Computed Tomography-Derived Extracellular Volume Fraction and Splenic Size for Liver Fibrosis Staging.

OBJECTIVE: Extracellular volume fraction (fECV) and liver and spleen size have been correlated with liver fibrosis stages and cirrhosis. The purpose of the current study was to determine the predictive value of fECV alone and in conjunction with measurement of liver and spleen size for severity of liver fibrosis. METHODS: This was a retrospective study of 95 subjects (65 with liver biopsy and 30 controls). Spearman rank correlation coefficient was used to assess correlation between radiological markers and fibrosis stage. Receiver operating characteristic analysis was performed to assess the discriminative ability of radiological markers for significant (F2+) and advanced (F3+) fibrosis and cirrhosis (F4), by reporting the area under the curve (AUC). RESULTS: The cohort had a mean age of 51.4 ± 14.4 years, and 52 were female (55%). There were 36, 5, 6, 9, and 39 in fibrosis stages F0, F1, F2, F3, and F4, respectively. Spleen volume alone showed the highest correlation (r = 0.552, P < 0.001) and AUCs of 0.823, 0.807, and 0.785 for identification of significant and advanced fibrosis and cirrhosis, respectively. Adding fECV to spleen length improved AUCs (0.764, 0.745, and 0.717 to 0.812, 0.781, and 0.738, respectively) compared with splenic length alone. However, adding fECV to spleen volume did not improve the AUCs for significant or advanced fibrosis or cirrhosis. CONCLUSIONS: Spleen size (measured in length or volume) showed better correlation with liver fibrosis stages compared with fECV. The combination of fECV and spleen length had higher accuracy compared with fECV alone or spleen length alone.

Long-Term Survival in an Adolescent and Young Adult with Metastatic Relapse of an Undifferentiated Embryonal Sarcoma of the Liver.

Undifferentiated embryonal sarcoma of the liver (UESL) is an extremely rare and aggressive malignancy in adults.1 Adults with UESL have a worse prognosis compared to pediatric population.2 Due to the rarity of this disease in adults, there has been a lack of information that assists in treatment decisions within this group. Improved understanding of UESL in adults might assist in understanding biological differences compared to pediatric cohorts as well as tailor treatments to improve their overall outcome. We described the management and outcome of a young adult managed at our center with metastatic relapsed UESL. For comparison, a PubMed search for adolescent and young adult (AYA) and adults with UESL was performed with the aim to review and address any distinct clinical features, different aspects of management and survival outcomes within this population. A 21-year-old male underwent right hepatectomy for a large 16 cm localized UESL with clear surgical margin and did not receive adjuvant chemotherapy. Seven months postsurgery, he relapsed with both local and metastatic disease and underwent chemotherapy with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide achieving a complete metabolic response. This was followed by Stereotactic Ablative Radiation Therapy and surgical resection of residual disease. He remains free of disease 3 years since his diagnosis. We subsequently reviewed 42 AYA and adults (aged >15) with UESL (median age, 33 years) between 1991 and 2022. Most patients presented with localized UESL and for those treated with surgery alone, 67% developed recurrences. Those receiving multimodality treatment, better outcomes, and reduced relapse rate was achieved. Twenty-seven patients developed recurrences, 13 with local recurrences and 14 with metastatic relapse. The median time to relapse was 12 months. We reported a successful outcome in multimodality treatment which resulted in long remission in a young adult with relapsed UESL. Combination of perioperative chemotherapy with locoregional treatment is important to improve long-term survival in adults with metastatic UESL.

Survival outcomes of intracranial extraventricular neurocytomas: a systematic review and individual patient data meta-analysis.

OBJECTIVE: The rarity of intracranial extraventricular neurocytomas (EVNs) has precluded accurate definition of its surgical characteristics to date. The authors present the first survival analysis of this unique entity that aims to clarify tumor characteristics, surgical outcomes, and efficacy of postoperative adjuvant therapy. METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches of the MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Database of Systematic Reviews databases were performed from inception to date. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Prognostic variables were age, sex, tumor consistency, extent of resection, and receipt of postoperative adjuvant therapy. Survival data were analyzed using Kaplan-Meier survival curves and the log-rank test to compare dichotomized cohorts. Multivariate Cox regression models were constructed, interrogated with Schoenfeld residuals, and subsequently utilized to identify independent prognostic factors. Risk of bias was assessed with the Mayo Clinic instrument. RESULTS: Five hundred fourteen articles were initially retrieved, which was distilled to 10 included articles consisting of 101 cases of intracranial EVNs. The 5-year OS rate was 90.4% (95% CI 81.8%-99.8%) and the PFS rate was 48.6% (95% CI 34.46%-68.8%). The median PFS was 60 months. Patients younger than 50 years of age experienced superior OS (p = 0.03) and PFS (p < 0.01). Gross-total resection (GTR) was superior to subtotal resection (STR) in reducing mortality (p < 0.01). Adjuvant therapy following either STR or GTR did not significantly improve survival. CONCLUSIONS: Intracranial EVNs are rare tumors that portend a poorer prognosis than central neurocytomas, despite both being WHO grade 2 tumors. Complete surgical extirpation is the cornerstone of management. There is no clearly established role for adjuvant postoperative therapy, but each case should be managed on an individual basis.

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy.

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

Intraductal tubulopapillary neoplasm.

A man aged above 70 years old with a medical history of ulcerative colitis presented with unintentional weight loss. A pancreatic mass associated with pancreatic duct dilatation was detected on imaging procedures. Initial investigations including fine needle aspiration and cytology examination were inconclusive. A diagnosis of intraductal tubulopapillary neoplasm (ITPN) was made with histopathology and immunohistochemistry examination on a surgically resected specimen. Two years after surgery, the patient remained well with no radiological evidence of recurrence.ITPN is a rare pancreatic duct tumour with limited case reports in medical literature. Risk factors are not well established. We report the first case of ITPN occurring in a patient with ulcerative colitis. A typical presentation of this rare tumour is reported to encourage clinicians to consider ITPN in the differential diagnoses of a pancreatic mass.

A critical evaluation of the role of iron overload in fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has been associated with a condition known as the dysmetabolic iron overload syndrome, but the frequency and severity of iron overload in NAFLD is not well described. There is emerging evidence that mild to moderate excess hepatic iron can aggravate the risk of progression of NAFLD to nonalcoholic steatohepatitis and eventually cirrhosis. Mechanisms are postulated to be via reactive oxygen species, inflammatory cytokines, lipid oxidation, and oxidative stress. The aim of this review is to assess the evidence for true hepatic iron overload in NAFLD, to discuss the pathogenesis by which excess iron may be toxic, and to critically evaluate the studies designed to deplete iron by regular venesection. In brief, the studies are inconclusive due to heterogeneity in eligibility criteria, sample size, randomization, hepatic iron measurement, serial histological endpoints, target ferritin levels, length of venesection, and degree of confounding lifestyle intervention. We propose a trial designed to overcome the limitations of these studies.

The AR in bone marrow progenitor cells protects against short-term high-caloric diet-induced weight gain in male mice.

We previously identified a novel pathway of testosterone action via the androgen receptor (AR) in bone marrow mesenchymal precursor cells (BM-PCs) to negatively regulate fat mass and improve metabolic function in male mice. This was achieved using our PC-AR Gene Replacement mouse model in which the AR is only expressed in BM-PCs and deleted in all other tissues. We hypothesise that the markedly reduced fat mass and increased insulin sensitivity of PC-AR Gene Replacements will confer protection from diet-induced overweight and obesity. To test this, 6-week-old male PC-AR Gene Replacements and controls (WT, global-AR knockouts (KOs)) were fed a chow or high-caloric diet (HCD) for 8 or 18 weeks. Following 8 weeks (short-term) of HCD, WT and Global-ARKOs had markedly increased subcutaneous white adipose tissue (WAT) and retroperitoneal visceral adipose tissue (VAT) mass compared to chow-fed controls. In contrast, PC-AR Gene Replacements were resistant to WAT and VAT accumulation following short-term HCD feeding accompanied by fewer large adipocytes and upregulation of expression of the metabolic genes Acaca and Pnlpa2. Following long-term HCD feeding for 18 weeks, the PC-AR Gene Replacements were no longer resistant to increased WAT and VAT adiposity, however, maintained their improved whole-body insulin sensitivity with an increased rate of glucose disappearance and increased glucose uptake into subcutaneous WAT. In conclusion, the action of testosterone via the AR in BM-PCs to negatively regulate fat mass and improve metabolism confers resistance from short-term diet-induced weight gain and partial protection from long-term diet-induced obesity in male mice.

Low Levels of Hepatocyte-Specific Methylation in Cell-Free DNA Are a Strong Negative Predictor for Acute T Cell-Mediated Rejection Requiring Treatment Following Liver Transplantation.

Graft-derived cell-free DNA (gdcfDNA) quantification is a promising, minimally invasive tool for detecting acute T cell-mediated rejection (ATCMR) following liver transplantation (LT). We investigated the utility of measuring hepatocyte-specific methylation in cfDNA (HS-cfDNA) to quantify gdcfDNA, examining its accuracy in detecting ATCMR in a prospective, cross-sectional study. Blood was collected from LT recipients immediately prior to graft biopsy for suspected rejection. HS-cfDNA was quantified using droplet-digital polymerase chain reaction. Prebiopsy liver function tests (LFTs) and HS-cfDNA levels were correlated with biopsy results and the primary outcome of treated biopsy-proven acute rejection (tBPAR). A total of 51 patients were recruited; 37 had evidence of rejection on biopsy and 20 required treatment. As much as 11 patients needed inpatient treatment for rejection. HS-cfDNA significantly outperformed LFTs in identifying patients with tBPAR, particularly those needing inpatient treatment (area under the curve, 73.0%; 95% confidence interval, 55.4%-90.6%; P = 0.01). At a threshold of <33.5% of the total cfDNA fraction, HS-cfDNA had a specificity of 97%, correctly excluding tBPAR in 30/31 patients. Quantifying graft-specific methylation in cfDNA has a major advantage over previous gdcfDNA techniques: it does not require genotyping/sequencing, lending it greater feasibility for translation into transplantation care. Low levels of HS-cfDNA were a strong negative predictor for tBPAR (negative predictive value, 86%) and may have a future role in triaging patients prior to invasive graft biopsies.

The Measurement of Donor-Specific Cell-Free DNA Identifies Recipients With Biopsy-Proven Acute Rejection Requiring Treatment After Liver Transplantation.

BACKGROUND: Assessment of donor-specific cell-free DNA (dscfDNA) in the recipient is emerging as a noninvasive biomarker of organ rejection after transplantation. We previously developed a digital polymerase chain reaction (PCR)-based approach that readily measures dscfDNA within clinically relevant turnaround times. Using this approach, we characterized the dynamics and evaluated the clinical utility of dscfDNA after liver transplantation (LT). METHODS: Deletion/insertion polymorphisms were used to distinguish donor-specific DNA from recipient-specific DNA. Posttransplant dscfDNA was measured in the plasma of the recipients. In the longitudinal cohort, dscfDNA was serially measured at days 3, 7, 14, 28, and 42 in 20 recipients. In the cross-sectional cohort, dscfDNA was measured in 4 clinically stable recipients (>1-y posttransplant) and 16 recipients (>1-mo posttransplant) who were undergoing liver biopsies. RESULTS: Recipients who underwent LT without complications demonstrated an exponential decline in dscfDNA. Median levels at days 3, 7, 14, 28, and 42 were 1936, 1015, 247, 90, and 66 copies/mL, respectively. dscfDNA was higher in recipients with treated biopsy-proven acute rejection (tBPAR) when compared to those without. The area under the receiver operator characteristic curve of dscfDNA was higher than that of routine liver function tests for tBPAR (dscfDNA: 98.8% with 95% confidence interval, 95.8%-100%; alanine aminotransferase: 85.7%; alkaline phosphatase: 66.4%; gamma-glutamyl transferase: 80.1%; and bilirubin: 35.4%). CONCLUSIONS: dscfDNA as measured by probe-free droplet digital PCR methodology was reflective of organ health after LT. Our findings demonstrate the potential utility of dscfDNA as a diagnostic tool of tBPAR.

Successful liver transplantation in common variable immune deficiency with reversal of hepatopulmonary syndrome.

Common variable immune deficiency (CVID) is a primary immunodeficiency disorder that is associated with abnormal liver function tests, however advanced liver disease is uncommon. Hepatopulmonary syndrome (HPS) is a rare but debilitating complication of CVID-associated liver disease. We report a case of CVID complicated by HPS that was successfully treated with orthotopic liver transplant, with the patient recovering to normal hepatic function and successfully weaning off domiciliary oxygen post-transplantation.

Primary bladder amyloidosis as a cause of haematuria.

We report the case of a 46-year-old man who initially presented with macroscopic haematuria. Although initially concerning for a malignancy in the bladder, histology demonstrated a primary bladder amyloidosis that has remained stable for 6 years since the initial diagnosis. Primary bladder amyloidosis is an important clinical entity that can mimic bladder malignancy on clinical history, radiological investigation and cystoscopic evaluation. Although uncommon, it should not be neglected as a possible diagnosis in patients presenting with haematuria.

Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation.

Primary sclerosing cholangitis (PSC) is a liver disease that leads to progressive destruction and stricturing of the biliary tree. Unfortunately, apart from orthotopic liver transplantation (OLT), there are no universally accepted therapies to treat this disease. Even following transplantation, recurrence of PSC is seen in approximately one quarter of patients and leads to high rates of graft failure. Oral vancomycin, through possible immunomodulatory and anti-inflammatory mechanisms, has been shown in small-scale studies to be successful in improving liver function tests in patients with pretransplant PSC. We report the first case of an adult patient diagnosed with recurrent PSC 4 years after OLT who was treated with oral vancomycin leading to complete normalisation of his liver biochemistry. This case adds to the growing literature of a potential therapeutic role for this antibiotic in PSC and highlights interesting questions regarding mechanisms of disease.

Mycophenolate mofetil toxicity mimicking acute cellular rejection in a small intestinal transplant.

Mycophenolate mofetil (MMF) is an important medication used for maintenance immunosuppression in solid organ transplants. A common gastrointestinal (GI) side effect of MMF is enterocolitis, which has been associated with multiple histological features. There is little data in the literature describing the histological effects of MMF in small intestinal transplant (SIT) recipients. We present a case of MMF toxicity in a SIT recipient, with histological changes in the donor ileum mimicking persistent acute cellular rejection (ACR). Concurrent biopsies of the patient's native colon showed similar changes to those from the donor small bowel, suggesting a non-graft specific process, raising suspicion for MMF toxicity. The MMF was discontinued and complete resolution of these changes occurred over three weeks. MMF toxicity should therefore be considered as a differential diagnosis for ACR and graft-versus-host disease in SITs.

Somatostatinoma of the minor papilla treated by local excision in a patient with neurofibromatosis type 1.

CONTEXT: Somatostatinoma arising from the minor papilla in a patient with neurofibromatosis type 1 (NF1) is a known but very rare condition, which may cause non-specific symptoms and can present because of its mass effect. CASE REPORT: A fifty-year-old female presenting with ongoing non-specific abdominal pain for a few months duration was found to have a mass involving the minor papilla. She had a history of NF1 but was otherwise well. Magnetic resonance imaging showed a dilated pancreatic duct and the finding of pancreatic divisum. The lesion was (18)fluorine-fluoro-2-deoxyglucose positron emission tomography/computed tomography and (68)gallium (Ga) DOTATATE negative. Endoscopic ultrasound revealed a 1.7 cm lesion confined to the minor ampulla. Endoscopic retrograde pancreatography attempts with biopsy and endoscopic ultrasound fine needle aspiration biopsy were inconclusive and resulted in mild pancreatitis on two occasions. Open local excision of the minor papilla was undertaken without complications. Histology confirmed a completely excised grade 1 neuroendocrine tumor with intense diffuse somatostatin staining. CONCLUSION: Somatostatinoma of the minor papilla is a rare tumor that most commonly occurs in the setting of NF1 and may be amenable to local excision.