Search Results (33)

Immunotherapy (IT) and especially immune checkpoint blockade (ICB) changed the therapeutic approach in non-small cell lung cancer (NSCLC). Nevertheless, primary or secondary resistance and a percentage of long responders and survivors have been observed. The aim of this study is to gain a deeper understanding of the complex mechanisms of primary and secondary resistance to IT, involving tumor cells, the tumor microenvironment (TME), and the host, in order to find strategies to overcome it. With this aim in mind, a search for key words has been performed to identify relevant evidence in the literature. The most widely used approach is the combination of IT with chemotherapy (CT) and/or radiotherapy (RT), relying on the synergistic effect on the enhancement of immunogenic cell death. Since a dual role has been observed, a lot of questions are yet to be answered regarding the complex effect of these therapies, especially on the TME. Preclinical and clinical studies investigate the best sequencing and timing of chemoradiation with IT, and the optimal RT volumes, sites, and dose/fractionation regimens to favor immune stimulation over suppression on the TME. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors on immune or tumor cells are under evaluation. The huge potential of combination therapies becoming apparent. Questions regarding targets, selection of patients, and time and sequence of administration are yet to be answered, considering the complex mechanisms of resistance. Dynamic biomarkers to guide personalized treatment decisions are needed. Full article

This prospective single-center study examined associations between serum cytokines—TNF-α, IL-2, and IL-10—and outcomes in stage IV non-small cell lung cancer (NSCLC, n = 43) and melanoma (n = 15) patients treated with Nivolumab at the Oncology Institute in Cluj-Napoca, Romania. Cytokines were measured at baseline (NSCLC: n = 43; melanoma: n = 15), 3 months (NSCLC: n = 20; melanoma: n = 7), and 6 months (NSCLC: n = 10; melanoma: n = 5). Melanoma patients showed sustained IL-2 and TNF-α increases, while NSCLC patients displayed heterogeneous cytokine dynamics. In NSCLC, elevated IL-10 at 3 months correlated with shorter survival (ρ = −0.51, 95% CI −0.78 to −0.12, p = 0.022) and poorer response (ρ = −0.65, 95% CI −0.86 to −0.23, p = 0.002). TNF-α showed a borderline association with response (ρ = −0.44, 95% CI −0.74 to 0.01, p = 0.050). In melanoma, 3-month TNF-α was inversely associated with survival (ρ = −0.82, 95% CI −0.97 to −0.15, p = 0.023) and response (ρ = −0.90, 95% CI −0.99 to −0.39, p = 0.006). Strong inter-cytokine correlations were observed (NSCLC: TNF-α vs. IL-10, ρ = 0.60, 95% CI 0.19–0.82; melanoma: ρ = 0.93, 95% CI 0.44–0.99). Baseline cytokines had limited utility, particularly in melanoma due to the small sample size. The most informative finding was the association of elevated 3-month IL-10 with adverse outcomes in NSCLC. These results support the value of dynamic cytokine monitoring in immunotherapy and warrant validation in larger cohorts. Full article

Background: Perioperative factors significantly impact oncologic outcomes after radical cystectomy (RC) for bladder cancer. This study aimed to identify key perioperative predictors for overall (OS) and progression-free survival (PFS) and to develop a prognostic nomogram for the identification of high-risk patients adapted to the clinical routines and standard of care of our country. Methods: We retrospectively analyzed 121 patients undergoing RC (2014–2024). Data on patient demographics, comorbidities, tumor pathology, neoadjuvant treatments, extensive intraoperative factors, and postoperative events were assessed using COX models. A prognostic nomogram for 3-year OS was constructed. Results: Median follow-up was 44.33 months. Significant predictors for worse OS included lymphovascular invasion (LVI) (HR 2.22), higher T stage (HR 8.75), N+ status (HR 1.10), and intraoperative complications (HR 3.04). Similar predictors were noted for PFS. The developed nomogram incorporated T-, N-stages, sex, grade, intraoperative complications and early (12 months) recurrence, and was able to significantly identify patients with a higher mortality risk (p < 0.001) with a C-index of 0.74. Conclusions: Our nomogram for mortality prediction of BC patients offers a promising tool for individualized risk stratification. Further studies are required for its external validation. Full article

The tumor microenvironment (TME) in advanced solid tumors is determined by immune checkpoints (PD-1, CTLA-4, and CD95) and cytokine networks (IL-2, IL-10, and TNF-α) that drive CD8+ T cell exhaustion, metabolic reprogramming, and apoptosis resistance, enabling immune evasion. Some studies revealed PD-1/CD95 co-expression is a marker of T cell dysfunction, while CTLA-4 upregulation correlates with suppressed early T cell activation. IL-10 has emerged as a potential biomarker for chemoresistance and tumor aggressivity, consistent with its role in promoting anti-apoptotic signaling in cancer stem cells (CSCs). Engineered IL-2 variants and TNF-α modulation are highlighted as promising strategies to revitalize exhausted CD8+ T cells and disrupt CSC niches. This prospective single-center study investigated the dynamic TME alterations in 16 patients with immunotherapy-naïve stage IV non-small-cell lung cancer (NSCLC) and metastatic melanoma treated with anti-PD-1 nivolumab. The longitudinal immunophenotyping of peripheral blood lymphocytes (via flow cytometry) and serum cytokine analysis (via ELISA) were performed at the baseline, >3, and >6 months post-treatment to evaluate immune checkpoint co-expression (PD-1/CD95 and CTLA-4/CD8+) and the cytokine profiles (IL-2, IL-10, and TNF-α). Full article

Background/Objectives: Lymphovascular invasion (LVI) has been consistently linked to poor outcomes in patients with bladder cancer (BC), yet its independent prognostic value, especially after adjusting for established pathological features, remains debated. This study aimed to evaluate the prognostic value of LVI in the context of other pathological features of patients undergoing radical cystectomy. Methods: We conducted a retrospective cohort study including 200 patients treated at the Municipal Clinical Hospital in Cluj-Napoca, Romania. Associations between LVI and overall survival (OS) were assessed using univariable and multivariable Cox proportional hazards models, with Kaplan–Meier curves used for visualizing survival distributions. Results: In univariable analysis, increasing age, presence of LVI, advanced pathological tumor stage (pT ≥ 2), and nodal involvement (pN ≥ 1) were significantly associated with worse OS. LVI was a strong predictor of poor survival (HR 3.13; 95% CI: 2.09; 4.69; p < 0.001). However, in multivariable analysis, only tumor stage (HR 4.85; 95% CI: 2.19; 10.77; p < 0.001) and nodal involvement (HR 1.87; 95% CI: 1.13; 3.09; p = 0.015) remained independently associated with OS. In patients with incomplete nodal staging (Nx), LVI was significantly associated with OS (p = 0.028). Conclusions: Our findings reinforce the prognostic relevance of LVI in bladder cancer and support its role as a marker of aggressive tumor biology, highlighting its value in clinical risk assessment, especially in patients with incomplete nodal staging. Routine reporting of LVI in pathology and consideration in treatment planning are warranted. Full article

This paper examines the Daoist stelae of the Northern Dynasties through the lens of Eliade’s religious theory, with particular focus on the transformation of profane objects into sacred ones and the transition of local believers from the profane to the sacred. Utilizing Eliade’s notions of “symbol”, “myth”, and “sacred space”, this study investigates two critical dimensions of the Daoist stelae. First, it analyzes their visuality by closely examining the imagery and symbolic systems presented on the stelae—namely, the “mythical pattern” identified by Eliade—with particular attention to representations of the main deity, the Heavenly Palace, and the Xiwangmu Xianjing (Queen Mother of the West’s transcendent realm). Second, it addresses their materiality by reconstructing the invisible processes associated with the stelae, focusing on the formation of sacred space and the Daoist rituals enacted therein. Applying phenomenology of religion to Daoist stelae analysis helps compensate for the limitations of extant Daoist scriptures and official historical records. Full article

Background: Comprehensive molecular profiling is essential for precision oncology in non-small cell lung cancer (NSCLC). However, genomic data from Eastern European populations, including Romania, remain limited. Methods: We analyzed 398 consecutive NSCLC cases tested at the PATHOS Molecular Pathology Laboratory (Cluj-Napoca, Romania) between April 2024 and February 2025 using the Ion Torrent™ Genexus™ System and the Oncomine™ Dx Target Test, which evaluates SNVs/indels in 46 genes, fusions in 23 genes, and CNVs in 19 genes from FFPE samples. Results: The cohort was predominantly male (66%) with a median age of 67 years. Adenocarcinoma represented 70% of cases with known histology. Genomic profiling revealed a high frequency of actionable alterations. KRAS mutations were the most common (29.1%), with p.G12C detected in 10.3% of all the cases. EGFR mutations were present in 14.3% of patients, mostly exon 19 deletions and L858R substitutions. BRAF alterations (5.3%) included both V600E and non-V600E variants. RET alterations were detected as eight missense mutations, two canonical fusions (KIF5B–RET, CCDC6–RET), one amplification, and three transcript imbalances. EML4-ALK fusions (1.77%), ERBB2 mutations/amplifications (3.0%), and FGFR1/FGFR3 amplifications were also observed. Conclusions: This study provides the first large-scale molecular snapshot of NSCLC in Romania. While the overall genomic profiles align with Western populations, the higher frequency of KRAS p.G12C and FGFR amplifications highlights the value of region-specific data to support targeted therapies in Eastern Europe. Full article

Upfront Next-Generation Sequencing (NGS) is increasingly recommended in advanced NSCLC to guide targeted therapy. This prospective single-center study in Romania evaluated routine, upfront NGS in advanced NSCLC at baseline (tissue and/or liquid) and progression (liquid). Baseline FoundationOne NGS (tissue/liquid) was performed in 119 consecutive stage IV NSCLC patients, along with PD-L1 immunohistochemistry (IHC, SP263). Liquid biopsy was repeated at progression. Turnaround time (TAT), the prevalence of actionable targets, and clinical utility were assessed. Patients were predominantly male (68.1%) with a median age of 62 years (range 30–86). Most had ECOG PS 0–1 (79%) and non-squamous histology (67.2%). Never-smokers accounted for 25.2%. The median TAT for the NGS results was 9 days (range 5–21). Overall, 671 genetic alterations were detected in 149 genes. The mean number of distinct mutations per patient dropped from 5.6 at baseline to 4.3 at progression. Tissue samples yielded more alterations (6 per patient) than baseline liquid biopsies (4.6). Squamous tumors had more alterations (7.1 vs. 4.8 in non-squamous), and the number of smokers exceeded that of never-smokers (6 vs. 4.5). TP53 was the most frequent (70.59%). Actionable variants were found in 74.8% of patients, though only 35.3% received personalized therapy, largely due to performance status deterioration, reimbursement, or trial availability barriers. Common targets in non-squamous tumors included EGFR (21%), KRAS G12C (11%), NF1 (11%), and ERBB2 (6%); in squamous tumors, common targets included NF1 (24%), PIK3CA (18%), and ERBB2 (8%). Among smokers, driver mutations were often NF1 (15%), PIK3CA (11%), KRAS G12C (9%), and ERBB2 (8%); never-smokers were dominated by EGFR (45%), NF1 (15%), and KRAS G12C (8%). TMB ≥ 10 mut/Mb was seen in 26.9%; no patients were MSI-H. PD-L1 TPS was <1% in 33% of patients, 1–49% in 20%, ≥50% in 18%, and unknown in 29%. Upfront NGS offers rapid, comprehensive genomic data, guiding tailored therapies and trials in advanced NSCLC. Liquid rebiopsy at progression further refines treatment decisions. Full article

Acute ischemic stroke (AIS) is frequently associated with long-term post-stroke cognitive impairment (PSCI) and dementia. While the mechanisms behind PSCI are not fully understood, the brain and cognitive reserve concepts are topics of ongoing research exploring the ability of individuals to maintain intact cognitive performance despite ischemic injuries. Brain reserve refers to the brain’s structural capacity to compensate for damage, with markers like hippocampal atrophy and white matter lesions indicating reduced reserve. Cognitive reserve involves the brain’s ability to optimize performance and use alternative networks to maintain function. Advanced methods of MRI and EEG processing may better assess brain reserve and cognitive reserve, with emerging predictive models integrating these measures to improve PSCI prediction. This article provides the design of a hospital-based study investigating the predictive role of functional connectivity and MRI radiomics in assessing PSCI occurrence one year after AIS. One hundred forty-four patients will be enrolled following strict inclusion/exclusion criteria. The patients will undergo comprehensive assessments, including neuropsychological testing, brain MRI, and quantitative EEG (QEEG), across four visits over a year. The primary outcome will be PSCI occurrence, and it will be assessed at six and twelve months after AIS. Secondary outcomes will include PSCI severity, recurrent AIS, and mortality. Statistical analyses will be performed to identify predictive factors using Cox proportional hazards models, and predictive models based on QEEG, MRI radiomics, and clinical data will be built. Early detection of AIS patients prone to developing PSCI might outline more effective therapeutic approaches, reducing the social and economic burden of ischemic stroke. Full article

Stroke is a major cause of mortality and long-term disability worldwide, making early diagnosis and effective treatment crucial for reducing its impact. In response to the limited efficacy of current treatments, alternative therapeutic strategies, such as novel biomarkers and therapies, are emerging to address this critical unmet medical need. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. Due to their dysregulation, they have been implicated in the onset and progression of various diseases. Recent research highlighted the important role of miR-181 family members in the context of stroke. Polymorphisms such as rs322931 in miR-181b are associated with increased stroke risk. miR-181 family members are aberrantly expressed and related to various aspects of stroke pathology, affecting inflammatory responses or neuronal survival. We provide a comprehensive overview of how alterations in miR-181 expression influence stroke mechanisms and their potential as therapeutic targets. Full article

Background: The Improved Health Care in Neurology and Psychiatry—Longer Life (IHCNP) study was an 18-month prospective, observational, non-interventional research study focused on patients with mild cognitive impairment (MCI) following ischemic stroke. Objectives: Our secondary analysis of the IHCNP data aimed to document the progression of MCI in this patient group. Methods: A total of 100 patients from Romania were recruited, all of whom underwent cognitive assessments using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Rey Auditory Verbal Learning Test (RAVLT). Clinical evaluations were also conducted as part of the study. Baseline cognitive scores were recorded, and subsequent follow-ups documented cognitive changes over time. Results: At baseline, cognitive scores indicated mild impairment, with averages of MMSE 25.41, MoCA 23.27, and RAVLT 33.63. By the end of the study, patients exhibited a significant cognitive decline, with MMSE scores dropping by 8.7%, MoCA by 10.0%, and RAVLT by 29.5% (p < 0.0001 for all measures), reflecting the progressive nature of MCI post-stroke. Conclusions: These findings highlight the importance of early diagnosis and intervention to mitigate cognitive decline in post-stroke patients. The study underscores the need for ongoing cognitive monitoring to improve patient outcomes and manage MCI progression effectively. Full article

Background: Cognitive deficits following ischemic stroke significantly impair quality of life, highlighting the need for effective interventions. This study evaluates the efficacy and safety of extended N-Pep-12 dietary supplementation in enhancing cognitive recovery post-stroke. Methods: In this randomized, open-label, controlled study, 106 patients with supratentorial ischemic stroke were enrolled to receive either 90mg N-Pep-12 or no supplementation daily for 360 days and were followed-up for 360 days. Cognitive function and emotional well-being were assessed using established neuropsychological scales at baseline, 90 days, and 360 days post-stroke. Safety was monitored through adverse events and mortality rates. Results: Significant improvements were observed in the N-Pep-12 group compared to controls, particularly in the Montreal Cognitive Assessment scores at both 90 and 360 days, and in the Digit Symbol Coding scores at 360 days, suggesting enhanced cognitive recovery with extended N-Pep-12 supplementation. A linear regression for a composite outcome analysis at day 360 further confirmed the efficacy of N-Pep-12 in contributing to cognitive improvement. Safety profiles were favorable, with no significant adverse effects attributed to N-Pep-12. Conclusions: Extended dietary supplementation with N-Pep-12 appears to offer a safe and effective approach to support cognitive recovery in ischemic stroke survivors. These findings underscore the potential of the supplement as an add-on intervention for managing post-stroke cognitive impairments. Full article

Purpose. Different combination modalities between an anti-PD-1/PD-L1 agent and a platinum-based chemotherapy or another checkpoint inhibitor (with or without a short course or full course of a platinum doublet) proved superior to chemotherapy alone in multiple clinical trials, but these strategies were not directly compared. The aim of this study is to report the real-world data results with different immunotherapy combinations in a series of patients treated in consecutive cohorts at the Ion Chiricuță Oncology Institute. Methods. A total of 122 patients were successively enrolled in three cohorts: (1A) nivolumab + ipilimumab (18 patients), (1B) nivolumab + ipilimumab + short-course chemotherapy (33 patients), and (2) pembrolizumab plus full-course chemotherapy (71 patients). Endpoints included overall survival (OS), progression-free survival (PFS), objective response (ORR), and univariate and multivariate exploratory analysis of prognostic factors. RESULTS. Median follow-up in the consecutive cohorts 1A, 1B, and 2 was 83 versus 59 versus 14.2 months. Median OS and PFS for all patients were 22.2 and 11.5 months, respectively, and 2-year actuarial OS and PFS were 49% and 35%, respectively. For the nivolumab + ipilimumab (cohorts 1A and 1B) versus pembrolizumab combinations (cohort 2), median OS was 14 vs. 24.8 months (p = 0.18) and 2-year actuarial survival 42% vs. 53%; median PFS was 8.6 vs. 12.7 months (p = 0.41) and 2-year actuarial PFS 34% vs. 35%; response rates were 33.3% vs. 47.9% (p = 0.22). Older age, impaired PS (2 versus 0–1), corticotherapy in the first month of immunotherapy, and >3.81 neutrophils to lymphocytes ratio were independent unfavorable prognostic factors in the multivariate analysis of survival (limited to 2 years follow-up). The 5-year long-term survival was 30.5% and 18.8% for cohorts 1A and 1B, respectively (not enough follow-up for cohort 2). Conclusions. Efficacy results using different immunotherapy combination strategies were promising and not significantly different between protocols at 2 years. Real-world efficacy and long-term results in our series were in line with those reported in the corresponding registration trials. Full article

Lung cancer, primarily non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), is distinguished by its high prevalence and marked mortality rates. Traditional therapeutic approaches, encompassing chemotherapy, radiation, and targeted therapies, frequently show limited efficacy due to acquired resistance and notable side effects. The objective of this review is to introduce a fresh perspective on the therapeutic strategies for lung cancer, emphasizing interventions targeting the epigenetic alterations often seen in this malignancy. This review presents the most recent advancements in the field, focusing on both past and current clinical trials related to the modulation of methylation patterns using diverse molecular agents. Furthermore, an in-depth analysis of the challenges and advantages of these methylation-modifying drugs will be provided, assessing their efficacy as individual treatments and their potential for synergy when integrated with prevailing therapeutic regimens. Full article

This article explores the contribution of modern Muslim revivalism to Muslims’ political decolonization, and the paradoxical role the West plays in that process. On the one hand, revivalism rejects the founding principles of liberal political theory, and on the other hand, it readily adopts the salient structures and mechanisms of the modern polity with a view to Islamize them, all the while insisting on the Muslims’ need to de-Westernize. Toward revealing the hitherto neglected dimensions of revivalism, my analysis adopts an unconventional route by subjecting revivalism to a semiotic analysis in conversation with the archetypal theories of Mircea Eliade and Carl G. Jung. The analysis unveils the universal psychological structures of revival, and their specific Muslim symbolization. I conclude (a) that depth psychology makes modern Muslim revival inevitable, which will only grow stronger and gain wider appeal while the Muslims continue to suffer decline; (b) that among the different forms of Muslim revival, revivalism ventures the farthest in decolonizing Muslim political imagination; (c) that the revivalist imagination makes their espoused caliphate imperative for the purpose of ritual participation in Islam’s sacred origins; and (d) that a critical reconstruction and evolution of revivalism holds out the promise of a greater contribution to Muslim decolonization. For my analysis, I largely turn to the Pakistani political theologian Israr Ahmad (d. 2010), whose ideas have been disseminated widely across the Muslim world, yet who has not received the requisite academic scrutiny. Moreover, intra-revivalist critique of revivalism has been a neglected aspect in the study of revival, and its careful scrutiny should become a topic of investigation in its own right. In that regard, Ahmad offers a most important critique of earlier revival efforts and their entanglement with certain aspects of coloniality. Full article