Search Results (4,570)

Background: Women treated for cervical intraepithelial neoplasia grade 2 (CIN2) face an increased risk of disease recurrence due to persistent or newly acquired human papillomavirus (HPV) infections, suggesting a potential role for adjuvant HPV vaccination. While a growing body of literature evaluates the outcomes of HPV vaccination following a large loop excision of the transformation zone (LLETZ) for high-grade squamous intraepithelial lesions (CIN2–3), data specifically focused on isolated CIN2 remain limited. This study aims to evaluate the clinical efficacy of the nonavalent HPV vaccine (9vHPV) as an adjuvant strategy to reduce CIN2+ recurrence in women undergoing LLETZ for histologically confirmed, isolated CIN2. Methods: Between November 2017 and November 2024, women undergoing LLETZ for histologically confirmed CIN2 received their first dose of adjuvant 9vHPV within one month of surgery. Patients who achieved double-negative co-testing (Pap test and high-risk HPV DNA test) at the 6-month post-LLETZ follow-up were included in the study group. Conversely, patients with at least one positive test result at 6 months were excluded to rule out residual disease. The study group underwent a subsequent Pap smear at 12 months and a full co-test at 18 months post-surgery; upon achieving negative results through the 18th month, patients returned to the organized screening program. The primary outcome was the recurrence rate, defined as histologically confirmed CIN2+ occurring more than 6 months post-treatment. It was compared against an unvaccinated historical control group treated with LLETZ prior to the study period. The secondary outcome evaluated the prevalence of HPV genotypes at baseline and at the time of recurrence. Results: In the vaccinated group, 3 women (2.03%) experienced CIN2+ recurrence compared to 6 women (5.71%) in the unvaccinated control group. This represents an absolute risk difference of 3.69% and a relative risk reduction of 64.6%, though the difference did not reach statistical significance via Fisher’s exact test (p = 0.165). In the study group, two recurrences were detected at 18 months (associated cytologies: ASC-H and LSIL; genotypes: HPV 51/53 and 16, respectively) and one at four years (cytology: HSIL; genotype: HPV 33/58). In the control group, recurrences occurred at 12 months (n = 3), 18 months (n = 2), and four years (n = 1). Associated cytology revealed HSIL in three cases, ASC-H in one case, LSIL in one case, and ASCUS in the final case. The corresponding HPV genotypes were 16 (two cases), 18, 51, 31 and 56 (co-infection), and one case of high-risk HPV, not further genotyped. Conclusions: Adjuvant 9vHPV administration after LLETZ for isolated CIN2 was associated with a clinically substantial lower absolute recurrence rate (2.03% vs. 5.71%, corresponding to a 64.6% relative risk reduction). Although this reduction did not achieve statistical significance ($p=0.165$) due to our small sample size and a low baseline recurrence rate in this isolated cohort, the effect size is highly comparable to broader CIN2+ studies. The study was likely underpowered to prove statistical significance, and larger multi-center studies are required to confirm the statistical value of adjuvant vaccination specifically in isolated CIN2 lesions. Full article

Background/Objectives: International Society of Urological Pathology (ISUP) Grade Group discordance between prostate biopsy and radical prostatectomy (RP) affects 25–50% of men with localized prostate cancer and has direct implications for active surveillance, nerve-sparing, and adjuvant-treatment decisions. We synthesized contemporary evidence on the frequency of biopsy-to-RP grade migration and on emerging imaging, molecular/genomic, and artificial-intelligence (AI)-based predictors of migration. Methods: MEDLINE (PubMed) was searched from 1 January 2010 to 5 May 2026, supplemented by citation searching of recent systematic reviews. Eligible studies reported paired biopsy–RP pathology under the modified 2005 Gleason or the 2014/2019 ISUP Grade Group system, with ≥50 paired cases. Risk of bias was assessed with QUIPS, PROBAST, and QUADAS-2; certainty of evidence was rated with a GRADE framework adapted for prognostic research. Synthesis followed the SWiM reporting guidance. Results: Thirty-seven primary studies and eight prior systematic reviews were included. Concordance ranged from 44% to ~70%, upgrading from 14% to 67%, and downgrading from 5% to 26%. Biopsy GG1 disease showed the highest absolute upgrading risk (55–67%). Four predictors reached moderate GRADE certainty: PI-RADS category, biopsy approach (combined vs. systematic), PSMA-PET maximum standardized uptake value, and PSA density (PSAD). Cribriform/intraductal carcinoma at biopsy, the Decipher genomic classifier, the Prostate Health Index, and machine-learning and radiomics models reached very low certainty; clinical nomograms reached low certainty; germline alterations as direct predictors reached very low certainty. PROBAST flagged the analysis domain as high risk in five of eight prediction-model studies, and only one of eight models was externally validated. Conclusions: Despite a decade of refinements in grading, imaging, biopsy technique, and molecular profiling, biopsy-to-RP grade discordance remains substantial. Contemporary evidence supports incorporating PI-RADS, biopsy approach, and PSAD into shared decision-making; emerging molecular and AI-based predictors require prospective external validation in adequately powered, geographically representative cohorts before routine clinical adoption. Full article

Head and neck squamous cell carcinoma (HNSCC) remains a significant global health burden with limited survival improvement in locally advanced disease despite multimodal therapy. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have demonstrated substantial clinical benefit in recurrent or metastatic HNSCC, establishing PD-1 blockade as a standard of care. Similar approaches in locally advanced disease, including concurrent administration with chemoradiotherapy or use in the adjuvant setting, have not demonstrated improvement in survival outcomes across multiple randomized trials. Perioperative strategies incorporating neoadjuvant and adjuvant checkpoint inhibition have shown improved event-free and disease-free survival in resectable disease. Meta-analyses of concurrent and adjuvant approaches confirm limited benefit in unselected populations, with modest improvements restricted to biologically defined subgroups. Trial outcomes across disease settings demonstrate a consistent pattern in which therapeutic efficacy varies despite the use of similar agents. Rather than simply summarizing these clinical findings, this review integrates evidence across recurrent/metatstatic, unresected locally advanced and perioperative disease settings into a biologically focused framework to help explain the varying efficacies of immune checkpoint inhibition in HNSCC. Current evidence indicates that the effectiveness of immunotherapy in HNSCC is determined by the biologic context of treatment, including tumor antigen availability, host immune competence, and timing of immune activation. Administration of checkpoint blockade in the presence of intact tumor antigen and preserved immune function is associated with improved outcomes, whereas treatment delivered during or after cytotoxic therapy is limited by lymphopenia and reduced antigen exposure. By synthesizing randomized clinical evidence through this biologic framework, the review provides a conceptual perspective that may help explain previous trial outcomes and inform future biomarker-driven patient selection and treatment sequencing. Optimization of immunotherapy in HNSCC will depend on the integration of immune activation with disease context rather than an escalation of therapeutic intensity. Full article

Background/Objectives: Antimicrobial resistance (AMR) poses a major global health challenge, particularly in opportunistic pathogens such as Pseudomonas aeruginosa. This study aimed to identify metabolic adaptations associated with antibiotic resistance by integrating transcriptomic data from drug-resistant clinical isolates with a genome-scale metabolic model (GEM) of P. aeruginosa under four antibiotic treatments: ceftazidime (CAZ), ciprofloxacin (CIP), meropenem (MEM), and tobramycin (TOB). Methods: Transcriptomic data from 414 clinical isolates were integrated with the iPau21 genome-scale metabolic model (GEM) of P. aeruginosa. Differential gene expression analysis was performed using DESeq2, and differentially expressed genes (DEGs) were identified using a false discovery rate (FDR)-adjusted p-value < 0.05 and a fold-change threshold of ≥2 or ≤0.5. Reporter metabolites (RMs) were identified using the Reporter Metabolite algorithm with an FDR-adjusted p-value < 0.05. Pathway enrichment analysis was performed to characterize condition-specific metabolic alterations, and pathway significance was determined using the Benjamini–Hochberg procedure with an adjusted p-value < 0.05. Results: The analysis revealed predominantly antibiotic-specific transcriptional responses, with limited overlap in DEGs across treatment conditions. Reporter metabolite and pathway enrichment analyses identified distinct metabolic adaptations associated with biofilm formation, virulence, and stress response pathways. Several metabolites, including propionic acid, acetic acid, L-inositol, glutamine, glutarate, fumarate, and melatonin, were computationally prioritized candidate metabolites for future metabolite-based adjuvant strategies aimed at enhancing antibiotic efficacy. Conclusions: This systems biology approach provides a comprehensive framework for identifying metabolic vulnerabilities associated with AMR in P. aeruginosa. The identified metabolites represent candidate antibiotic adjuvant molecules generated through computational prioritization and should be regarded as hypotheses for future experimental validation rather than validated therapeutic interventions. These findings provide a foundation for future studies exploring metabolism-based strategies to improve antibiotic efficacy and combat antimicrobial resistance. Full article

Background/Objectives: Oral mucosal melanoma (OMM) is a malignancy in which durable local control must be balanced against preservation of speech, swallowing, mastication, and oral structure. Although cryotherapy is a repeatable and function-preserving local modality, its role within contemporary multidisciplinary care has not been clearly defined. This study describes a stage-adapted cryotherapy-based management framework for primary OMM and evaluates survival, local recurrence, and prognostic factors in a contemporary single-center cohort. Methods: We retrospectively reviewed 43 patients with primary OMM treated between 2016 and 2026. Treatment allocation was non-randomized and made through multidisciplinary assessment: stage II–III patients received cryotherapy alone, whereas stage IV patients received cryotherapy combined with wide local excision; postoperative adjuvant therapy was considered individually. Overall survival (OS) was estimated using Kaplan–Meier methods, and prognostic factors were explored using univariable Cox regression. Results: Median follow-up was 35 months. Estimated 2-year and 5-year OS for the whole cohort were 93.0% and 69.8%, respectively. Local recurrence occurred in 2/11 stage II–III patients and 18/32 stage IV patients. Among stage IV patients, postoperative adjuvant therapy was associated with OS in an unadjusted exploratory comparison (p = 0.03); this association may be affected by confounding by indication and selection bias and should not be interpreted as a treatment effect. Nodal metastasis was associated with worse OS in univariable analysis (HR, 3.342; p = 0.036). Conclusions: This small, single-center, non-randomized cohort describes an institutional stage-adapted cryotherapy-based management framework for OMM. The findings do not establish comparative efficacy or objectively demonstrate functional preservation. Prospective multicenter studies with standardized treatment selection, complete treatment reporting, validated functional outcomes, and quality-of-life measures are required. Full article

Background: Demographic change is leading to an increasing portion of octogenarians with pancreatic ductal adenocarcinoma (PDAC). Surgery remains a central component of curative-intent treatment. Nevertheless, it carries a risk of potentially life-threatening complications and high morbidity. Whether octogenarians benefit from surgery remains unclear. Methods: Using data from the clinical cancer registries of the 10th National Oncology Quality Conference of the ADT, we divided all patients with PDAC diagnosed between 2015 and 2023 into three age groups (≤65 years, n = 944; 66–79 years, n = 1535; ≥80 years, n = 537) and compared demographics, histopathology, treatment patterns, and survival data. Results: We observed an increasing proportion of octogenarians over the years from 15% in 2015 to 32% in 2023. While they were diagnosed with more favorable tumor stages, they more often received palliative chemotherapy (28% vs. 18%/19% in the younger cohorts). Only 24% of octogenarians who underwent surgery received adjuvant chemotherapy. Octogenarians had a worse overall and disease-free survival and 90-day mortality than the younger age groups. Furthermore, octogenarians with surgery or chemotherapy with curative intent alone had survival rates comparable to patients with palliative care. Conclusions: Octogenarians largely do not benefit from surgery alone. As only a quarter of octogenarians received adjuvant chemotherapy after surgery, neoadjuvant concepts might be useful for selecting patients who are fit enough to undergo and benefit from multimodal treatment. Full article

Breast cancer (BC) can be treated by combinations of surgery, radiotherapy, chemotherapy, endocrine therapy and targeted therapies. High-risk patients, including all patients with axillary involved lymph nodes with triple-negative BC (TNBC) and Her2-positive BC, are treated by neoadjuvant chemotherapy (NAC). For high-risk patients, immunotherapy for TNBC, trastuzumab and pertuzumab then trastuzumab deruxtecan for Her2-positive BC have improved survival. In this narrative review, we will discuss therapy for small triple-negative and HER2-positive early BC without involved or suspicious axillary lymph nodes. Upfront surgery is recommended for cT1a-b cN0 usN0 TNBC and Her2-positive BC with adjuvant therapy for pT1b pN0 BC, discussed case by case for pT1a pN0 Her2-positive BC. No adjuvant chemotherapy is considered for pT1a TNBC. However, lymph vascular invasion can also be contributive on pathologic results. For pT1c pN0 TNBC and Her2-positive BC, adjuvant therapy is recommended. For cT2 or cN+ TNBC and Her2-positive BC, NAC is the treatment recommended with adjuvant therapy after surgery according to pathologic results. For cT1c cN0 usN0 TNBC and Her2-positive BC, upfront surgery is the usual treatment proposed but NAC can be strongly considered according to clinic pathologic characteristics, tumor size 10–15 mm or 16–20 mm, grade, young age (≤35-years) and co-morbidities, particularly for elderly patients. Recent tools such as TIL level determined on core needle biopsy may help when considering NAC or upfront surgery and systemic therapy regimens. Other prognostic tools can contribute to the determined therapeutic strategy and systemic therapy regimens with escalation or de-escalation, such as TNBCDX or HER2DX, possibly in combination with TIL level. Full article

Introduction: Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers, with a subset progressing to locally advanced (laSCC) or metastatic (mSCC) stages. The introduction of anti-PD1 immunotherapy has transformed treatment, but real-world data remain limited, particularly in immunosuppressed patients. Methods: This single-centre, retrospective study included 189 patients with advanced cSCC treated between 2012 and 2022. Demographic, clinical, and treatment data were analyzed to assess clinical management and outcomes before and after the introduction of anti-PD1. Results: Among the 189 patients, 72.5% were male, with a median age of 79 years. Overall, 86 patients presented with laSCC and 103 with mSCC. In 100 patients, a preceding primary cSCC was documented, and its complete resection (R0) was associated with significantly better overall survival (OS) after diagnosis of advanced disease (p < 0.001). Immunosuppressed patients, including organ transplant recipients and those with chronic lymphocytic leukemia (CLL), had significantly reduced OS (p = 0.017 and p = 0.0059, respectively). First-line treatment prior to 2018 predominantly involved surgery and radiotherapy. Following the introduction of anti-PD1 therapy, its use increased rapidly in both first- and second-line settings. From 2018 onward, the number of advanced cSCC cases discussed at the multidisciplinary tumorboard increased approximately threefold. Median OS was significantly longer for mSCC patients treated in the post-2018 era (p = 0.025), while the survival disadvantage of CLL patients compared to non-CLL patients widened, suggesting limited benefit from advances in systemic therapy in this subgroup. Best overall response to first-line anti-PD1 correlated significantly with OS, with complete responders achieving a 1-year progression-free survival of 83.3%. Conclusions: The introduction of anti-PD1 has demonstrated improved survival outcomes in advanced cSCC, though significant challenges remain for immunosuppressed patients, particularly those with CLL and solid organ transplant recipients. Future research should focus on optimizing treatment for these high-risk groups, therapeutic sequencing, and the role of perioperative (neoadjuvant and adjuvant) immunotherapy strategies. Full article

One of the main issues in oncology is tumor recurrence following resection, which is responsible for a large number of patient deaths and treatment failures in a variety of malignancies. Despite advancements in adjuvant chemotherapy and radiation, residual disease that remains inside or close to the resection cavity and is difficult for systemic therapies to eradicate is the cause of further local recurrence. Hydrogel-nanoparticle (HNP) composites are a new class of therapeutic platforms that emerged from the recent convergence of biomaterial science and nanomedicine. Their specific goals are to fill the surgical gap, provide long-term localized drug release, and energetically remodel the post-surgical tumor microenvironment (TME). This paper includes the biological foundations of localized post-surgical therapy, important physicochemical considerations of the hydrogel matrix and nanoparticle carrier design, and a compilation of mechanistic and preclinical evidence for HNP hybrid platforms. Immunomodulatory strategies, stimuli-responsive release mechanism engineering, and novel techniques, including combination immunotherapy and 3D-printed customized scaffolds, are all given special attention. Examples of translational challenges are also addressed, such as manufacturing repeatability, biocompatibility, and regulatory classification. When considered collectively, the data demonstrate that HNP platforms are a convincing, practically feasible approach to reducing post-surgical recurrence rates and enhancing patient outcomes. Full article

Colorectal cancer (CRC) treatment with standard chemotherapeutics such as capecitabine (CAP) and irinotecan (IRT) is frequently limited by toxicity and resistance. To identify novel adjuvant strategies, we investigated the dichloromethane–methanol (DM) Soxhlet extract of the red alga Jania rubens, previously shown to exert intrinsic antiproliferative effects via reactive oxygen species (ROS) induction, inhibition of epithelial–mesenchymal transition (EMT), and suppression of TET enzymes. The present study evaluated the effect of the DM extract in combination with chemotherapeutic agents in HCT-116, Caco-2, and HT-29 colorectal cancer cell lines, assessing its potential to enhance treatment response. Co-treatment with the DM extract significantly enhanced the cytotoxic and anti-migratory effects of CAP and IRT in HCT-116 and Caco-2 cells. Combination treatment also impaired long-term clonogenic survival, suggesting the inhibition of therapy-resistant subpopulations. Flow cytometric analysis (Annexin V-FITC/PI) revealed a dose-dependent increase in apoptosis in HCT-116 cells following DM treatment. Western blot analysis further supported the pro-apoptotic activity of the DM extract by demonstrating reduced BCL-2 protein expression. The extract additionally modulated the mRNA expression levels of cytokines (TNF-α, IL-6, and IL-10), suggesting potential immunomodulatory effects in colorectal cancer cells. Notably, co-administration of IRT and the DM extract enhanced apoptosis, primarily through the downregulation of the anti-apoptotic gene BCL-2. Together, these findings indicate that the Jania rubens DM extract modulates multiple cellular pathways and enhances the response to conventional CRC chemotherapeutic agents. Full article

Colorectal cancer (CRC) kills approximately 850,000 people annually and is the second leading cause of cancer mortality worldwide. After curative-intent surgical resection, recurrence rates of 15–20% in stage II and 30–40% in stage III diseases highlight the fundamental limitations of pathological staging as the sole basis for adjuvant treatment decision-making. Circulating tumor DNA (ctDNA), which comprises tumor-derived cell-free DNA fragments shed into the bloodstream by dying cancer cells, offers a direct and dynamic readout of molecular residual disease (MRD) in the postoperative period. Because ctDNA clears within hours of macroscopically complete surgery, any persistently detectable postoperative signal reflects viable microscopic disease rather than surgical contamination. Over the past decade, evidence has matured rapidly from proof-of-concept observational studies to completed randomized clinical trials, culminating in the recent publication of DYNAMIC-III and ALTAIR in 2025–2026. The DYNAMIC trial established that ctDNA-guided management reduced adjuvant chemotherapy use from 27.9% to 15.3% in stage II colon cancer while maintaining an equivalent five-year recurrence-free survival (88% vs. 87%; difference 1.1%, 95% CI 5.8% to 8.0%). The GALAXY study confirmed ctDNA as the most powerful prognostic biomarker in resected CRC, with a disease-free survival hazard ratio of 11.99. Critically, DYNAMIC-III demonstrated that escalating chemotherapy intensity in ctDNA-positive stage III patients did not improve recurrence-free survival (HR 1.11, p = 0.6), and the phase III ALTAIR trial showed that trifluridine/tipiracil failed to significantly improve disease-free survival at the point of molecular recurrence (HR 0.79, p = 0.107). This review critically synthesizes the current evidence for ctDNA-guided treatment decisions in resected CRC across three therapeutic strategies: de-escalation in ctDNA-negative patients, escalation in ctDNA-positive patients, and post-adjuvant therapy at the point of molecular recurrence. Future progress requires biomarker-matched escalation strategies, adaptive trial designs, and formal validation of ctDNA clearance as a surrogate endpoint for predicting patient outcomes. Full article

Obesity is a global metabolic disease closely associated with dyslipidemia, insulin resistance, hepatic steatosis, and chronic oxidative stress. Cydonia oblonga Miller (COM, Quince) from Xinjiang Uygur Autonomous Region of China is a traditional medicinal and edible plant rich in polyphenols, flavonoids, polysaccharides, and other bioactive constituents. Our previous studies suggested that total polyphenols of Cydonia oblonga Miller (TPCOM) may exert promising anti-obesity effects. Objective: This study aimed to investigate the therapeutic effects of TPCOM on high-fat diet-induced obese C57BL/6 mice and to explore its underlying molecular mechanisms related to glycolipid metabolism. Methods: TPCOM was extracted and purified from Xinjiang Cydonia oblonga fruits, and its total polyphenol content was determined using the Folin–Ciocalteu method. C57 mice were randomly divided into normal diet, model, and TPCOM intervention groups. After 12 weeks of high-fat diet feeding and 6 weeks of TPCOM treatment, body weight was monitored continuously. Serum levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and total antioxidant capacity (T-AOC) were measured using commercial kits. Hepatic pathological changes were observed by hematoxylin–eosin (HE) staining. Bioinformatics analyses including GO and KEGG were performed to predict key targets and pathways related to lipid metabolism. The protein expression levels of PPARGC1A, FFAR1, KLF15, Adipolin, GLUT4, and phosphorylated p38 MAPK in liver tissues were detected by Western blotting. Results: TPCOM intervention significantly reduced body weight gain in obese mice in a dose-dependent manner. Serum biochemical assays showed that TPCOM decreased TC, TG, and LDL-C levels, increased HDL-C levels, and markedly enhanced total antioxidant capacity (T-AOC). Bioinformatics analysis suggested that PPARG and FFAR1 were highly expressed in liver tissue and may participate in glucose and lipid metabolism regulation. Western blot results confirmed that TPCOM significantly upregulated the expression of PPARGC1A, FFAR1, KLF15, Adipolin, GLUT4, and phosphorylated p38 MAPK in the liver of obese mice. Conclusions: TPCOM effectively ameliorates obesity, dyslipidemia, hepatic steatosis, and oxidative stress in high-fat diet-induced obese mice. The underlying mechanism may be related to the regulation of glycolipid metabolism, mitochondrial function, insulin sensitivity, and antioxidant signaling via activating the FFAR1–PPARG–p38 MAPK axis and downstream targets including PPARGC1A, KLF15, Adipolin, and GLUT4. This study provides a scientific basis and theoretical support for the development and application of TPCOM as a natural functional ingredient in the prevention and adjuvant treatment of obesity and related metabolic disorders. Full article

Cyclin-dependent kinase 4/6 inhibitors have fundamentally changed the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. However, these drugs are not interchangeable and the field is moving away from the notion of a uniform “class effect.” In early breast cancer, adjuvant abemaciclib and ribociclib improve invasive disease-free survival in patients at a high risk of recurrence, whereas palbociclib does not. This difference likely stems from agent-specific pharmacological profiles, differences in trial design, and patient selection, rather than simply dosing nuances. In metastatic breast cancer, all three agents prolong progression-free survival when combined with endocrine therapy, but only ribociclib and potentially abemaciclib have shown an overall survival advantage. In addition, resistance remains a major obstacle in clinical practice. We propose that resistance mechanisms can be meaningfully grouped into two categories: target-driven (e.g., RB1 loss, CDK6 amplification) and bypass-driven (e.g., ESR1 mutations, PI3K/AKT pathway activation, APOBEC3-mediated mutagenesis). Distinguishing between these classes helps in the design of rational sequencing algorithms and combinatorial regimens. Emerging strategies, such as next-generation protein degraders, oral selective estrogen receptor degraders, antibody–drug conjugates, and inhibition of autophagy, are promising methods for overcoming resistance. Moving forward, the greatest need in breast cancer treatment will be not simply developing additional agents but using current therapies more intelligently by refining biomarker-guided patient selection, tailoring treatment duration, and ensuring broad global access. Full article

Background and Objectives: Neuropathic pain presents a significant therapeutic challenge, often due to resistance to opioids. This study examined how selective adenosine receptor agonists and allopurinol modulate spinal mu-opioid receptor (MOR) mRNA expression in a rat model of neuropathic pain, aiming to develop a novel strategy for restoring opioid homeostasis. Materials and Methods: Male Sprague-Dawley rats were subjected to L5 spinal nerve ligation (SNL). The animals received treatment with selective A1AR (CCPA, 1 mg/kg) or A3AR (IB-MECA, 1 mg/kg) agonists, or allopurinol (10 or 50 mg/kg) for three days. Spinal MOR mRNA expression was measured on day 7 post-SNL using qRT-PCR. Results: SNL resulted in a non-significant upward trend in MOR transcription. Selective agonists (CCPA and IB-MECA) appeared to enhance or maintain MOR levels compared to the vehicle-treated group, but the most pronounced trend toward recovery of MOR mRNA expression was observed with high-dose allopurinol (50 mg/kg). Effect size analysis revealed large Cohen’s d values for high-dose allopurinol (d = 1.05) and CCPA (d = 0.90) versus sham, supporting the biological relevance of these preliminary trends. Conclusions: These preliminary findings suggest that augmenting endogenous adenosine bioavailability with allopurinol may be more effective than targeting individual receptor subtypes in modulating the spinal opioid system. As this is an exploratory pilot investigation, these results should be interpreted as hypothesis-generating rather than confirmatory. Since allopurinol is already a clinically established drug, these findings offer a mechanistic rationale warranting further investigation of its potential as an adjuvant for opioid resistance in chronic pain management. Full article

Immune checkpoint inhibitors (ICIs) are now being introduced into perioperative treatment for several solid tumors. This strategy is usually explained by tumor reduction before surgery or by the elimination of minimal residual disease (MRD) after surgery. However, these explanations may not be sufficient to understand why the timing of ICI treatment, especially before lymph node (LN) removal, is important. In this review, we discuss tumor-draining lymph nodes (tdLNs) from two different aspects. tdLNs are anatomical routes for regional and distant metastasis, but they are also sites where tumor antigens are presented and tumor-specific T cell responses are generated. In particular, preclinical and translational studies suggest that tdLNs may maintain stem-like or progenitor-exhausted T cells (TPEX) that can respond to PD-1 blockade and supply more differentiated exhausted T cells to tumor sites. However, current clinical trials of perioperative ICIs demonstrate therapeutic benefit in specific diseases and regimens, but do not directly establish tdLN preservation or tdLN-resident TPEX maintenance as the decisive mechanism of efficacy. We therefore present the tdLN-reservoir model as a hypothesis-generating framework rather than as a clinically validated basis for modifying lymph node management. We also discuss the possible roles of neoadjuvant and adjuvant ICI in relation to antigen flow, minimal residual disease, metastatic-site draining LNs, postoperative lymphatic dysfunction, and future immune-guided clinical trials. Importantly, current evidence does not support altering standard lymph node surgery or radiotherapy solely to preserve putative tdLN immune-reservoir function. Full article