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PubMed2025

Blood from septic patients with necrotising soft tissue infection treated with hyperbaric oxygen reveal different gene expression patterns compared to standard treatment.

BACKGROUND: Sepsis and shock are common complications of necrotising soft tissue infections (NSTI). Sepsis encompasses different endotypes that are associated with specific immune responses. Hyperbaric oxygen (HBO2) treatment activates the cells oxygen sensing mechanisms that are interlinked with inflammatory pathways. We aimed to identify gene expression patterns associated with effects of HBO2 treatment in patients with sepsis caused by NSTI, and to explore sepsis-NSTI profiles that are more receptive to HBO2 treatment. METHODS: An observational cohort study examining 83 NSTI patients treated with HBO2 in the acute phase of NSTI, fourteen of whom had received two sessions of HBO2 (HBOx2 group), and another ten patients (non-HBO group) who had not been exposed to HBO2. Whole blood RNA sequencing and clinical data were collected at baseline and after the intervention, and at equivalent time points in the non-HBO group. Gene expression profiles were analysed using machine learning techniques to identify sepsis endotypes, treatment response endotypes and clinically relevant transcriptomic signatures of response to treatment. RESULTS: We identified differences in gene expression profiles at follow-up between HBO2-treated patients and patients not treated with HBO2. Moreover, we identified two patient endotypes before and after treatment that represented an immuno-suppressive and an immune-adaptive endotype respectively, and we characterized the genetic profile of the patients that transition from the immuno-suppressive to the immune-adaptive endotype after treatment. We discovered one gene MTCO2P12 that distinguished individuals who altered their endotype in response to treatment from non-responders. CONCLUSION: The global gene expression pattern in blood changed in response to HBO2 treatment in a direction associated with clinical biochemistry improvement, and the study provides potential novel biomarkers and pathways for monitoring HBO2 treatment effects and predicting an HBO2 responsive NSTI-sepsis profile. TRIAL REGISTRATION: Biological material was collected during the INFECT study, registered at ClinicalTrials.gov (NCT01790698) 04/02/2013.

Humans↗

PubMed2026

Heightened frequency of innate immunity risk alleles in south Indian diabetics with urinary tract infections.

Urinary Tract Infections are an emerging public health concern among individuals with diabetes mellitus, particularly in South Asia where high disease burden, genetic diversity and increasing drug resistance contribute to the progressive increase in burden. While metabolic and clinical risk factors are well studied, the role of host innate immune genetic variations in shaping UTI susceptibility among diabetics remains poorly understood. This case-control study evaluated functional polymorphisms in key innate immunity genes, TLR4 (rs4986790, rs4986791), MBL2 (rs1800450) and LTA (rs909253), in 70 T2D patients with UTI and 70 T2D patients without UTI. Genotyping was performed using 5'-hydrolysis probe assay. Across all the four SNPs, the risk allele consistently showed a higher frequency among T2D patients with UTI, indicating a directional trend suggestive of cumulative susceptibility. Also, a strong and significant protective association was observed for the LTA rs909253 'G' allele, which was less frequent in cases than controls. This low-inflammatory 'AA' genotype was also markedly enriched among rUTI cases compared to controls. Clinically, 34.3% of cases experienced rUTIs. This observed directional increase of risk alleles across all four innate immunity SNPs, along with the protective role of LTA rs909253 'G' allele, highlights cumulative host genetic modulation of UTI risk in T2D and supports translational use of genetic profiling in infection risk prediction.

Humans↗

PubMed2026

Accelerated Biological Aging Increases the Risk of Head and Neck Cancer: Insights From Genetic Instruments of Epigenetic Clocks.

Epigenetic clocks are robust biomarkers of biological aging and have been associated with cancer susceptibility. However, the relationship between genetically predicted epigenetic age acceleration and head and neck cancer risk remains unclear. Using a large case-control study of 2189 head and neck squamous cell carcinoma (HNSCC) cases and 2189 age- and sex-matched controls, we investigated the associations between polygenic scores (PGSs) for multiple epigenetic clocks and HNSCC risk, and evaluated their potential causal roles using two-sample Mendelian randomization (MR). Genome-wide association study (GWAS)-identified single nucleotide polymorphisms (SNPs) associated with four epigenetic clocks (HannumAge, HorvathAge, GrimAge, and PhenoAge) were used to construct clock-specific PGSs. Logistic regression models were applied to assess associations between PGSs and HNSCC risk, while MR analyses, including inverse-variance weighted (IVW), weighted median, and MR-Egger methods, were used to infer potential causal relationships. Among the 48 epigenetic clock-associated SNPs, 12 showed nominal associations with HNSCC risk, and one variant (rs2275558 in PBX1) remained significant after Bonferroni correction (OR = 0.67, 95% CI: 0.60-0.76). PGSs for all four epigenetic clocks were higher in cases than in controls. In logistic regression analyses, each standard deviation increase in HannumAge PGS was associated with a 25% higher risk of HNSCC (OR = 1.25, 95% CI: 1.10-1.41), whereas HorvathAge, GrimAge, and PhenoAge PGSs showed weaker positive associations (ORs ranging from 1.06 to 1.10). Individuals in the highest PGS quartile for all four epigenetic clocks exhibiting 14%-25% higher risk than those in the lower three quartiles. MR analyses supported potential causal effects of genetically predicted HannumAge (IVW OR = 1.24 per SD increase, 95% CI: 1.09-1.42) and GrimAge (IVW OR = 1.23 per SD increase, 95% CI: 0.98-1.56) on HNSCC risk, with consistent estimates in weighted median analyses. Our results highlight biological aging as a potential etiologic mechanism for HNSCC and suggest that epigenetic clock-related genetic profiles may improve HNSCC risk stratification.

Humans↗

PubMed2025

Association of cancers with the occurrence and 28-day mortality of sepsis: a mendelian randomization and mediator analysis.

Observational studies have indicated an association between cancer and the occurrence of sepsis, with an increased risk of mortality in cancer-related sepsis. However, whether a causal relationship exists between the two remains unknown. Summary statistics of thirteen cancers from the largest available genome-wide association studies (GWAS) of GWAS catalog and FinnGen biobank were extracted for the MR analysis. GWAS data for sepsis and its 28-day mortality were obtained from MRC-IEU. Univariable, multivariable, and reverse MR analyses were employed to explore potential associations between cancers and sepsis and its 28-day mortality. Moreover, a two-step mediation MR analysis was performed to investigate independent positive causal relationships between cancers and sepsis and its 28-day mortality. In univariable Mendelian randomization (MR) analysis, significant causal relationships were found between genetically predicted lung cancer (OR = 1.17, 95% CI = 1.08-1.26, adjusted p = 0.001), squamous cell lung carcinoma (OR = 1.10, 95% CI = 1.02-1.18, adjusted p = 0.042), lung adenocarcinoma (OR = 1.12, 95% CI = 1.03-1.21, adjusted p = 0.032), small cell lung carcinoma (OR = 1.07, 95% CI = 1.02-1.12, adjusted p = 0.031), and sepsis. Subsequent multivariable MR analysis revealed that these three types of lung cancer were independently associated with the risk of sepsis. Additionally, a causal relationship was found between lung cancer and 28-day mortality from sepsis, while no causal link was observed between non-solid tumors and the onset or death of sepsis. Reverse MR analysis did not indicate a potential for sepsis to trigger the onset of cancers. Furthermore, TRAIL was found to have promotive effects on the occurrence and mortality of sepsis. Lung cancer causally correlates with increased sepsis occurrence and 28-day mortality, as evidenced by Mendelian Randomization analysis. Genetic predispositions enhance this risk, underscoring the potential of genetic profiling to guide early, precise sepsis interventions in these patients.

Humans↗

PubMed1977

Sero-genetic studies on the San of South West Africa.

The San, a physically, culturally and linguistically distinctive people, have been shown by archaeological records anciently to have inhabited the whole of Eastern and Southern Africa. They, in common with the Khoi, the other members of the Khoisan race, are confined now to Southern Africa and principally to Botswana and South West Africa, though a number are also found in Angola. Sero-genetic data concerning seven South West African groups are presented in this study, and confirm a shared overall genetic profile characteristic of the San in general, slightly different from that of the Khoi and in significant contrast with that of the Negroes.

ABO Blood-Group System↗

PubMed2025

Genomic signature and evolutionary history of completely cleistogamous lineages in the non-photosynthetic orchid Gastrodia.

Despite a long-standing interest since Darwin's time, the genomic implications of obligate self-fertilization remain elusive. Complete cleistogamy-the obligate production of closed, self-pollinating flowers-represents an extreme reproductive strategy. Here, we present the genomic profiles and evolutionary history of two lineages of the mycoheterotrophic orchid Gastrodia, both of which independently acquired complete cleistogamy, based on detailed sampling and a combination of simple sequence repeat (SSR), multiplexed ISSR genotyping by sequencing (MIG-seq) and RNA-seq data. Our analysis reveals clear species delimitation, with no evidence of introgression between the completely cleistogamous species and their co-occurring allogamous sisters. Intriguingly, all analyses indicate that both the completely cleistogamous Gastrodia species and their allogamous sisters exhibit genetic profiles typical of self-pollinating plants. This pattern suggests that their ancestors, probably bearing allogamous flowers, had already evolved mechanisms to mitigate the deleterious effects of selfing, potentially facilitating the emergence of complete cleistogamy through benefits such as reproductive assurance, enhanced colonization ability and species reinforcement. Meanwhile, further analyses suggest that complete cleistogamy evolved very recently (possibly within the last 1000-2000 years) in these two Gastrodia lineages. Combined with the scant evidence of complete cleistogamy outside Gastrodia, our findings imply a limited and ephemeral role for complete cleistogamy in plant speciation.

Biological Evolution↗

PubMed1975

Sero-genetic studies on the G/wi and G//ana San of Botswana.

The G/wi and G//ana San ('Bushmen') of the Central Kalahari Reserve, Botswana, live as cyclically migrant hunter-gatherer bands. They have some contact with one another, with the Negro Kgalagadi, and with White farmers near Ghanzi. Studies carried out on samples of these peoples from the Okwa Valley reveal a sero-genetic profile characteristic of the San in general, deviant from that of the Khoi ('Hottentots') and quite different from that of the Negroes. These findings help to substantiate the claim that the Khoisan peoples should be regarded as one of the major divisions of mankind and not simply as having comparatively recently evolved from a common stock with the Negroes.

ABO Blood-Group System↗

PubMed2025

Treatment-resistant depression: role of genetic factors in the perspective of clinical stratification and treatment personalisation.

Treatment-resistant depression (TRD) is associated with chronic depression, suicidal behaviours, and reduced quality of life. TRD has a demonstrated genetic component, estimated around 8% based on common genetic variation in unrelated individuals. However, only six genome-wide association studies of TRD were published, and no replicated signals at locus or gene level have been identified; furthermore, apparently opposite results were reported in terms of genetic overlap between TRD and other traits. Other than limited power, an important issue of previous studies was the scarce consideration of TRD heterogeneity, as TRD likely comprises different groups and talking about TRDs could be more appropriate. This review points out important issues in the definition of TRD and differences across samples included in previous studies, which can be partly responsible for the inconsistency across results. Different definitions of TRD should not be expected to have similar genetic profiles, and the whole TRD group can partitioned into subgroups, based on clinical and biological features, to increase reproducibility, as exemplified by recent findings. This can be a key factor to develop/repurpose targeted treatments, or simply to aid a more personalised prescription of available medications compared to current clinical practice, that is largely concentrated on the prescription of a limited number of antidepressants compared to those available.

Humans↗

PubMed2025

Pharmacogenomic insights into angiotensin converting enzyme inhibitors and calcium channel blockers for personalized hypertension treatment.

Arterial hypertension is a complex disorder influenced by extensive genetic variability, which contributes to interindividual differences in drug response by altering metabolism, transport, and receptor interaction. Current antihypertensive therapies effectively control arterial hypertension in only about half of patients, emphasizing the need for precise strategies. Genetic variation plays a crucial role in modulating drug response, and integrating this knowledge into clinical practice could significantly transform the management of hypertension through personalized medicine. This review examines the impact of genetic factors on the efficacy of antihypertensive drug classes, including angiotensin converting enzyme inhibitors and calcium channel blockers. It also examines advances in pharmacogenomic research that can aid in tailoring drug selection and dose adjustment based on genetic profiles. Beyond genomics, this review also highlights the impact of multiomics approaches, such as proteomics, metabolomics, and microbiomics, in advancing precision medicine and enabling a comprehensive, personalized approach to hypertension management. Pharmacogenomics can help refine hypertension care, improve patient outcomes, and reduce the burden of the disease. The future of hypertension treatment lies in precision medicine, where therapy is tailored to individual needs for effective and personalized management.

Humans↗

PubMedDate not supplied

The Njinga of Angola: a serogenetic study.

The Njinga, a matrilineal kiMbundu-speaking Negro people of northern Angola, inhabited the coast near Luanda during the sixteenth century, and were driven inland by Portuguese expansion subsequently. There is no evidence from the present sterogenetic study that they have received any appreciable contribution of Caucasoid genes. Nor is there any evidence of San ('Bushman') admixture apart from a moderate frequency of Gm; their genetic profile and their anthroposcopic traits disclose a greater similarity to West African than to Southern African Negroes. The present study confirms previous findings on the ABO, MNSs, Kell, Duffy, erythrocyte acid phosphatase, adenosine deaminase and adenylate kinase systems, and contributes the first account of the peptidase A, B, C and D, first and second locus phosphoglucomutase, glucose-6-phosphate dehydrogenase, esterase D, haptoglobin, transferrin, Gm and Inv systems in the Njinga.

ABO Blood-Group System↗

PubMed2026

Comparative in vitro antimicrobial susceptibility profiles of clofazimine and pyrifazimine against clinical isolates of Mycobacterium tuberculosis in southwest China.

UNLABELLED: Clofazimine (CFZ) is a key drug used to treat drug-resistant tuberculosis (DR-TB), while pyrifazimine (TBI-166) is an improved riminophenazine derivative with better pharmacokinetics. However, there is a lack of data on its susceptibility and resistance in regions with a high disease burden, such as southwestern China. We compared the in vitro antimicrobial activities of CFZ and TBI-166 against 249 DR-TB clinical isolates (99 multidrug-resistant TB [MDR-TB] and 150 pre-extensively drug-resistant TB [pre-XDR-TB] isolates) from southwestern China. TBI-166 exhibited a concentration-dependent biphasic antimicrobial pattern compared to CFZ. TBI-166 showed significantly greater potency at low concentrations (MIC₅₀ = 0.031 µg/mL TBI-166 vs 0.25 µg/mL for CFZ; P < 0.001), but attenuated inhibition at high concentrations (MIC₉₀ > 4 µg/mL vs 1 µg/mL for CFZ; P < 0.001). However, at high concentrations, the antibacterial effect of TBI-166 is weaker than that of CFZ (40% of TBI-166-resistant isolates have MIC > 4 µg/mL, compared to 6.67% of CFZ-resistant isolates, P < 0.001). Epidemiological cutoff values (ECOFFs) were 1.0 µg/mL for CFZ and 0.25 µg/mL for TBI-166. Based on these in vitro ECOFFs, the resistance rate to TBI-166 (20.1%, 50/249) was significantly higher than that to CFZ (6.0%, 15/249, P < 0.0001). Whole-genome sequencing revealed that mutations in Rv0678 were prevalent in dual-resistant isolates (10/14) and TBI-166 monoresistant isolates (5/40), while Rv1979c mutations were less frequent, and no pepQ mutations were detected. These mutations differed from known hotspots, suggesting potential novel resistance mechanisms. IMPORTANCE: Drug-resistant tuberculosis (DR-TB) remains a major global health challenge, and optimizing treatments for high-burden regions like southwest China is crucial. This study is the first to detail the differential in vitro activities of clofazimine (CFZ) and the novel TBI-166 against clinical DR-TB isolates from southwest China, alongside their resistance-associated genetic profiles. Findings show TBI-166 has enhanced low-concentration potency but higher resistance rates, plus novel mutations in Rv0678 and Rv1979c linked to resistance. These insights will help refine clinical regimens for DR-TB and strengthen regional resistance surveillance, both of which are essential for controlling the spread of DR-TB in southwest China and informing treatment and surveillance strategies in other similar high-burden areas globally.

Clofazimine↗

PubMed2024

Urinary Metal Levels, Cognitive Test Performance, and Dementia in the Multi-Ethnic Study of Atherosclerosis.

IMPORTANCE: Metals are established neurotoxicants, but evidence of their association with cognitive performance at low chronic exposure levels is limited. OBJECTIVE: To investigate the association of urinary metal levels, individually and as a mixture, with cognitive tests and dementia diagnosis, including effect modification by apolipoprotein ε4 allele (APOE4). DESIGN, SETTING, AND PARTICIPANTS: The multicenter prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA) was started from July 2000 to August 2002, with follow-up through 2018. A total of 6303 MESA participants were included. Data analysis was performed from October 12, 2023, to June 13, 2024. EXPOSURE: Urine samples were collected at baseline (2000-2002), and arsenic, cadmium, cobalt, copper, lead, manganese, tungsten, uranium, and zinc levels were measured in 2020-2022. MAIN OUTCOMES AND MEASURES: Digit Symbol Coding (DSC) (n = 3819) (possible score range, 0-133), Cognitive Abilities Screening Instrument (CASI) (n = 3918) (possible score range, 0-100), and Digit Span (DS) (n = 4176) (possible score range, 0-30) cognitive tests were administered in 2010-2012; higher scores of each test indicate increasing levels of positive response. RESULTS: A total of 6303 participants were followed up for dementia diagnosis through 2018. The median age at baseline was 60 (IQR, 53-70) years, and 3303 participants (52.4%) were female. The median cognitive scores were 51 (IQR, 38-64) for DSC, 90 (IQR, 84-95) for CASI, and 15 (IQR, 12-18) for DS. There were 559 cases of dementia through the follow-up period. Inverse associations with DSC were identified: mean differences in z scores per IQR increase in metal levels were -0.03 (95% CI, -0.07 to 0.00) for arsenic, -0.05 (95% CI, -0.09 to -0.004) for cobalt, -0.05 (95% CI, -0.07 to -0.02) for copper, -0.04 (95% CI, -0.08 to -0.001) for uranium, and -0.03 (95% CI, -0.06 to -0.01) for zinc. Among 1058 APOE4 carriers, manganese was also inversely associated with DSC. The joint mean difference of DSC comparing percentile 95th with the 25th of the 9-metal mixture was -0.30 (95% CI, -0.47 to -0.14) for APOE4 carriers and -0.10 (95% CI, -0.19 to -0.01) for noncarriers. Arsenic, cadmium, cobalt, copper, tungsten, uranium, and zinc were individually associated with dementia, with hazard ratios per IQR of metal ranging from 1.15 (95% CI, 1.03-1.29) for tungsten to 1.46 (95% CI, 1.06-2.02) for uranium. The joint hazard ratio of dementia comparing percentiles 95th with the 25th of the 9-metal mixture was 1.71 (95% CI, 1.24-3.89), with no significant difference by APOE4 status. CONCLUSIONS AND RELEVANCE: In this study, participants with higher concentrations of metals in their urine, compared with those with lower concentrations, had worse performance on cognitive tests and greater likelihood of developing dementia. The findings of this multicenter multiethnic cohort study might inform screening and potential interventions for prevention of dementia based on individuals' metal exposure levels and genetic profiles.

Humans↗

PubMed2026

Placental Site Trophoblastic Tumor Acquires Immune Functions by Incorporating Host Maternal Genes.

Although it was proposed that cell fusion of cancer cells with leukocytes creates mobile hybrids with a metastatic phenotype, it has been difficult to genetically confirm cell fusion events in human cancer in vivo. Here, we experienced 4 cases of placental site trophoblastic tumor (PSTT) that produced immunoglobulin (Ig). Three cases showed recurrence and responded well to pembrolizumab therapy. Among them, we could analyze temporal changes in the genetic profiles on one case of daughter-derived PSTT, which relapsed after pembrolizumab therapy. In this case, we found that PSTT incorporated the exogenous genes from host maternal cells. The rearrangement patterns of Ig genes and protein expressions sequentially increased. By analyzing single-nucleotide variants, PSTT incorporated daughter-non-inherited maternal alleles (DNIMA), including the Ig lambda and HLA-DQA2 loci. Protein expressions of TLR10 and SIGLEC10 increased during tumor progression concomitantly with DNIMA incorporation. DNIMA mapping indicates the incorporation of exogenous maternal genes was widely distributed through the whole chromosomes, suggesting the involvement of cell fusion in gene transfer mechanisms. These findings indicate that PSTT sequentially incorporated exogenous genes from maternal cells to express immune-related molecules and suggest that cancer cells acquired B cell-related functions, including Ig production by cell fusion with host immune cells.

Humans↗

PubMed1979

Dietary management of nystagmus.

Two case reports illustrate the therapeutic response of congenital nystagmus to a diet eliminating synthetic food colors, synthetic food flavors, the antioxidant preservatives butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), and a small group of foods thought to contain a natural salicylate radical. A brief discussion of the hyperkinetic syndrome is offered with the proposal that a variety of neurologic and neuromuscular disturbances (grand mal, petit mal, psychomotor seizures; La Tourette syndrome; autism; retardation; the behevioral component of Down's syndrome; and oculomotor disturbances) may be induced by identical chemicals, depending upon the individual's genetic profile and the interaction with other environmental factors. It is perhaps the failure to integrate all the signs presented by the various clinical patterns with hyperkinesis or Minimal Brain Dysfunction (MBD) under a single heading that eye muscle involvement manifested as either nystagmus or strabismus has not been emphasized as part of the hyperkinetic syndrome.

Child, Preschool↗

PubMed2026

Risk factors for lung metastasis in children and adolescent patients with papillary thyroid cancer: A retrospective cohort study.

BACKGROUND: Pediatric papillary thyroid cancer (pPTC) exhibits a higher incidence of lung metastasis (LM) compared to its adult counterpart. This study supplements the gap in pediatric management guidelines by exploring factors associated with LM in pPTC and characterizing relevant genetic alterations. METHODS: We retrospectively analyzed pPTC patients under 20 years who underwent initial surgery at our center between December 2008 and December 2022. Clinicopathological features, treatment approaches, outcomes, and target-gene sequencing were reviewed to identify risk factors and genetic variations. RESULTS: Among 114 pPTC cases, 17 developed LM. Risk factors associated with LM included younger age, male gender, larger tumor size, multifocality, extrathyroidal extension, lymphatic invasion, and the number of metastatic lymph nodes (NMLNs), with NMLNs > 14 identified as an independent predictor (OR = 18.20, p = 0.037). Treatment responses with radioiodine related to postoperative stimulated thyroglobulin (sTg) levels (p = 0.003). Genomic analysis identified 1007 somatic mutations, including in the BRAF, APC, RET, and ATM genes, with RET-NCOA4 fusions observed in the LM subgroup. CONCLUSION: LM is common in pPTC, and NMLNs > 14 is a critical risk indicator. The genetic profile, particularly RET mutations, highlights potential therapeutic targets. Further large-scale studies are needed to validate these findings.

Humans↗

PubMed2026

Machine learning-ready genomic biomarkers: ATF3 polymorphisms predict postoperative analgesic demand through AI-compatible phenotyping.

PURPOSE: To determine whether ATF3 polymorphisms can serve as genetic biomarkers for machine learning-based precision analgesia by establishing a genotype-phenotype association suitable for predictive modeling of postoperative opioid requirements. METHODS: In a prospective cohort of 167 adults undergoing abdominal surgery, ATF3 SNPs rs3122721 and rs3125293 were genotyped. A structured dataset architecture was developed to represent genetic profiles as input features for supervised learning models, enabling translational analysis of genotype‑dependent opioid consumption over 72 h. RESULTS: Patients with homozygous genotypes of the ATF3 SNPs had significantly higher opioid requirements than non‑carriers, despite reporting similar subjective pain scores. This consistent genotype‑dependent pattern provided a clinically relevant phenotype suitable for integration into predictive algorithms. CONCLUSION: ATF3 genotyping offers a promising biomarker for computationally informed precision analgesia. By linking genomic variability to clinically meaningful outcomes within a structured clinical and genomic framework, this approach supports the future development of risk-stratified clinical decision-support systems to optimize postoperative pain management.Trial registration ChiCTR1900021991, registered 30 April 2019. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13755-026-00480-9.

ATF3↗

PubMed2026

Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC): An Aggressive Disease Course and Limitations for Personalized Oncology.

Neuroendocrine carcinoma (NEC) is a rare, aggressive malignancy with limited treatment options and poor prognosis. We report a male patient diagnosed with a gastroenteropancreatic (GEP)-NEC with synchronous liver metastasis at the time of surgery who underwent a radical resection attempt. Despite radical-intent surgery followed by adjuvant carboplatin/etoposide, early recurrence developed with progression through multiple subsequent chemotherapy lines. During the treatment process, genetic profiling was performed twice to identify actionable genomic targets, with inclusion in the national IMPRESS study as a last resort. Comprehensive genomic profiling revealed TP53 mutation and RB1 loss but no actionable alterations. A patient-derived organoid (PDO) was successfully established from resected tumor tissue and retained key neuroendocrine and proliferative features, with partial genomic concordance to the primary tumor. Differences between the primary and subsequent PDO in variant allele frequencies suggest clonal selection during culture. Exploratory metabolomic profiling of tryptophan pathway metabolites in patient serum and PDO-culture media indicated tumor-associated metabolic alterations. We present clinical and translational efforts in difficult-to-treat NEC, illustrating both the translational challenges and the potential role of PDOs in advancing personalized treatment strategies for a cancer with very limited treatment options.

Gastroenteropancreatic neuroendocrine carcinoma↗

PubMed2026

Clinical Characteristics and Outcomes of Patients With Biventricular and Left-Dominant Arrhythmogenic Cardiomyopathy With Ring-Like Late Gadolinium Enhancement Pattern.

BACKGROUND: The ring-like pattern of late gadolinium enhancement (RL-LGE) on cardiac magnetic resonance (CMR) has been proposed as a distinctive imaging marker of arrhythmogenic cardiomyopathy (ACM) with left ventricular (LV) involvement. However, the clinical characteristics and prognostic significance remain to be further clarified. OBJECTIVES: This study sought to assess the clinical profile, genetic background, and prognostic significance of RL-LGE in ACM with LV involvement. METHODS: In this observational cohort study, we included consecutive patients with a diagnosis of biventricular or left-dominant ACM (BIV-ACM or LD-ACM). RL-LGE was defined as subepicardial or midmyocardial LGE involving ≥3 contiguous LV segments on the same short-axis slice. The primary endpoint was a composite of sudden cardiac arrest, sustained ventricular tachycardia, or implantable cardioverter-defibrillator (ICD) interventions. RESULTS: Among 149 patients (mean age 36 ± 12 years, 66% male), RL-LGE was identified in 73 (49%), most frequently in association with DSP variants, with a higher prevalence in BIV-ACM (70%) than in LD-ACM (30%). Over a median follow-up of 31 months, 24 patients experienced the primary endpoint, 67% of whom had RL-LGE. In multivariable Cox regression, RL-LGE emerged as an independent predictor of the primary endpoint (HR: 2.47; 95% CI: 1.10-6.02; P = 0.042), along with nonsustained ventricular tachycardia (HR: 2.62; 95% CI: 1.17-6.41; P = 0.033), whereas genetic status did not provide additional prognostic information. Incorporating RL-LGE into the arrhythmogenic right ventricular cardiomyopathy risk model significantly improved its predictive performance (likelihood ratio test: P = 0.006). CONCLUSIONS: RL-LGE independently predicts arrhythmic events in ACM, regardless of genotype status, and refines the prognostic performance of traditional risk models. Its detection may aid in early recognition of high-risk patients and inform primary-prevention ICD therapy.

Adult↗