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PubMed2026

Dysregulation of the serum and IgG N-glycome in decompensated cirrhosis and its association with Model for End-Stage Liver Disease-Sodium (MELD-Na).

BACKGROUND AND AIMS: N-glycans modulate glycoprotein structure and function and are altered during chronic inflammation. We sought to define the extent of serum and IgG N-glycan disruption in patients with decompensated liver cirrhosis from alcohol-related liver disease (ALD), primary sclerosing cholangitis (PSC), and ALD-related hepatocellular carcinoma (HCC). Finally, we aimed to examine whether serum and IgG glycosylation is associated with changes in Model for End-stage Liver Disease-Sodium (MELD-Na) scores, a clinical marker used to prioritise liver transplantation. METHODS: Serum samples were obtained from patients with ALD (n = 17), PSC (n = 7), ALD-related HCC (n = 4), and healthy controls (n = 10). N-glycans were released, fluorescently labelled, and profiled by hydrophilic interaction ultra performance liquid chromatography (HILIC-UPLC). Chromatograms were integrated into 46 and 23 glycan peaks for serum and IgG respectively. These peaks and their associated glycosylation traits were statistically compared with healthy controls using age- and sex-adjusted linear regression models. RESULTS: In serum, decompensated cirrhosis shows statistically significant shifts toward less complex, agalactosylated and asialylated biantennary glycans, accompanied by significant losses of highly branched, galactosylated and sialylated structures. IgG mirrored this pattern, which is characteristic of a pro-inflammatory signature, with increased agalactosylation and bisected glycan levels, along with reduced levels of digalactosylated and sialylated species. N-glycan profiles showed significant associations with MELD-Na scores, indicating that inflammatory processes in decompensated liver cirrhosis continue to reshape serum glycoproteins. CONCLUSION: Decompensated liver cirrhosis shows profound remodelling of serum and IgG N-glycans. These data establish a reference framework for terminal glycomic disruption in liver disease and highlight the potential value of incorporating glycosylation analysis into broader assessments of liver disease progression.

Humans↗

PubMed2026

Genetic regulation of AIF1 shapes immune and liver injury profiles in chronic alcohol use.

BACKGROUNDIn chronic alcohol consumers, immune cells may drive the progression from mild liver injury to more severe alcohol-associated liver disease (ALD), including alcohol-associated hepatitis (AAH) and cancer. Liver macrophages, both resident and infiltrating, express allograft inflammatory factor 1 (AIF1), which is upregulated during inflammation and enhances immune activation.METHODSUsing serum and urine samples from 868 individuals classified as having alcohol use disorder or not, based on DSM-IV/V criteria, along with serum and liver biopsy tissue from a second cohort of 27 patients diagnosed with AAH, we evaluated the impact of the AIF1 promoter single-nucleotide polymorphism (SNP) (rs3132451; C/C, C/G, G/G) on liver function markers and immune cell profiles.RESULTSAIF1 transcript levels were genotype dependent: C/C homozygotes expressed 5.2% of the levels observed in G/G individuals, while C/G heterozygotes expressed 46%. Unlike most SNPs associated with harmful effects, the G/G genotype is highly prevalent, present in about 70% of patients. Among chronic alcohol users, G/G individuals exhibited elevated markers of liver injury and a more than 3-fold increase in hepatic immune cells, including infiltrating AIF1+ macrophages and neutrophils. Despite similar durations of alcohol misuse, G/G individuals had higher Model for End-Stage Liver Disease scores compared with C/G individuals, indicating a significantly greater 90-day mortality risk. Notably, some immune abnormalities, such as elevated neutrophils, persisted in G/G males even after alcohol abstinence.CONCLUSIONThese findings suggest that functional genetic variation in AIF1 may contribute to the severity and persistence of ALD.TRIAL REGISTRATIONClinicalTrials.gov NCT02231840.FUNDINGResearch support was provided from the National Institute on Alcohol Abuse and Alcoholism of the NIH under grants 1ZIAAA000440-02 and R24AA025017.

Humans↗

PubMed1979

Liver transplantation.

This assessment of the role of liver transplantation in treating end-stage liver disease today is based on two major series, one from Denver and the other from the Cambridge/Kings College Hospital, England. The findings of these groups are highlighted, as are the changes in technique that have led to considerably improved survival in the past two years.

Age Factors↗

PubMed1977

Changes of plasma cholinesterase activity during orthotopic liver transplantation in man.

Variations of plasma cholinesterase activity were studied in eight patients with end stage liver disease having orthotopic liver transplantation and five other patients with hepatic cirrhosis undergoing surgical procedures. Serum cholinesterase activity was found to be below normal limits in every patient, even more so in those having hepatic homotransplantation, probably because of the greater severity of their disease. Blood transfusions increased pseudocholinesterase activity to normal or nearly normal levels; but only after successful transplantation did these levels remain within normality, thus suggesting that the homografts promptly assume production of the serum enzyme.

Cholinesterases↗

PubMed1979

Metabolic clearance and plasma half-disappearance time of exogenous somatostatin in man.

The MCR and half-disappearance time of exogenously administered somatostatin have been measured during and after cessation of a constant infusion. Studies were performed on normal volunteers and patients with chronic liver disease and failure. Immunoreactive somatostatin was measured by a sensitive and specific RIA using an antiserum directed against the core of the molecule. Normal subjects had a mean MCR of 1949 +/- 250 ml/min (28.4 +/- 4.2 ml/min . kg BW) (mean +/- SEM), similar to values found in five patients with chronic liver disease. However, patients with chronic renal failure showed a highly significant (P less than 0.001) lowering of the MCR (501 +/- 32.7 ml/min or 7.8 +/- 0.6 ml/min . kg). The rate of disappearance of somatostatin after infusion was linear for 7-10 min, after which a much slower component was observed. In normal subjects, the t 1/2 of the first component varied from 1.1-3.0 min, in patients with liver disease it varied from 1.2-4.8 min, and in patients with chronic renal failure it varied from 2.6-4.9 min. Exogenously administered somatostatin is rapidly cleared in normal subjects and patients with chronic liver disease, but the MCR in end stage chronic renal failure is markedly lowered. The kidney may have a role in the metabolic clearance of exogenously administered somatostatin, or uremia may impair catabolism nonspecifically.

Adult↗

PubMed2026

Clinical Trial: Phase 3 Trial of Resmetirom Versus Placebo in Metabolic Dysfunction-Associated Steatohepatitis-Reanalysis of Fibrosis Stage 2-3 Subset.

BACKGROUND: Resmetirom is an oral thyroid hormone receptor beta agonist clinically used to treat metabolic dysfunction-associated steatohepatitis (MASH) among adults with stage F2 or F3 fibrosis. AIMS: Because the pivotal, 52-week, randomized, controlled, phase 3 MAESTRO-NASH trial (once-daily oral resmetirom 80 or 100 mg or placebo) included patients with F1, F2, or F3 fibrosis, we conducted a post hoc analysis aimed at assessing treatment response in the subset of patients with stages F2 and F3 fibrosis, consistent with the approved label population. METHODS: Co-primary end points were MASH resolution (hepatocellular ballooning score 0, lobular inflammation score ≤ 1, and ≥ 2-point nonalcoholic fatty liver disease activity score [NAS] reduction from baseline) with no fibrosis worsening, and ≥ 1-stage fibrosis improvement with no NAS worsening at Week 52. RESULTS: Among 917 patients with F2 or F3 fibrosis, metabolic risk factor prevalence was high (hypertension, 78.0%; dyslipidemia, 71.1%; type 2 diabetes, 67.0%). MASH resolution was achieved by 25.7% in the 80-mg group, 29.9% in the 100-mg group, and 9.5% in the placebo group (p < 0.0001 for both comparisons with placebo). Respective percentages with fibrosis improvement were 26.5%, 28.9%, and 17.3% (p < 0.01 for both comparisons). From baseline to Week 24, low-density lipoprotein cholesterol decreased by 11.7% and 13.7% in the 80- and 100-mg resmetirom groups, respectively, and increased by 2.3% with placebo (p < 0.0001 for both comparisons). No new safety signals emerged. CONCLUSION: Results among patients with F2 and F3 fibrosis were consistent with the primary MAESTRO-NASH analysis population, demonstrating efficacy and safety of resmetirom after 52 weeks.

Humans↗

PubMed1979

Systemic karyomegaly associated with chronic interstitial nephritis. A new disease entity?

In 3 patients, two 26 and one 29 years of age, a nephropathy was accidentally discovered which progressed to end stage renal failure within 4 to 6 years. Renal biopsy revealed an unusually marked karyomegaly particularly of the tubular epithelium. These cytopathological changes were associated with chronic interstitial nephritis. Biopsies of other organs, i.e. liver, colon, bronchus and lungs indicated in 2 patients a systemic distribution of the karyomegaly, particularly in mesenchymal cells. Neither the chronic interstitial nephritis nor the karyomegaly could be ascribed to a recognized etiology. This suggests, therefore, that there is a relationship between these changes. The karyomegaly could be the result of the action of some antimitotic agent such as chemical toxins or virus infections.

Adult↗

PubMed1977

Spontaneous glomerulonephritis in dogs. II. Correlation of glomerulonephritis with age, chronic interstitial nephritis and extrarenal lesions.

A morphologic study of 103 dogs, including two with renal amyloidosis, showed that different types of diffuse glomerulonephritis are correlated with different age groups. Membranous and membranoproliferative glomerulonephritis were more common in middle-aged and older animals, whereas mesangial lesions were found predominantly in younger dogs and considered to be early glomerular changes. Glomerulonephritis largely occurred independently of interstitial nephritis. The incidence of interstitial lesions was 71%. Chronic interstitial nephritis was rare in dogs under 1 year old. Glomerulonephritis did not seem to induce interstitial nephritis. Glomerulonephritis occurred not only in kidneys with severe interstitial damage, but also in those with slight damage. The indicated that glomerulonephritis occurred independently of interstitial nephritis. In end-stage kidneys with severe fibrosis, mesangial changes seemed to predominate.

Age Factors↗

PubMed1977

Cystic cholangiofibrosis of the liver.

We have studied with electron microscope the cysts formed in the liver of rats fed acetylaminofluorene in order to further characterize the lesion and its histogenesis. The cysts were lined by cuboidal and flattened epithelium or both and resembled bile ductular cells. Most of the flattened cells showed adaptive and degenerative changes indicative of pressure atrophy. The cuboidal cells lining the smaller ducts showed ultrastructural signs of activity. Similar "active" cells were seen in the outpouchings of the larger cysts. Our data indicate that the cysts are of cholangiocellular origin. Ultrastructurally the cells forming the cysts showed no signs of anaplasia and represent more likely the end point of bile ductular proliferation than a stage in development of biliary neoplasia.

Animals↗

PubMed1979

A critical analysis of response criteria in patients with prostatic cancer treated with cis-diamminedichloride platinum II.

Cis-diamminedichloride platinum II (DDP), 50--70 mg/m2 iv, q 3w was administered to 25 patients with Stage D adenocarcinoma of the prostate. Since the assessment of tumor regression in a disease-oriented phase II study demands a clear end-point of response, case selection was restricted to patients who had objectively measurable lesions, i.e., nodes, skin, lung, and liver metastasis. Partial remission occurred in 3 (12%) and stabilization of disease in 1 patient. Responders lived 53 weeks vs. 20 weeks for non-responders. In the dosage and schedule used in this protocol, DDP was not an active agent in the treatment of prostatic cancer. Various patient characteristics are examined and correlations made between remission rates and survival in this study vs. 4 other response schemata. A critical analysis of patient selection, "lead time" -- diagnosis to chemotherapy, and the definitions of the terms "measurable" lesions, "evaluable" parameters, "objective response", stabilization of disease and response criteria employed in the 4 schemata are also discussed.

Adenocarcinoma↗

PubMed1978

Androgen trial in renal anaemia.

A double blind cross-over trial of Nandrolone decanoate (Decadurabolin) was carried out in 27 patients with anaemia due to end stage renal disease, stabilised on regular haemodialysis. Sixteen patients completed the study, the other patients being excluded from the final analysis for a variety of reasons including side effects related to the androgen. There was no sustained significant rise in haemoglobin concentration or in red cell mass. Erythropoietin levels did not alter, they were within or below the normal range, but were lower than would be expected for the degree of anaemia. A majority of patients reported increased well-being including exercise tolerance, appetite and libido. Voice changes and hirsutism were noted, mainly in the females. Instability of anticoagulant therapy and abnormalities in liver function were found in some patients. The benefits, though real, were restricted essentially to the improvement in subjective findings and were unrelated to laboratory measurements. These effects might be obtained with a lower dosage of the drug.

Adult↗

PubMed2026

Circulating Methylated SEPT9 for Detection of Hepatocellular Carcinoma in Cirrhosis.

IMPORTANCE: Hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis remains suboptimal, with inadequate early-stage detection. α-Fetoprotein (AFP) demonstrates insufficient sensitivity. Circulating methylated septin 9 (SEPT9) has shown diagnostic promise. OBJECTIVE: To determine whether methylated SEPT9 improves detection of HCC when combined with AFP in patients with cirrhosis undergoing surveillance. DESIGN, SETTING, AND PARTICIPANTS: In this prospective, cross-sectional, diagnostic accuracy study, patients with cirrhosis undergoing routine HCC surveillance with ultrasonography and AFP were enrolled at 2 French academic centers from February 2018 through October 2024. HCC was diagnosed per international guidelines with centralized radiologic review, blinded to methylated SEPT9 results. Data were analyzed from October 2025 to January 2026. EXPOSURES: Plasma methylated SEPT9 was analyzed from 3 independent plasma aliquots and classified by number of positive replicates (single-positive, double-positive, or triple-positive). Serum AFP was evaluated at a threshold of 20 ng/mL. Biomarkers were evaluated individually and in combination using disjunction logic (tier 1; maximizing sensitivity) or conjunction logic (tier 2; maximizing specificity). MAIN OUTCOMES AND MEASURES: The primary outcome was the presence of HCC at enrollment. The primary end point was comparison of the area under the receiver operating characteristic curve (AUROC) between methylated SEPT9 and AFP. Secondary end points included diagnostic performance stratified by Barcelona Clinic Liver Cancer (BCLC) stage. RESULTS: Among 574 participants, 414 (72.1%) were male, and the median (IQR) age was 63 (57-70) years. A total of 118 had HCC, including 51 (43.2%) with BCLC stage 0-A. Methylated SEPT9 outperformed AFP (AUROC: 0.79 [95% CI, 0.74-0.84] vs 0.71 [95% CI, 0.66-0.76], respectively; P = .002; posterior probability of superiority >99.8%). Tier 1a (at least single-positive methylated SEPT9 or AFP >20 ng/mL) achieved 87.8% (95% CI, 81.6-93.5) sensitivity and a negative likelihood ratio of 0.2 (95% CI, 0.1-0.3). Among 64 HCC cases missed by AFP, tier 1a recovered 50 (78%). For BCLC 0-A disease, tier 1a sensitivity was 74.5% (95% CI, 62.2-86.5) vs 23.5% (95% CI, 12.5-35.8) for AFP, 3.2-fold increase. Tier 2 (triple-positive methylated SEPT9 and AFP >20 ng/mL) achieved 99.6% (95% CI, 98.9-100) specificity, a positive likelihood ratio of 76.0 (95% CI, 26.9-181.0), and a diagnostic odds ratio of 112.1 (95% CI, 37.8-294.7). CONCLUSIONS AND RELEVANCE: In this diagnostic study, combining methylated SEPT9 with AFP substantially improved HCC detection in patients with cirrhosis, particularly for early-stage disease amenable to curative treatment. Prospective studies are needed to determine whether improved detection translates into survival benefit.

Humans↗

PubMed1978

[What are the dangers of splenectomy in Hodgkin's disease?].

Splenectomy is a surgical procedure of medium severity, the mean lethality rate is 1%, the complication rate 10 to 20%. The surgical risk is dependent upon age and general condition of the patient, the severity of the disease, and the experience of the surgeon. The risk of late complications due to surgery is determined mainly by infections as well as ileus, requiring relaparatomy. The risk of infections is higher in children than in adults: one has to be aware of miningitis and sepsis in about 10% of the patients; half of those cases end lethal. An analysis of advantages versus risks of splenectomy must be made for each patient individually. For optimal treatment it is necessary to know the stage of the disease. Concerning M. Hodgkin, explorative laparatomy combined with splenectomy should be performed in stage I to III A. If, however, the surgical risk is rather high primarily and if there are no therapeutical consequences to be expected, splenectomy should not be performed because of the known risks and disadvantages.

Adult↗

PubMed1977

Successful renal transplantation in infancy.

This infant's post renal transplantation course, representing apparently the smallest long term survivor, illustrates that neither age nor size are contraindications to successful renal transplantation in infants with end stage renal failure. Additional experience with the transplantation of a single kidney into a 1-yr-old baby weighing 4650 gm with congenital bilateral renal hypoplasia has also been successful with a 3-mo follow-up. Both cases demonstrate that single or double renal transplantation in infants is feasible and should be considered when indicated.

Acute Kidney Injury↗

PubMed1978

Operative treatment of alveolar echinococcosis of the liver.

This study is based on the experience with 51 cases of hepatic alveolar echinococcosis underwent operative treatment up to the end of 1976. Hepatic resection was carried out in 28 cases with overall operative mortality of 25 per cent, but no death occurred in the last 10 years period during which 12 cases were subjected to the procedure. This apparent improvement of the result is ascribed to the establishment of the strict criteria for operative intervention, i.e., when less than three segments are involved, the hepatic hilum is not highly involved, and the inferior vena cava is not invaded. Marsupialization is employed when hepatic resection is not indicated and the lesion shows liquefaction. Ten cases underwent the procedure with one operative death. Biliary tract reconstruction was carried out in two cases with hilar involvement, but the prognosis was poor. Eleven cases were only with celiotomy. The follow-up studies indicated that the hepatic resection offers the best hope for cure followed by marsupialization. Unlike unilocular echinococcosis in which a cyst grows expansively, the alveolar echinococcosis should be considered clinically malignant, in that it grows invasively and often shows metastatic lesions. Surgical intervention at its early developmental stage is the only definitive way of the treatment. Only recent advances in diagnostic procedures and development of type specific serological studies made it possible to bring the disease under control.

Adolescent↗

PubMed2026

PKD1 upstream open reading frames affect Polycystin-1 expression and polycystic kidney disease phenotypes.

Autosomal dominant polycystic kidney disease (ADPKD) accounts for 5%-10% of prevalent end-stage kidney failure (ESKD). ADPKD cysts result from a loss of sufficient functional expression of PKD1/Polycystin-1 (PC1) in approximately 80% of families. Kidney disease severity correlates with the extent to which PC1 dosage is reduced below a critical level, and evidence suggests therapeutic benefit from increasing PC1 expression in these conditions. Upstream open reading frame (uORF) translation can reduce translation of a protein's coding sequence. Ribosome profiling data and bioinformatic predictions suggested the presence of conserved PKD1 uORFs, so we sought to explore their biological role. We generated luciferase reporters and two humanized PKD1 5' UTR mouse models with or without single nucleotide edits removing uORF start codons (ΔuORF) to define active uORFs and test their impact on PC1 translation. PKD1 uORF start codons can robustly initiate translation, and ΔuORF conveys a 2-4 fold increase in PC1 protein expression and resultant prevention of kidney cysts in Dnajb11 as well as in Pkd1 missense models. PKD1 uORF1-blocking steric antisense oligonucleotides (ASOs) substantially increase PC1 expression in vitro. PKD1 uORFs play an important role in the low basal expression of WT PKD1, and their inhibition represents an opportunity to therapeutically increase PC1 translation in polycystic kidney and liver disease resulting from reduced dosage of PC1.

Animals↗

PubMed1979

Cancer of the breast. Staging methods, primary treatment options and end results.

A totally satisfying concept of treatment is not easy to formulate from the complex and often conflicting results of local therapeutic interventions for breast cancer. It seems evident that clinically occult cancer is often beyond the pale of both resection and irradiation at primary treatment, particularly when cancer is found in regional lymph nodes. Despite all combinations of local treatment, the ultimate risk of failure correlates more closely with the stage of the disease at the time of treatment than with the particular form of treatment. Thus the extent of disease must be considered the major, perhaps the ultimate determinant of prognosis. Because, under controlled conditions, several therapeutic alternatives have appeared to provide virtually identical end results in terms of survival and ultimate dissemination of the disease, the adequacy of control within the field of treatment may, in fact, be the most meaningful end result of local treatment. The experience that has accumulated with treatment of breast cancer supports the thesis that removal of the breast accomplishes all that can be achieved in terms of curing the disease, and wider treatment with surgery or irradiation serves only to improve the prospects for local control. Halsted demonstrated this principle with his radical mastectomy and it still seems to be the case. This fact provides further impetus for detecting and treating cancer while it is still localized to the breast. With these generalizations in mind some empirical observations can be added. An anatomic fact is that multiple microscopic foci of cancer that are not evident clinically are often present in the mammary parenchyma. Undisturbed, at least some, and perhaps eventually all, of these foci of cancer progress to become clinical cancers. Thorough removal of the entire breast (the entire mammary parenchyma) eliminates this particular hazard and, one may presume, terminates the disease if it is still limited to the breast. Removal of the underlying pectoralis major muscle provides additional margin around the tissues primarily involved, but sacrific of the muscle is apparently needless unless it is directly invaded by cancer. Microscopic metastases are also often present in regional lymph nodes without being clinically detectable and, left untreated, have the capacity to enlarge and become clinically apparent. Routine wide removal of regional lymph nodes improves the control of cancer at these sites when metastases are present, but whether it improves the chances for cure is doubtful. The fact is that approximately 25 per cent of patients with axillary metastases enjoy prolonged survival free of recurrence, some remaining well even after thirty years (Adair et al., 1974). Whether they would survive as well without removal of the metastases is uncertain. Desease-free survival is highest if metastases are removed while still microscopic, but this phenomenon may simply reflect treatment at an earlier phase in the evolution of the disease...

Bone and Bones↗