TGF-β1 and FGF2 expression demonstrated region-specific increases, particularly in the thoracic tissue. p53 expression remained relatively stable in the TXA group but was elevated in specific regions in the PDC and TQ groups. Importantly, the increased inflammatory infiltration, edema, vascular proliferation, and fibrin deposition observed in the TQ group may reflect not only active tissue remodeling processes but also prolonged inflammatory activation and enhanced fibrotic responses and should therefore be interpreted cautiously. Conclusions: PDC, TXA, and TQ differentially modulate postoperative seroma formation via distinct biological mechanisms. While TXA primarily exerts a targeted anti-seroma effect and PDC enhances extracellular matrix stabilization, TQ is associated with broader angiogenic, inflammatory, and tissue remodeling responses within this preclinical rat model. These findings should be considered exploratory and hypothesis-generating, and additional mechanistic studies and clinical investigations are necessary before definitive therapeutic conclusions can be established regarding the use of TQ in human breast surgery settings. Full article

Cutaneous Melanoma is a biologically heterogeneous malignancy. Although recent therapeutic advances have improved survival, durable remissions remain elusive for many patients. Surgical excision with stage-appropriate margins and selective nodal staging remains the cornerstone of curative-intent management. In contrast, conventional cytotoxic chemotherapy now plays a limited, largely palliative role given its modest efficacy and substantial toxicity. Targeted therapy with BRAF/MEK inhibitors has improved outcomes in patients with BRAF V600-mutant melanoma, resulting in rapid tumor regression and meaningful survival benefits. However, long-term disease control is frequently compromised by adaptive resistance, commonly driven by MAPK pathway reactivation or compensatory PI3K/AKT signaling. In parallel, immune checkpoint inhibitors targeting PD-1, CTLA-4, and emerging pathways have reshaped treatment across disease stages, enabling deep and sometimes durable responses. Despite this progress, primary and acquired resistance, as well as acute and chronic immune-related toxicities, continue to pose significant clinical challenges. Current therapeutic strategies focus on rational combinations of targeted therapy, checkpoint blockade, IL-2-based approaches, oncolytic viruses, and adoptive cell therapies such as tumor-infiltrating lymphocytes to enhance response depth and durability. However, these intensified regimens carry increased toxicity risks, highlighting the need for improved patient selection and monitoring. Overall, emerging evidence supports a paradigm shift toward optimized treatment sequencing, response-adapted surgical strategies, and biomarker-guided personalization to maximize clinical benefit while minimizing toxicity. Full article