Search Results (410)

Background/Objectives: While ART effectively suppresses HIV viremia, many PLWH exhibit persistent immune dysfunction. This study aimed to assess immune recovery and immune exhaustion (PD-1/PD-L1 expression) in newly diagnosed versus long-term ART-treated individuals. Methods: We analyzed 79 PLWH: 52 newly diagnosed individuals (12-month follow-up) and 27 long-term-treated patients (Ukrainian refugees). Flow cytometry was used to evaluate CD4+ and CD8+ counts, the CD4+/CD8+ ratio, and PD-1/PD-L1 expression on CD3+, CD4+, and CD19+ lymphocytes. ART regimen and HIV subtype were included as covariates in linear regression models. Results: At 12 months, CD4+ counts were similar between groups (median 596.5 vs. 621 cells/μL, p = 0.22), but newly diagnosed patients had higher CD8+ counts (872 vs. 620 cells/μL, p = 0.028) and a lower CD4+/CD8+ ratio (0.57 vs. 1.05, p = 0.0027). Immune exhaustion markers were significantly elevated in newly diagnosed individuals: CD4+ PD-1+ T cells (24.4% vs. 3.85%, p = 0.0002) and CD3+ PD-1+ T cells (27.3% vs. 12.35%, p < 0.0001). Linear regression confirmed group membership independently predicted higher CD3+ (β = +21.92, p < 0.001), CD4+ (β = +28.87, p < 0.0001), and CD19+ (β = +8.73, p = 0.002) percentages. Lipid parameters and SCORE2 did not differ significantly. Conclusions: Despite virologic suppression and CD4+ recovery, immune exhaustion markers remain elevated in newly diagnosed PLWH, suggesting incomplete immune normalization. Traditional parameters (CD4+ count and CD4+/CD8+ ratio) may not fully capture immune status, warranting broader immunologic profiling in HIV care. Full article

Gastric-type cervical adenocarcinoma (GCA) is a rare and aggressive subtype of cervical adenocarcinoma. Despite its clinical significance, its molecular carcinogenesis and therapeutic targets remain poorly understood. This study aimed to compare the clinicopathological, immunohistochemical, and molecular profiles of GCA and usual-type cervical adenocarcinoma (UCA), exploring prognostic and therapeutic biomarkers in a Japanese population. A total of 110 cervical adenocarcinoma cases, including 16 GCA and 94 UCA cases, were retrospectively analyzed for clinicopathological features, and a panel of immunohistochemical markers was assessed. Sanger sequences were performed for the KRAS, PIK3CA, and BRAF genes, and survival and clinicopathological correlations were assessed using Kaplan–Meier and Cox regression analyses. GCA was significantly associated with more aggressive features than UCA, including lymph node involvement, advanced FIGO stages, increasing recurrence rate, and poor survival status. High ARID1B expression was observed in a subset of GCA cases and correlated with worse progression-free and overall survival. Additionally, PD-L1 expression was more frequent in GCA than UCA and was associated with unfavorable prognostic factors. Conversely, UCA cases showed strong p16 expression, supporting their HPV-driven pathogenesis. Molecular profiling revealed KRAS and PIK3CA mutations in both subtypes, while BRAF mutations were identified exclusively in GCA. These findings reveal distinct clinical and molecular profiles for both tumor types and underscore ARID1B and PD-L1 as predictive prognostic and therapeutic biomarkers in GCA, implicating the use of subtype-specific treatment strategies. Full article

Background: Consolidation therapy with durvalumab after definitive chemoradiotherapy (CRT) has become the standard care for patients with stage III non-small-cell lung cancer (NSCLC) following the PACIFIC trial. However, real-world data evaluating outcomes under routine clinical conditions remain limited, particularly in European cohorts. Methods: In this retrospective single-center study, we analyzed clinical data from 72 patients with stage III NSCLC treated with definitive CRT between 2017 and 2022. The patients were stratified by receipt of durvalumab consolidation. Univariable and multivariable Cox regression models were used to assess overall survival (OS) and progression-free survival (PFS). Stepwise variable selection based on the Akaike Information Criterion (AIC) was used to construct an optimized multivariable model. A sensitivity analysis with adjustment for treatment period (2017–2018 vs. 2019–2022) was conducted to account for the introduction of durvalumab into routine clinical practice. Results: Among 72 patients, 35 received durvalumab and 37 did not. The median OS was 2.08 years; the 3- and 5-year OS rates were 38.6% and 30.3%, respectively. Multivariable regression revealed significantly improved OS associated with Karnofsky performance status (KPS) > 80% (HR 0.29, p = 0.003), Charlson Comorbidity Index (CCI) ≤ 2 (HR 0.39, p = 0.009), and durvalumab treatment (HR 3.99, p = 0.008). PD-L1 expression ≥ 1% showed a trend toward improved OS (HR 3.72, p = 0.063). The median progression-free survival (PFS) for the total cohort was 1.17 years. The estimated 3- and 5-year PFS rates were 31.1% and 26.3%, respectively. Patients treated with durvalumab had a longer median PFS (20.5 months) compared to those without durvalumab (12.0 months). In the multivariable analysis, KPS > 80% (HR 0.29, p < 0.001), CCI ≤ 2 (HR 0.53, p = 0.048), and durvalumab treatment (HR 2.81, p = 0.023) were significantly associated with improved PFS. A sensitivity analysis adjusting for treatment period—reflecting the introduction of durvalumab into routine clinical practice from 2019—confirmed the robustness of these findings. Conclusions: Our findings support the clinical benefit of durvalumab consolidation following CRT in a real-world population, especially in patients with good performance status and low comorbidity burden. These results confirm and extend the PACIFIC trial findings into routine clinical practice, highlighting the prognostic value of functional status and comorbidity alongside PD-L1 expression. Full article

TP (tumor protein) 53 mutation status plays a critical role in cancer progression and may influence survival outcomes in non-small cell lung cancer (NSCLC) patients receiving immunotherapy. This study investigates the impact of TP53 mutation status and immunotherapy treatment on survival in NSCLC patients. This retrospective study analyzed NSCLC patients treated with pembrolizumab or ipilimumab plus nivolumab, stratified by TP53 mutation status and PD-L1 (programmed death-ligand 1) expression (<1%, 1–49%, >50%). Survival outcomes (overall survival (OS) and progression free survival (PFS) were assessed using Kaplan–Meier curves and log-rank tests, with subgroup analysis by histological subtype. In squamous cell cancer (SCC) patients, no significant differences in OS or PFS were found based on TP53 mutation status or treatment type. A trend toward improved survival was observed with pembrolizumab (p = 0.088). In adenocarcinoma patients, significant differences in OS and PFS were observed based on TP53 mutation status. Pembrolizumab showed superior survival outcomes compared to ipilimumab plus nivolumab in TP53 wild-type patients (p < 0.001). PD-L1 ≥ 1% also predicted better outcomes, especially in adenocarcinoma patients. TP53 mutation status and immunotherapy type significantly influence survival outcomes in NSCLC, particularly in adenocarcinoma patients. Pembrolizumab demonstrated superior efficacy in TP53 wild-type patients, with PD-L1 expression further refining survival predictions. These findings underscore the importance of personalized treatment strategies based on TP53 status and PD-L1 expression in NSCLC. Further studies are needed to validate these results and optimize treatment approaches. Full article

Background: Advanced and recurrent vulvar squamous cell carcinoma (VSCC) presents a major therapeutic challenge with limited treatment options and poor outcomes. Immune checkpoint inhibitors (ICIs) have shown efficacy in other HPV-associated malignancies, but their role in VSCC remains poorly defined due to the rarity of the disease and limited clinical trial data. Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines and registered in PROSPERO (CRD420251067565). A comprehensive literature search identified prospective clinical trials evaluating ICIs in patients with advanced, unresectable, recurrent, or metastatic VSCC. The primary outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Risk of bias was assessed using the MINORS tool. Meta-analyses were performed using random-effects models, with subgroup analyses based on PD-L1 status and treatment regimens (monotherapy vs. combination therapy). Results: Six non-randomized single-arm trials involving 181 patients were included. The pooled ORR was 21%, with higher response rates observed in combination therapy (46%) compared to monotherapy (11%), though not statistically significant. Median PFS and OS were 2.2 months and 6.4 months, respectively. ORRs were similar between PD-L1-positive and PD-L1-negative subgroups. A safety analysis showed treatment-related adverse events (AEs) in 73% of patients and grade ≥ 3 AEs in 23%. The incidence of treatment-related death was 3%. Conclusions: ICIs demonstrate modest but durable efficacy and an acceptable safety profile in advanced VSCC. The current evidence supports their use in selected patients. However, response variability and the lack of reliable predictive biomarkers, such as PD-L1 or HPV status, underscore the need for biomarker-driven clinical trials and improved patient selection strategies. Full article

Glioblastoma is a highly aggressive brain tumor with an overall poor prognosis due to its immunosuppressive tumor microenvironment (TME). Microglia and tumor-associated macrophages (TAMs) with pro-tumorigenic properties are dominant populations of immune cells in the glioblastoma TME. To date, several studies targeting TAMs to fight tumor progression in different tumor entities have been initiated. However, the impact of standard therapy schemes of glioblastoma cells on macrophage polarization, activation, and phagocytosis remains controversial. The same applies to the relevance of PD-1/PD-L1 blockade in the interaction between macrophages and tumor cells. Our study, therefore, investigated patient-oriented treatment of GLIOBLASTOMA by examining the phagocytic capacity of polarized M1- and M2-like macrophages using GL261-luc2 tumor cells as a preclinical model system. Additionally, we analyzed the expression of activation and immune checkpoint markers on these macrophage subtypes following contact with tumor cells and their microenvironment. These factors were also determined after PD-1 blockade was initiated. The analyses revealed that the immunoregulatory M2-like macrophages generally exhibited a higher phagocytosis rate than the pro-inflammatory M1-like macrophages; however, this was not influenced by the pretreatment of glioblastoma cells with chemo- or radiotherapy. This could not be improved by blocking the PD-1 receptor. Furthermore, there were no modulations in the expression of differentiation, activation, or immune checkpoint molecules of M1- and M2-like macrophages after cell-to-cell contact with glioblastoma cells. But the medium conditioned by tumor cells strongly altered M1-like macrophages toward a more activated state, whereas M2-like cells were only mildly influenced. This was further enhanced by tumor cell treatment, with the most prominent effect after irradiation. These results suggest that conventional GLIOBLASTOMA tumor cell treatment affects the immunogenic status of macrophage subtypes, which is relevant for enhancing the anti-tumor immune response in brain tumors. Full article

Background/Objectives: Duodenum-preserving pancreatic head resection (DPPHR) preserves digestive and absorptive functions better than pancreaticoduodenectomy (PD). Zinc is primarily absorbed in the duodenum and proximal jejunum and plays a critical role in nutritional maintenance and pancreatic regeneration. However, no studies have compared the postoperative pancreatic volume and serum zinc levels between DPPHR and PD. Methods: We retrospectively analyzed 41 patients who underwent DPPHR (n = 23) or subtotal stomach-preserving PD (n = 18) for low-grade pancreatic malignancies at our institution. The remnant pancreatic volumes on postoperative day 7 and 1 year were measured via computed tomography. Nutritional parameters, including serum albumin, prognostic nutritional index (PNI), and serum zinc levels, were compared between the groups. Serum zinc levels were evaluated in patients with DPPHR (n = 11) or PD (n = 7). Results: The DPPHR group demonstrated significantly better preservation of remnant pancreatic volume on postoperative day 7 and 1 year compared to the PD group (p = 0.045 and p = 0.041, respectively). Volume maintenance ratios were also significantly higher in the DPPHR group. Serum albumin levels at 1 year postoperatively were significantly better in the DPPHR group, although no significant difference was found in the PNI. Among patients evaluated for serum zinc, the DPPHR group showed significantly higher zinc levels compared to the PD group (80.3 vs. 65.8 μg/dL, p = 0.017). Conclusions: DPPHR preserves remnant pancreatic volume and maintains serum zinc levels better than PD, potentially contributing to improved postoperative nutritional status and quality of life. Further prospective studies with larger cohorts are warranted to validate these findings. Full article

Background/Objectives: Despite advances in immunotherapy, reliable biomarkers beyond PD-L1 expression are urgently needed to optimize treatment decisions in advanced non-squamous NSCLC. Thyroid Transcription Factor-1 (TTF-1), a biomarker associated with favorable prognosis in chemotherapy-treated patients, has unclear prognostic implications in the immunotherapy era. Methods: We conducted a multicenter retrospective study involving 163 advanced non-squamous NSCLC patients treated with first-line immunotherapy or chemo-immunotherapy and an additional historical chemotherapy-only cohort (n = 37). We evaluated the prognostic significance of TTF-1 expression for progression-free survival (PFS) and overall survival (OS). A systematic review and meta-analysis, performed following PRISMA guidelines, integrated our findings with existing evidence. Hazard ratios (HRs) were calculated using Cox proportional hazards models. Results: TTF-1 negativity was associated with significantly worse median PFS (6.7 vs. 16 months; HR 2.22, 95% CI 1.59–3.13; p < 0.001) and OS (11.5 vs. 26.4 months; HR 2.33, 95% CI 1.64–3.45; p < 0.001) compared to TTF-1 positivity. The prognostic value of TTF-1 was independent of PD-L1 status, with limited predictive relevance of PD-L1 expression observed within TTF-1-negative tumors. Meta-analysis (9 studies, 14 cohorts, n = 2019 patients) confirmed significantly inferior outcomes for TTF-1-negative patients across multiple immunotherapy-based regimens (pooled HR for PFS: 1.75, 95% CI 1.50–2.04; OS: 1.76, 95% CI 1.45–2.14). Conclusions: TTF-1 negativity independently predicts poor prognosis in advanced non-squamous NSCLC treated with immunotherapy-based regimens, identifying patients with limited benefit despite high PD-L1 expression. Integrating TTF-1 status into clinical practice may guide personalized treatment strategies, highlighting the need for prospective validation. Full article

The global aging population has led to a growing incidence of malignancies, including metastatic non-small-cell lung cancer (mNSCLC). Immunosenescence may affect the efficacy of immune checkpoint inhibitors (ICIs). The prognostic role of age in ICI-treated mNSCLC remains uncertain. Objectives: This study aims to assess whether age independently influences survival, response, and toxicity in mNSCLC patients treated with ICIs, and to examine potential interactions with clinical factors. Methods: In this retrospective cohort study, 105 patients with mNSCLC treated with ICIs were enrolled. Patients were stratified into four groups based on age quartiles. Clinical, pathological, and treatment data were collected. Survival outcomes were analyzed using Kaplan–Meier curves, ROC curve and multivariable Cox regression models adjusted for confounders. Interaction and restricted cubic spline analyses were performed to explore age-related effects. The p < 0.05 was considered as statistically significant. Results: The median age was 60.8 years. Clinical benefit—defined as objective response rate (51.4%) and disease control rate (86.6%)—did not significantly differ across age quartiles (p = 0.551 and p = 0.257, respectively). Median overall survival also did not differ significantly (p = 0.2853). Cox regression and spline modeling demonstrated no independent association between chronological age and all-cause mortality (Model 3: HR = 1.00, 95% CI: 0.95–1.04, p = 0.889). However, interaction analyses revealed that poor ECOG performance status (p = 0.001), longer duration of ICI treatment (p < 0.0001), and low PD-L1 expression (p = 0.017) were stronger predictors of mortality in older patients. Age was associated with increased immune-related adverse events and higher Charlson Comorbidity Index scores, suggesting the need for age-specific management strategies. Conclusions: Age alone does not predict survival in mNSCLC patients receiving ICIs. However, functional status, treatment duration and PD-L1 expression may modify age-related outcomes. Full article

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is subclassified into small- and large-duct types. Small-duct-type iCCAs are associated with a better prognosis, and each subclassification requires different surgical strategies. The efficacy of chemotherapy, including immune checkpoint inhibitors, may vary between subclassifications. However, there are no reports on tumor immune microenvironment (TIME) analyses based on iCCA subclassifications. This study investigated subclassification-specific TIMEs in iCCAs for the purpose of establishing appropriate pharmacotherapy. Methods: A total of 131 resected iCCA cases were analyzed, comprising 73 tumors classified as small-duct-type and 58 as large-duct-type based on pathological evaluation. Immunohistochemical analyses targeting CD8, PD-1, PD-L1, CTLA-4, and S100 protein (a dendritic cell [DC] marker) were performed to investigate the immune-cell status in each subclassification. Results: Large-duct-type iCCA had a significantly higher CD8 expression in tumor-infiltrating cells than small-duct-type ICC. However, the expression of other molecules did not significantly differ between the two tumor types. The proportion of tumors with a high level of S100 protein expression (DC-high group) in tumor-infiltrating cells was significantly higher in small-duct-type ICCs than in large-duct-type iCCAs (30% vs. 1.7%). In small-duct-type iCCAs, the expression levels of CD8, PD-1, PD-L1, and CTLA-4 were significantly higher in the DC-high group than in the DC-low group. Conclusions: We revealed subclassification-specific TIMEs in iCCAs. A subset of small-duct-type iCCAs exhibited strong DC infiltration. In these patients, the tumors may establish an immunosuppressive TIME to evade antitumor immunity triggered by DC-mediated antigen presentation. These findings may contribute to the development of tailored pharmacotherapy for each iCCA subclassification. Full article

Background/Objectives: Fabry disease (FD) is a lysosomal storage disorder often associated with early-onset neuropathic pain, attributed to small fibre neuropathy (SFN). The dorsal root ganglion (DRG) has emerged as a critical site of early pathophysiological involvement in FD, with structural and functional alterations implicated in the development of neuropathic symptoms. This exploratory study introduces DRG proton density (DRG-PD) as a novel MRI-derived biomarker and evaluates its association with SFN. Methods: Eighty genetically confirmed FD patients underwent high-resolution 3T MRI with DRG-PD quantification at the lumbosacral levels L5 and S1. DRG-PD was derived from B1-corrected multi-echo spin echo sequences and normalised to cerebrospinal fluid intensity. All patients underwent clinical, biochemical and histological evaluation to determine SFN status. Associations between DRG imaging parameters and clinical variables were analysed using correlation and regression models. Diagnostic performance was evaluated using receiver operating characteristic curve analysis. Results: DRG-PD values were significantly increased in patients with classical FD and SFN, demonstrating a large effect size (Cliff’s δ = 0.92) and excellent discriminatory performance (AUC = 0.96). In contrast, DRG volume and T2 relaxation time were not significantly associated with SFN status. DRG-PD remained an independent predictor of SFN in multivariable logistic regression (p = 0.019). Conclusions: DRG-PD is a non-invasive correlate of SFN in classical FD. It may provide superior diagnostic value compared to existing MRI metrics and reflects proximal ganglionic pathology not captured by distal histological assessments. Full article

Colorectal cancer (CRC) is the third most common cancer in the world, with increasing incidence and mortality rates. Standard conventional treatments for CRC are surgery, chemotherapy, and radiotherapy. Recently, immunotherapy has been introduced as a promising alternative to CRC treatment that utilizes patients’ immune system to combat cancer cells. The beneficial effect of immune checkpoint inhibitors, specifically anti-PD-1/ PD-L1, has been ascribed to the abundance of DNA replication errors that result in the formation of neoantigens. Such neoantigens serve as distinct flags that amplify the immune response when checkpoint inhibitors (ICIs) are administered. DNA replication errors in CRC patients are expressed as two statuses: the first is the deficient mismatch repair (MSI-H/dMMR) with a higher overall immune response and survival rate than the second status of patients with proficient mismatch repair (MSS/pMMR). There is a limitation to using anti-PD-1/PD-L1 as it is only confined to MSI-H/dMMR, where there is an abundance of T-cell inhibitory ligands (PD-L1). This calls for investigating new therapeutic interventions to widen the scope of ICIs’ role in the treatment of CRC. Autophagy modulation provides a good example. Autophagy is a cellular process that plays a crucial role in maintaining cellular homeostasis and has been studied for its impact on tumor development, progression, and response to treatment. In this review, we aim to highlight autophagy as a potential determinant in tumor immune response and to study the impact of autophagy on the tumor immune microenvironment. Moreover, we aim to investigate the value of a combination of anti-PD-1/PD-L1 agents with autophagy modulators as an adjuvant therapeutic approach for CRC treatment. Full article

Background/Objectives: The Lung Immune Prognostic Index (LIPI) has emerged as a promising biomarker for predicting outcomes in advanced non-small cell lung cancer (aNSCLC). We assessed whether LIPI, in combination with baseline clinical characteristics, can guide first-line treatment selection between pembrolizumab (P) and pembrolizumab plus platinum-based chemotherapy (PCT) in patients with PD-L1 tumor proportion score (TPS) ≥ 50% and EGFR/ALK/ROS1 wild-type. Methods: A predictive score was developed using baseline clinical variables, including age, sex, smoking status, and LIPI, in a proof-of-concept cohort (n = 241). This model was then validated in an independent cohort of 409 patients. OS was compared between patients treated with P versus PCT, stratified by predictive score. Results: In the proof-of-concept cohort, the median OS was 18.3 months for P and 26.6 months for PCT (p = 0.001). In the validation cohort, the median OS was 28.0 months for P and 22.2 months for PCT (p = 0.062). Stratification using the predictive score showed that patients with high scores (3–5) had improved OS with PCT compared to P (31.2 vs. 25.5 months, p = 0.001), while those with low scores (0–2) derived similar benefits from both treatments. Conclusions: This LIPI-based predictive score may assist in identifying aNSCLC patients who derive greater benefit from chemo-immunotherapy over immunotherapy. Its simplicity and clinical relevance support integration into treatment decision-making, pending prospective validation. Full article

Background: Advances in the treatment of non-small cell lung cancer in the last 5 years (new techniques in radiotherapy, including stereotactic ablative radiotherapy, new targeted therapies and advances in immunotherapy) have increased the survival rates of patients diagnosed with this disease. Methods: Our study refers to a patient diagnosed in July 2017 with stage IV A lung cancer, cT3 N3 M1b (poorly differentiated adenocarcinoma, EGFR, ALK and PDL 1 negative), who underwent five lines of treatment and who has, at the time of writing this article (March 2025), a very good performance status, currently undergoing maintenance chemotherapy. Results: The results obtained confirm the revolutionary role of immunotherapy, but also the importance of chemotherapy and external radiotherapy, suggesting the synergistic effect between these three therapies. We also performed a literature review, highlighting the resistance to immunotherapy, rechallenge with immunotherapy, progression of metastatic NSCLC after first-line chemo-immunotherapy and the role of chemotherapy in line II and III after progression of NSCLC to immunotherapy. Conclusions: Results of studies evaluating new agents and their combinations, along with analysis of the mechanisms of evolution of primary and acquired resistance to immunotherapy are awaited, with the aim of selective and personalized treatment options to improve the survival and the quality of life for this category of patients. Full article

Background: Pembrolizumab monotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC) patients whose tumors express a PD-L1 tumor proportion score (TPS) of ≥50%. However, real-world data regarding its effectiveness outside of clinical trials, particularly in Eastern European populations, are limited. Methods: We conducted a retrospective, multicenter study including 225 patients with metastatic NSCLC and PD-L1 TPS ≥ 50% who received first-line pembrolizumab monotherapy in Serbia between 2019 and 2022. Patient demographics, clinical characteristics, and treatment outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and multivariable Cox proportional hazards regression was performed to identify predictors of outcomes. Results: The median PFS was 9.7 months (95% CI: 7.979–11.421), and the median OS was 17.0 months (95% CI: 12.813–20.187) at a median follow-up of 18.1 months. The overall response rate (ORR) was 36.4%, and the disease control rate (DCR) was 73.4%. Multivariable analysis identified good performance status (ECOG PS 0–1), PD-L1 TPS ≥ 90%, and the occurrence of immune-related adverse events (irAEs) as independent predictors of improved PFS and OS. Conclusions: Our study highlights the efficacy and safety of first-line pembrolizumab monotherapy in a real-world Serbian population with metastatic NSCLC and high PD-L1 expression. Furthermore, it confirms the prognostic value of ECOG PS, high PD-L1 expression, and the development of irAEs in predicting favorable clinical outcomes. Full article