The growing population of childhood cancer survivors faces an elevated risk of developing subsequent malignant neoplasms (SMNs). Over the past decades, childhood cancer treatments have evolved. Although reductions in radiation dose have been shown to lower SMN risk, the impact of changes in chemotherapy remains unclear. We evaluated whether treatment changes have affected SMN risk over time and examined treatment-related risk factors. We included 10,612 five-year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort (1963 to 2014). Multivariable Cox proportional hazard regression was used to estimate SMN risks, and to evaluate effects of treatment changes over time. After a median follow-up of 20.4 years, 493 survivors developed an SMN. Overall, the risk for SMN declined over period of diagnosis (p-trend 0.04). The decline in SMN risk was primarily associated with a decreased use of radiotherapy (p-trend after radiotherapy adjustment : 0.51). Chemotherapy seemed to have the opposite effect, mainly due to the use of anthracyclines and/or epipodophyllotoxins (p-trend after chemotherapy adjustment:<0.001). Survivors treated with anthracyclines (HR : 1.3, 95%CI : 1.0 to 1.6), epipodophyllotoxins (HR : 1.3,95%CI : 1.0 to 1.7) or radiotherapy (HR : 2.3, 95%CI : 1.9-2.8) had significantly increased risks of SMN. While reductions in radiotherapy have lowered SMN risk throughout periods of diagnosis, the increased use of chemotherapy, especially anthracyclines and epipodophyllotoxins, increased SMN risk. Furthermore, survivors treated with radiotherapy, anthracyclines, or epipodophyllotoxins have an elevated risk of any SMN. This highlights the importance of continued optimization of treatment protocols, eg through chemotherapy dose reduction, to balance treatment efficacy with long-term health risks and to better identify survivors at risk.
The ProtecT randomized trial found similar survival between active surveillance (AS), radiotherapy (RT), and radical prostatectomy (PT) in localized prostate cancer (PC), but observational studies yielded conflicting results. This study aims to emulate ProtecT by comparing survival outcomes of men with localized PC undergoing PT or RT versus AS/watchful waiting (WW). This target trial emulation study used the Korean Nationwide Health Insurance, Cancer Registry, and Death Registry linkage data (2012-2020). We included men (50-69 years) diagnosed with a first malignant localized PC. Primary outcome was PC-specific death, and secondary outcomes were all-cause death, metastasis, and antidepressant initiation. Two cohorts (PT vs. AS/WW and RT vs. AS/WW) were analyzed using Cox regression to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Among 8,036 localized PC patients, 1,191 PT vs. 1,191 AS/WW and 428 RT vs. 428 AS/WW individuals were identified. During a mean follow-up of 4.4 years, PC-specific death occurred in 2 men (0.2%) in PT and 2 men (0.2%) in AS/WW, and 3 men (0.7%) in RT with 1 man (0.2%) in AS/WW. AS/WW showed comparable risks of PC-specific and all-cause death and metastasis as PT and RT. Compared to AS/WW, PT and RT showed lower risks of antidepressant initiation (HR [95% CI] 0.73 [0.58-0.93] for PT and HR 0.38 [0.24-0.61] for RT, respectively). In this target trial emulation study, AS/WW showed similar risks of mortality and metastasis as PT and RT, while PT and RT showed favorable outcomes with antidepressant initiation in Asian men with localized PC.
Long-term survivors of pediatric Hodgkin lymphoma are at risk of late treatment-related mortality, cancer, and heart disease. While modified treatments have reduced radiation exposure, long-term risks in late adulthood are unknown. Using a simulation model based on data from the Childhood Cancer Survivor Study and national databases, we projected overall survival and cumulative incidence of breast cancer and heart failure for 5-year survivors treated with extended-field RT, chest RT ≥ 35 Gy, chest RT < 35 Gy, or chemotherapy only. Estimates were compared with general population individuals who faced only age-related risks. We report the mean and 95% uncertainty intervals (UIs) among 1000 iterations. At age 65, projected overall survival ranged from 24.7% (95% UI, 17.7 to 32.5) after extended-field RT to 71.8% (44.9 to 81.8) after chemotherapy only, compared with 86.4% (83.8 to 88.8) in the general population. Cumulative breast cancer incidence among female survivors was 61.1% for extended-field RT, 59.7% for chest RT ≥ 35 Gy, 49.8% for chest RT < 35 Gy, and 17.9% for chemotherapy only, respectively, versus 6.1% in the general population. Heart failure risks among all survivors were 34.8%, 33.4%, 28.4%, and 16.0, respectively, versus 4.3%. Across all subgroups, breast cancer and heart failure were projected to occur 16.1-31.7 and 21.0-25.9 years earlier, respectively, relative to general population risks at age 65. Although historical reductions in RT dose and field have substantially improved long-term survival, survivors treated with lower-dose or chemotherapy alone remain at markedly elevated risk for early-onset breast cancer and heart failure.
The treatment landscape for Chronic Hand Eczema (CHE) is evolving; however, evidence on patients' preferences regarding CHE treatment attributes is sparse. This discrete choice experiment (DCE) assessed how treatment attributes influence preferences among patients with moderate to severe CHE in the USA. Adults with moderate to severe CHE recruited from an online panel completed a web-based DCE survey (August-September 2025). Seven treatment attributes, identified via literature review, qualitative patient interviews, and clinical expert input, reflected efficacy (improvements in itch, skin appearance, and pain), safety (risks of infections, cancer, and major heart problems), and administration mode/frequency. Patient preferences were analyzed using conditional logistic regression. Attributes' relative importance and willingness to trade off were calculated. Sensitivity analysis excluding participants who failed ≥ 1 validity test was conducted. Of the 300 participants with CHE included (mean age: 44.9 years; 50% female; 84.7% employed), most reported multiple CHE subtypes (70.3%). The vast majority of participants reported life impairment due to CHE, including for activities of daily living (96.3%) and work productivity (92.9%). In the DCE, all treatment attributes had a significant impact on treatment preferences (p < 0.001). Attributes with the highest relative importance were related to efficacy: itch improvement (22%) and skin appearance improvement (21%); followed by those related to safety: avoiding risk of cancer (16%) and risk of infections (14%). Other important attributes for patients included pain improvement (13%) and administration mode/frequency (7%). Participants would forgo 28.1, 11.4, and 1.3 percentage points of itch improvement probability to avoid a 1-percentage-point risk of cancer, major heart problems, and infections, respectively. Improvement in efficacy outcomes (itch and skin appearance) and lower risks of certain adverse events (cancer, infections) were the most important treatment attributes for patients with CHE. This study provides insights that may help support shared decision-making to ultimately improve treatment satisfaction and adherence.
This letter to the editor offers a constructive commentary on a recently published multivariate analysis of predictors of complications in abdominoplasty. The authors commend the original study for its rigorous surgical standardization, consecutive patient enrollment, and single‑surgeon design, and agree that high body mass index and active smoking are independent risk factors, while preservation of Scarpa's fascia appears protective. However, three methodological limitations are identified. First, the sample size and number of events barely meet the minimum recommended events‑per‑variable ratio for multivariate regression. Second, treating seroma, necrosis, and dehiscence as independent outcomes ignores competing risks among these complications, which may bias risk estimates. Third, the single‑center, single‑surgeon design limits external validity, and the finding that diabetes is not a risk factor contradicts some existing literature. The letter suggests that future analyses adopt competing‑risk models and include multicenter external validation. It also notes that no new patient data are provided, so the proposed statistical refinements await empirical verification.Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Ischemic stroke (IS) is the most prevalent cerebrovascular disease, with a high proportion of patients developing lifelong disability. Cerebral microcirculatory dysfunction is a key driver of poor IS prognosis. Hypoxia-induced cerebral angiogenesis could improve cerebral perfusion but risks blood-brain barrier (BBB) disruption, worsening outcomes. We previously found that intermittent hypoxia (IH) promotes cerebral angiogenesis and improves IS outcomes, but whether it maintains BBB integrity during angiogenesis and the underlying mechanism remains unclear. This study established mouse hypoxia models, including IH and continuous hypoxia (CH) treatment groups. We found that both IH and CH transiently increased cerebrovascular permeability via angiogenesis activation. However, IH restored permeability to baseline over time, with astrocyte end-foot wrapping, pericyte coverage, and tight junction protein ZO-1 level in neovessels comparable to controls. In contrast, CH failed to recover vascular leakage and BBB integrity within the same period. Mechanistically, IH uniquely activated both hypoxia-inducible factor (HIF)-1α and HIF-2α, while CH only activated HIF-2α. HIF-1α-specific activation in the IH group promoted downstream vascular endothelial growth factor (VEGF)-B transcription, which antagonized VEGFA-mediated endothelial barrier disruption and adhesion molecule upregulation. This study demonstrates that IH maintains neovascular BBB integrity via the HIF-1α/VEGFB pathway, providing a theoretical basis for novel IS interventions and targeted drug development.
Symptomatic vertebrobasilar dolichoectasia (VBD) is associated with an extremely poor natural prognosis and presents significant clinical challenges. This study aims to evaluate the safety and efficacy of a flow reversal strategy based on extracranial carotid artery-radial artery-posterior cerebral artery (ECA-RA-PCA) bypass, combined with individualized proximal parent artery intervention, for the treatment of symptomatic VBD. We retrospectively analyzed the clinical data of 23 consecutive patients with symptomatic VBD treated with microsurgery between October 2019 and July 2025. Patients were categorized into ischemia-dominant (n = 13), compression-dominant (n = 8), and hemorrhage-dominant (n = 2) subtypes based on their primary clinical presentation. All patients underwent ECA-RA-PCA bypass. Differentiated treatment strategies were implemented based on clinical subtypes: ischemia-dominant patients mostly received bypass alone (12/13, 92.3%), whereas compression-dominant (6/8, 75.0%) and hemorrhage-dominant (2/2, 100%) patients primarily underwent bypass combined with proximal occlusion. Surgical success was achieved in all cases, with a graft patency rate of 100% intraoperatively and during follow-up. Over a median follow-up of 38 months (IQR 23-51), 69.6% (16/23) of patients achieved radiographic improvement (43.5% with lesion regression and 26.1% with obliteration), with no instances of aneurysm rupture or progression. The median Modified Rankin Scale (mRS) score improved from 3 (IQR 2-4) preoperatively to 2 (IQR 1-4) at the last follow-up. The overall favorable clinical outcome rate was 69.6%; the ischemia-dominant group achieved the highest favorable rate (84.6%), followed by the compression-dominant group (62.5%). Major complications included brainstem infarction (30.4%) and pneumonia (39.1%), both of which occurred at higher rates in the compression and hemorrhage groups. For complex symptomatic VBD unsuitable for conventional endovascular treatment, an individualized flow reversal strategy based on ECA-RA-PCA bypass and clinical subtyping is a feasible and effective therapeutic option, albeit with inherent high surgical risks. This strategy maintains long-term flow patency, promotes benign remodeling of the diseased vessel, and may be associated with favorable long-term neurological outcomes in carefully selected patients.
Increasing availability of delta-9-tetrahydrocannabinol (Δ9-THC) analogs including Δ9-tetrahydrocannabutol (Δ9-THCB), Δ9-tetrahydrocannabihexol (Δ9-THCH), and Δ9-tetrahydrocannabiphorol (Δ9-THCP) in unregulated products has raised questions about the impact of alkyl sidechain length not only on potency, but on metabolism. Δ9-THC homologs were metabolized in vitro with human liver microsomes, and multiple time points were collected. Multiple reaction monitoring (MRM) and precursor ion (PI) scanning methods presumptively identified that Δ9-THCB, Δ9-THCH, and Δ9-THCP produced hydroxylated and carboxylated phase I biomarkers, similar to those of Δ9-THC. The use of universal product ions containing a common core highlights their potential to assist laboratories in future identification of novel Δ9-THC analogs. One carbon deviation in alkyl sidechain length resulted in a decreased formation of the hydroxylated biomarker; whereas two carbon deviations further decreased the amount produced. Although the metabolism rate of the hydroxylated biomarkers was reduced, any deviation from the five-carbon sidechain increased the conversion from the hydroxylated biomarker to the carboxylated biomarker by the cytochrome P450 enzymes. Presumptive identification of novel THC analog metabolites provides new analytical targets for toxicology laboratories seeking the causative agent(s) in cases of suspected intoxication and/or drug toxicity. By understanding the metabolism of novel THC analogs, critical information can then be provided to the public regarding the potential risks of these mass-produced products.
There is a limited understanding of the uptake of pharmacological treatments and incidence of clinical events in newly diagnosed heart failure (HF) patients, stratified by left-ventricular ejection fraction (LVEF) in contemporary clinical settings in Japan. A retrospective cohort study was conducted using a nationwide Japanese hospital database to evaluate the patterns of HF medications and clinical events in adult patients with a first confirmed HF diagnosis from January 1, 2020-July 31, 2023 (n = 16,001). Fine-Gray sub-distribution hazard models were applied to assess factors associated with HF medication initiations and clinical events. Overall, 5473 (34.2%), 3053 (19.1%), and 7475 (46.7%) patients with HF with reduced ejection fraction, mildly reduced ejection fraction (HFmrEF), and preserved ejection fraction (HFpEF) were included, respectively. Within the first 6 months, prescription rates of HF medications were: angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or angiotensin receptor blocker-neprilysin inhibitor (65.6%), beta-blockers (57.6%), mineralocorticoid antagonists (55.7%), and sodium-glucose cotransporter-2 inhibitors (33.2%), with the lowest rates in HFpEF patients. The increase in prescription rates between 6 and 12 months was modest across all medication classes. One-year incidence rates per 100 person-years (95% confidence interval) of in-hospital all-cause mortality and in-hospital cardiovascular death were 23.0 (22.1-24.0) and 16.6 (15.8-17.4), respectively. HFmrEF and HFpEF were associated with lower hazards of treatment initiation for most HF medications, whereas the risks of in-hospital all-cause mortality and in-hospital cardiovascular death did not differ significantly across all LVEF subtypes. The findings underscore the suboptimal uptake of pharmacological treatments, despite the poor prognosis of newly diagnosed HF patients. The disparities in initiations of recommended treatments reaffirm the importance of properly implementing evidence-based therapies within each LVEF subtype.
Environmental exposure assessment remains under-integrated in maternal and neonatal care despite growing evidence that pregnancy, fetal development, and early neonatal life are highly sensitive periods during which environmental exposures may influence immediate and longer-term health. This narrative mini-review highlights the clinical relevance of environmental exposures in maternal and neonatal practice, outlines why exposure assessment remains underused in routine care, and proposes a pragmatic framework for integration. Key barriers include limited clinician training, unclear referral pathways, and the perception that environmental risks are difficult to assess and interpret in clinical settings. A targeted approach may be most appropriate in high-risk pregnancies, unexplained adverse outcomes, fetal growth restriction, preterm birth, and medically vulnerable neonates. A practical framework based on recognizing higher-risk situations, obtaining a focused exposure history, and acting through counseling, referral, or selective testing is proposed to help bring environmental health closer to routine maternal and neonatal care. What is Known? • Pregnancy, fetal development, and early neonatal life are highly sensitive periods during which environmental exposures may influence health and development. • Environmental exposure assessment remains underused in routine maternal and neonatal care because of limited clinician training, unclear referral pathways, and uncertainty about how to act on exposure concerns. What is New? • This narrative mini-review proposes a practical framework for integrating environmental exposure assessment intomaternal and neonatal care through focused history taking, counseling, referral, and selective testing when appropriate. • A practical screening table is provided with example exposure questions, red flags, and suggested clinical actions to support real-world clinical decision-making.
Dengue transmission remains a major public health challenge in rapidly urbanising regions, yet spatial risk patterns may vary across residential environments. This study investigated how housing typology, surrounding land use, and built-vegetation interfaces may represent environmental zones associated with elevated dengue occurrence in Kuala Selangor, Malaysia. Using validated georeferenced dengue surveillance records collected between 2020 and 2024, we applied GIS-based spatial analyses across three dominant residential housing typologies: terrace/landed housing, high-rise housing, and traditional/rural housing. Terrace housing demonstrated relatively stronger and more spatially continuous clustering patterns compared with other housing environments. Dengue occurrence in these areas was more closely associated with dense built-up surroundings and nearby vegetation. High-rise housing showed more localized clustering within highly built environments, whereas traditional and rural housing exhibited broader but weaker clustering patterns across more environmentally mixed landscapes. Overall, the findings suggest that dengue spatial distribution patterns differ according to housing structure and surrounding environmental context. The built-vegetation interface may represent an important environmental zone associated with elevated residential dengue occurrence, particularly in dense terrace housing settings. These findings highlight the importance of adapting vector control strategies to local residential environments, including targeted management of peri-domestic vegetation in terrace housing, infrastructure-focused interventions in high-rise settings, and broader environmental management approaches in rural areas.
Variants in TPMT and NUDT15 genes that affect thiopurine metabolism can guide personalized dosing to minimize toxicity. Decreased or no appreciable NUDT15 activity demonstrates impaired breakdown of active thiopurine metabolites which can lead to severe adverse events including potentially life-threatening myelosuppression. Recently, the NUDT15*6 allele was re-classified from having uncertain function to no function by the Clinical Pharmacogenetics Implementation Consortium. Here, we present a pediatric patient with a NUDT15*1/*6 genotype who experienced significant thiopurine-induced myelosuppression. The patient is a 4-year-old female with standard risk-average precursor B-cell acute lymphoblastic leukemia treated per AALL1731. Exome sequencing determined TPMT*1/*1 (normal metabolizer) and NUDT15*1/*6 (indeterminate metabolizer). After 75 mg/m2/day mercaptopurine, myelosuppression necessitated a three-week delay prior to the next phase of therapy. With 60 mg/m2/day thioguanine in a subsequent phase of therapy, she was admitted twice for fever and neutropenia. In the final phase of therapy, mercaptopurine at standard dosing of 75 mg/m2/day caused severe neutropenia and thrombocytopenia with elevated metabolite levels that required stopping mercaptopurine. After neutrophil recovery, a trial of 50% standard dosing was not tolerated and her dose was reduced to 27%, which was tolerated. Among 339 patients with cancer, sequencing revealed an allele frequency of 0.88% for NUDT15*6. In a larger cohort sequenced for suspicion of rare genetic disease, the frequency of NUDT15*6 was 0.15% among 1011 unrelated individuals. This brief report supports the recent update that patients with the NUDT15*1/*6 genotype should be classified as intermediate metabolizers.
Psoriatic arthritis (PsA), a chronic inflammatory disease associated with psoriasis, may be influenced by cardiovascular health (CVH). This study aims to investigate the associations between three CVH scores (Life's Simple 7 (LS7), Life's Essential 8 (LE8), and Life's Crucial 9 (LC9)) and a psychological health (PH) score with PsA risk and potential interactions with genetic susceptibility. Using data from the UK Biobank and NHANES cohorts, we conducted prospective and cross-sectional analyses employing Cox proportional hazards and multivariable logistic regression models, respectively. Additionally, a polygenic risk score (PRS) was derived in the UK Biobank to quantify genetic susceptibility to PsA and examine its interactions with CVH and PH metrics. Higher scores in LE8, LC9, and PH showed consistent inverse associations with PsA, with the most pronounced association observed for LC9. Higher LC9 scores showed a strong inverse association with PsA (highest vs lowest group: OR = 0.25 (95% CI 0.05, 0.86), HR = 0.20 (95% CI 0.06, 0.65)). Each 10-point LC9 increase corresponded to lower PsA risk (OR = 0.76 (95% CI 0.58, 0.98), HR = 0.68 (95% CI 0.54, 0.86)). Genetic risk (assessed as the inverse of the PRS) showed significant antagonistic interactions with LE8, LC9, and PH scores. Inverse associations were observed between LE8, LC9, and PH scores and PsA risk, along with notable interactions with genetic predisposition. Key Points • Higher LE8, LC9, and PH scores showed inverse associations with PsA. • LC9 showed the strongest inverse association with PsA in both cohorts. • Genetic susceptibility showed antagonistic interactions with LE8, LC9 and PH scores.
Despite recent progress in improving patient survival, the outcomes in approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) remain poor. For many years, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard first-line treatment for DLBCL; however, pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone) has recently emerged as a new treatment option. In parallel, novel molecularly targeted therapies that target signaling pathways, cellular antigens, and epigenetic regulators associated with high-risk DLBCL are in development. Treatment strategies tailored to the cell of origin or to specific molecular subtypes are also being explored using subtype-specific targeted agents. In addition, agents that have demonstrated efficacy in patients with relapsed or refractory DLBCL-such as the anti-CD19 antibody tafasitamab and immunomodulatory drugs such as golcadomide-are currently under investigation for use in newly diagnosed patients. Immunotherapies, including anti-CD19-chimeric antigen receptor-T therapy and CD20×CD3 bispecific antibodies (BsAbs), have significantly improved outcomes in patients with relapsed or refractory disease and are now under evaluation as early-line therapies. BsAbs can enable more flexible treatment strategies, including combination regimens with cytotoxic or chemotherapy-free approaches. This review summarizes recent advances and ongoing trials that are investigating novel therapeutic strategies for newly diagnosed DLBCL that may soon be incorporated into clinical practice.
Hypoalbuminemia is a well-known marker of poor nutritional status and has been linked to adverse outcomes in various surgical specialties. However, its role in mastectomy remains underexplored. This study investigates the impact of hypoalbuminemia on 30-day postoperative outcomes in patients undergoing mastectomy for breast cancer. Using data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2011 to 2021, we identified 37,848 female breast cancer patients who underwent mastectomy without concurrent reconstructive procedures and had documented preoperative serum albumin levels measured within 30 days of surgery. Patients were stratified by albumin level (< 3.5 g/dL vs. ≥3.5 g/dL). Multivariate logistic regression was used to assess the association between hypoalbuminemia and postoperative 30-day outcomes. ROC analysis identified albumin thresholds predictive of complications. Among 37,848 patients, 3,210 (8.5%) were hypoalbuminemic. Hypoalbuminemia was significantly associated with higher rates of any complication (16% vs. 10%; OR 1.4, p < 0.001), surgical complications (10% vs. 5.5%; OR 1.5, p < 0.001), medical complications (0.37% vs. 0.13%; OR 1.8, p < 0.001). Similarly, readmissions were significantly more frequent in hypoalbuminemic patients (7.0% vs. 3.9%; OR 1.6, p < 0.001). The need for transfusion was over three times higher (5.0% vs. 1.4%, p < 0.001), and hypoalbuminemia was associated with longer hospital stays (2.2 vs. 1.3 days, p < 0.001). Subgroup analysis revealed that these trends persisted across both total and radical mastectomy procedures. Optimal albumin thresholds for predicting complications ranged from 3.7 to 4.1 g/dL, depending on the type of complication. Preoperative hypoalbuminemia is an independent predictor of increased postoperative morbidity following mastectomy. Clinicians may consider selective albumin assessment as a pragmatic tool for identifying patients with increased physiological vulnerability who may benefit from targeted preoperative optimization strategies, rather than as a stand-alone indicator of nutritional deficiency; however, further research is needed to establish optimal testing strategies and confirm clinical benefits.
Dysregulation in chemotaxis and activation of neutrophils may trigger cancer. Nevertheless, the function of neutrophils and their mechanism during the prognosis of pancreatic cancer (PC) remain unclear. From the databases of The Cancer Genome Atlas (TGCA) and GeneCards, the genes of tumor-associated neutrophils (TANs) were screened out leveraging the differential expression analysis. The constructed prognostic model for PC was analyzed through the least absolute shrinkage and selection operator (LASSO) regression and Cox univariate and multivariate regression. The dataset (GSE62452) provided by the Gene Expression Omnibus (GEO) database served as the validation cohort, and its potential mechanistic pathways and biological functions were analyzed leveraging Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The immune infiltration analysis, as well as the drug sensitivity prediction, were conducted. The gene expression in the prognostic model was checked through online databases, including Human Protein Atlas (HPA) and Tumor Immune Single-Cell Hub (TISCH). Finally, the genes were experimentally confirmed by immunohistochemistry (IHC) and qPCR in combination with clinical samples from patients with PC. AIM2, PSCA, IL18BP, and LIPE were four genes of TANs closely linked to the prognosis of PC. A model for the prognosis of PC was established utilizing these 4 genes. The AUC (area under the receiver operating characteristic curve (ROC curve)) values of this model for forecasting the survival rates of patients at 1, 2, and 3 years were 0.774, 0.841, and 0.953, respectively. The immune infiltration analysis revealed that resting dendritic cells (resting DCs), naive B cells, CD8T cells, as well as follicular helper T cells, were highly infiltrated among patients suffering from PC. According to the drug sensitivity analysis, the high-risk pancreatic ductal adenocarcinoma (PAAD) group had a significantly higher inhibitory concentration 50 (IC50) for dactolisib, docetaxel, gemcitabine, and ulixertinib compared to the group by patients with low-risk PAAD. The results of IHC and qPCR confirmed those of bioinformatics analysis. New TANs-related biomarkers have been found that effectively forecast the prognosis of patients suffering from PAAD.
Tacrolimus pharmacokinetics shows wide interindividual variability after allogeneic hematopoietic cell transplantation (HCT), potentially influencing both effectiveness and toxicity. The concentration-to-dose (C/D) ratio has been proposed as a simple surrogate marker of tacrolimus metabolism, enabling patient stratification into fast or slow metabolizers. In this retrospective single-center study, we evaluated the clinical applicability of the C/D ratio in 71 HCT recipients treated between 2014 and 2023. Fast metabolizers (< 420 ng/mL·1/mg/kg) required higher tacrolimus doses and exhibited lower trough concentrations compared with slow metabolizers (≥ 420). Slow metabolizers had a higher risk of moderate-to-severe acute kidney injury (AKI) within 21 days after starting tacrolimus (HR 3.72; 95% CI 1.19-11.61; p = 0.024). In contrast, fast metabolizers showed a trend toward increased incidence of acute graft-versus-host disease (aGVHD) (HR 1.91; 95% CI 0.93-3.92) and an almost universal need for dose escalation (96.8%). Tacrolimus metabolism exerts opposing effects on renal safety and immunosuppressive effectiveness, with faster clearance predisposing to immune activation and slower clearance to early AKI. The C/D ratio provides an early pharmacokinetic snapshot capable of anticipating individual exposure patterns and may serve as a practical tool to guide proactive dosing and optimize the balance between effectiveness and safety in HCT recipients.
Lynch syndrome is an inherited cancer predisposition syndrome caused by germline pathogenic variants in mismatch repair (MMR) genes and is primarily associated with colorectal and endometrial cancers. Classically, Lynch syndrome-associated tumors exhibit microsatellite instability (MSI) and loss of MMR protein expression on immunohistochemistry (IHC); therefore, MSI and IHC are routinely used in screening algorithms to support diagnostic evaluation. ; Methods: In this study, we present the molecular and pathological characteristics of four cases from three unrelated families carrying the same MSH2 variant [c.70C > T (p.Gln24Ter)], interpreted as pathogenic, who were diagnosed with breast and colorectal cancer. MSI analysis and MMR protein expression were evaluated in available tumor tissues. ; Results: Preserved MMR protein expression was observed in three cases, and two cases were microsatellite stable (MSS), whereas only one case demonstrated loss of MMR protein expression and an MSI-high phenotype consistent with the classical Lynch syndrome profile. These findings suggest that individuals carrying the same MSH2 variant may exhibit heterogeneous tumor-level MMR/MSI phenotypes. Early truncating variants in MSH2 may allow partially functional protein production via alternative translation initiation, potentially limiting complete loss of MMR function. Variability in somatic second-hit mechanisms and tumor-specific molecular pathways may also contribute to this heterogeneity. ; Conclusion: In conclusion, Lynch syndrome tumor biology may be more heterogeneous than expected, and MSI and IHC should not be interpreted in isolation as exclusionary tests for an underlying germline MMR variant, but rather as markers of tumor-level biological consequences. Therefore, germline findings, tumor characteristics, and family history should be evaluated together in Lynch syndrome diagnosis and risk assessment.
Vogt-Koyanagi-Harada (VKH) disease has been historically associated with specific ethnic groups, suggesting an underlying susceptibility. Prior to this study, no meta-analysis had synthesized the global epidemiology of VKH, and therefore, information on its geographic distribution remained incomplete. The present study aims to determine the global distribution of VKH disease diagnosis in individuals presenting with uveitis. A systematic review and meta-analysis of quantitative studies published between 2001 and 2025 in PubMed, SciELO, and LILACS was conducted following PRISMA-P guidelines. Case reports were excluded. Risk of bias was assessed using the Murad assessment tool for case series. A random-effects model was used to pool frequency estimates with 95% confidence intervals and prediction intervals. Of 7153 articles identified, 258 studies were analyzed, spanning six continents and 44 countries. The estimated frequency of VKH among uveitis cases was 5.11% (CI:4.31-5.90%; PI: 0.00-15.18%) overall, with predominance of females. When subgrouped into pediatric and adult populations, the estimated frequency was 2.43% (CI:1.83-3.02%; PI: 0.00-6.38%) and 6.15% (CI:4.06-8.24%; PI: 0.00-19.77%), respectively. Frequencies varied across regions, with higher rates reported in Southeast Asia, East Asia, and Africa, and lower rates in North America, Europe, and Oceania. Regarding the quality evaluation, most studies were considered as medium-high quality (162/169, 96%). This systematic review and meta-analysis support the existence of geographical differences in VKH disease expression and the need for additional epidemiological research, particularly in underrepresented regions. These findings should be interpreted in the context of methodological heterogeneity and potential publication and geographic bias.
To examine the surgical outcomes of surgical aortic valve replacement in the transcatheter aortic valve replacement era and propose a novel patient-specific prognostic model. We randomly divided 772 patients with aortic stenosis who underwent surgical aortic valve replacement in 2016-2021 into two cohorts (derivation, 515; validation, 257). In the derivation cohort, no data were missing for any patients for the candidate predictors including age, sex, body mass index, left ventricular ejection fraction, levels of albumin, hemoglobin, and serum creatinine, presence of chronic atrial fibrillation, and end-stage renal disease requiring hemodialysis. We developed possible scoring models using Cox proportional hazards regression with overall survival as the endpoint and calculated the cross-validated 5-year C-statistics to assess accuracy. The mean patient age was 74.2 years, and 46.9% were female. Kaplan-Meier analysis revealed overall 1- and 5-year survival rates of 96.6 and 88.7%, respectively. The 5-year C-statistic of the derivation cohort was 0.785 (95% confidence interval: 0.716-0.853), while the estimated 1-, 3-, and 5-year C-statistics of the validation cohort were 0.885 (0.806-0.965), 0.888 (0.824-0.953), and 0.801 (0.702-0.901), respectively. Calibration plots revealed good agreement between predicted and actual 5-year survival (intraclass correlation coefficient = 0.955; 95% confidence interval: 0.827-0.989). This novel survival prediction model after isolated surgical aortic valve replacement in the transcatheter aortic valve replacement era showed good survival prediction, and may guide the decision-making process for surgical aortic valve replacement versus transcatheter aortic valve replacement with lifetime management.