Sofosbuvir-velpatasvir in children 3-17 years old with hepatitis C virus infection.

BACKGROUND: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated. METHODS: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group. FINDINGS: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range. INTERPRETATION: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection.

Neonatal Hypocalcemia: Common, Uncommon, and Rare Etiologies.

Calcium homeostasis in the neonatal period is a reflection of the transition from placental regulation to hormonal maturation in the newborn. Hypocalcemia occurring within the first 72 hours after birth, termed early-onset hypocalcemia (EOH), is more common and often asymptomatic. Hypocalcemia occurring beyond 72 hours of age is termed late-onset hypocalcemia (LOH). LOH is less common than EOH, and affected patients are more likely to be symptomatic. To prevent and treat hypocalcemia in the newborn, neonatal clinicians should be familiar with the common, uncommon, and rare etiologies of EOH and LOH, as summarized in this review.

Outbreak of indeterminate acute liver failure in children with adenoviraemia - Not a new disease.

BACKGROUND & AIMS: In the year 2022, an outbreak of indeterminate acute hepatitis and indeterminate paediatric acute liver failure (ID-PALF) in association with adenoviraemia in immunocompetent children was reported in the UK. We postulate that this association is not a new disease in immunocompetent children. METHODS: Children with acute hepatitis during the outbreak who were referred to King's College Hospital, London for advice and management were included in the study. Data on the frequency of ID-PALF in 2022, as well as transplantation rates and the association with adenovirus infection, were obtained from electronic health records. The clinical presentation, histology and outcomes of children with ID-PALF and adenoviraemia in 2017-2021 were compared with those in 2022. RESULTS: From January to June 2022, 65 patients with acute hepatitis were referred. Ten children were admitted with ID-PALF. ID-PALF constituted 26% of all PALF cases in 2017-2021, in contrast to 58.8% during the 2022 outbreak. During the outbreak, adenoviraemia was present in 52% of children with acute hepatitis without liver failure (in whom adenoviraemia test results were available) and in 100% of ID-PALF cases. Adenoviraemia was seen in immunocompetent children in 6/13 (46%) of all ID-PALF cases between 2017-2019, with a clear absence of adenoviraemia in the 6 ID-PALF cases during 2020-2021. Compared to ID-PALF with adenoviraemia in 2017-2019 (n = 6), ID-PALF with adenoviraemia during the outbreak (n = 10) was associated with more frequent hepatic encephalopathy, hypotension requiring vasoactive medications and higher plasma ammonia levels (admission and peak), with similar native liver survival. CONCLUSIONS: The recent outbreak of ID-PALF with adenoviraemia in immunocompetent children does not appear to be a new disease, contrary to perception and other reports. The frequency of such cases over the years could be linked to background rates of adenovirus infections. IMPACT AND IMPLICATIONS: Indeterminate paediatric acute liver failure (ID-PALF) associated with adenoviraemia in immunocompetent children is not a new disease specific to 2022. The exclusive role of human adenovirus infection in the causation of this outbreak of acute hepatitis seems unlikely. Indeed, we provide histological data from explants in transplanted patients that do not support direct viral cytotoxicity. The disease is probably mediated by immunological injury directed towards adenovirus infection and/or adeno-associated virus-2.

Sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17 years old with HCV infection.

BACKGROUND AND AIMS: Sofosbuvir-velpatasvir-voxilaprevir is a pangenotypic regimen for chronic HCV infection. In the USA and Europe, sofosbuvir-velpatasvir-voxilaprevir once daily for 12 weeks is indicated for adults who previously received an HCV NS5A inhibitor. In Europe, sofosbuvir-velpatasvir-voxilaprevir is also indicated in the absence of prior HCV direct-acting antiviral (DAA) therapy as an 8-week or 12-week regimen. In an open-label study, we evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17 years with chronic HCV of any genotype. METHODS: In this Phase 2, multicenter study, sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg daily was administered to adolescents for 8 weeks if DAA-naïve or for 12 weeks for cirrhosis or prior DAA failure. The key efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Intensive pharmacokinetic sampling was done in 14 patients at week 2 or 4, and samples for population pharmacokinetics were collected in all patients. RESULTS: All patients (n = 21) were naïve to HCV DAAs, and none had cirrhosis. HCV genotype 3a infection was most common, occurring in 43% of patients. Overall, 100% of patients (21 of 21) reached SVR12. The most common adverse events were abdominal pain and headache (24% each) and nausea (19%); no adverse events led to discontinuation. The only serious adverse event, hypotension, was considered related to study drug and resolved the same day without interruption of treatment. Sofosbuvir-velpatasvir-voxilaprevir exposures were similar to those observed in adults. CONCLUSIONS: The pangenotypic regimen of sofosbuvir-velpatasvir-voxilaprevir is highly efficacious and well-tolerated in treating chronic HCV infection in adolescents.

A new proposal for secondary surveillance following potentially curative therapy of HCC: alternating MRI and CEUS.

PURPOSE: A high recurrence rate following ablative therapy of hepatocellular carcinoma (HCC) necessitates routine follow-up imaging (secondary surveillance) to facilitate early re-treatment. We evaluate our unique secondary surveillance algorithm (with use of alternating MRI and CEUS) by assessment of the relative diagnostic accuracy of MRI and CEUS in detection of residual/recurrent tumor. Potential benefits of alternating surveillance are compared to the use of MRI alone. MATERIALS AND METHODS: This prospective observational IRB approved study included 231 patients with 354 treated tumors between January 2017 and June 2020. Treated lesions underwent secondary surveillance for a minimum of 7 months and up to 3 years, median follow-up 14 months. Secondary surveillance involved MRI performed at 1 month after treatment, followed by CEUS and MRI at alternate 3-month intervals (i.e., CEUS at month 4, MRI at month 7, etc.), for a total of 2 years. An equivocal finding on one imaging modality triggered expeditious evaluation with the alternate modality. Arterial phase hyperenhancement and washout comprise the classic features of recurrent tumor on both modalities. RESULTS: A total of 746 MRI and 712 CEUS examinations were performed, and a total of 184 tumor recurrences detected, MRI (n = 82) and CEUS (n = 102) (p = 0.19). There was no difference in the sensitivity (71.0-85.0% and 80.9-92.0%), specificity (97.4-99.2% and 98.5-99.9%), and area under the ROC curve (0.85-0.92 and 0.91-0.96) between MRI and CEUS, respectively. 23 of 82 recurrent tumors identified on MRI were equivocal and confirmed with expedited CEUS. 9 equivocal cases on MRI were disproved by expedited CEUS. On CEUS, 1 of the 102 recurrent tumors was equivocal and confirmed on MRI, and 2 equivocal CEUS cases were disproved by MRI. CONCLUSION: MRI and CEUS performed similarly in our secondary surveillance algorithm for HCC in their ability to detect tumor recurrence, and showed no significant difference in their relative diagnostic test accuracy measures. Of greater interest, equivocal results on MRI (typically due to difficulty in distinguishing tumor recurrence from post-treatment change/shunting) were either confirmed or disproven by CEUS in all cases. Secondary surveillance of treated HCC with alternating MRI and CEUS shows equivalent performance of each modality. CEUS resolves equivocal MRI and optimally demonstrates APHE and washout in tumor recurrence.

Autoimmune Thyroid Disease and Psoriasis Vulgaris after COVID-19 in a Male Teenager.

COVID-19 is implicated in triggering autoimmune, dermatologic, and thyroid diseases. We present a first known case of development of Graves' disease and psoriasis vulgaris in a previously healthy male teenager without any family history, diagnosed after COVID-19 infection. Evaluation of "long COVID syndrome" should include thorough history and thyroid evaluation.

Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry.

BACKGROUND AND AIMS: Genetic predisposition to autoimmune hepatitis (AIH) in adults is associated with possession of human leukocyte antigen (HLA) class I (A*01, B*08) and class II (DRB1*03, -04, -07, or -13) alleles, depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH-1, AIH-2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD. APPROACH AND RESULTS: We studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8-17), including 100 with AIH-1, 59 with AIH-2, and 77 with ASC. The follow-up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence-specific primers. HLA B*08, -DRB1*03, and the A1-B8-DR3 haplotype impart predisposition to all three forms of AILD. Homozygosity for DRB1*03 represented the strongest risk factor (8.8). HLA DRB1*04, which independently confers susceptibility to AIH in adults, was infrequent in AIH-1 and ASC, suggesting protection; and DRB1*15 (DR15) was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD: DRB1*03 to AIH-1, DRB1*13 to ASC, and DRB1*07 to AIH-2. Possession of homozygous DRB1*03 or of DRB1*13 is associated with fibrosis at disease onset, and possession of these two genes in addition to DRB1*07 is associated with a more severe disease in all three subgroups. CONCLUSIONS: Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predicting responsiveness to immunosuppressive treatment and course.

Study of Acute Liver Failure in Children Using Next Generation Sequencing Technology.

OBJECTIVE: To use next generation sequencing (NGS) technology to identify undiagnosed, monogenic diseases in a cohort of children who suffered from acute liver failure (ALF) without an identifiable etiology. STUDY DESIGN: We identified 148 under 10 years of age admitted to King's College Hospital, London, with ALF of indeterminate etiology between 2000 and 2018. A custom NGS panel of 64 candidate genes known to cause ALF and/or metabolic liver disease was constructed. Targeted sequencing was carried out on 41 children in whom DNA samples were available. Trio exome sequencing was performed on 4 children admitted during 2019. A comparison of the clinical characteristics of those identified with biallelic variants against those without biallelic variants was then made. RESULTS: Homozygous and compound heterozygous variants were identified in 8 out of 41 children (20%) and 4 out of 4 children (100%) in whom targeted and exome sequencing were carried out, respectively. The genes involved were NBAS (3 children); DLD (2 children); and CPT1A, FAH, LARS1, MPV17, NPC1, POLG, SUCLG1, and TWINK (1 each). The 12 children who were identified with biallelic variants were younger at presentation and more likely to die in comparison with those who did not: median age at presentation of 3 months and 30 months and survival rate 75% and 97%, respectively. CONCLUSIONS: NGS was successful in identifying several specific etiologies of ALF. Variants in NBAS and mitochondrial DNA maintenance genes were the most common findings. In the future, a rapid sequencing NGS workflow could help in reaching a timely diagnosis and facilitate clinical decision making in children with ALF.

Peginterferon Alfa-2a (40KD) Plus Lamivudine or Entecavir in Children With Immune-Tolerant Chronic Hepatitis B.

OBJECTIVE: Treatment guidelines for chronic hepatitis B (CHB) do not recommend antiviral therapy for patients in the immune-tolerant phase of the disease, which generally occurs in children who acquire hepatitis B virus (HBV) vertically and may last for decades. On the basis of promising results of a pilot study, we conducted a randomized, controlled, multicenter study to evaluate the efficacy and safety of antiviral therapy in children and adolescents with immune-tolerant CHB. METHODS: Fifty-nine children aged 3 to <18 years hepatitis B e antigen-positive with an HBV DNA titer >20,000 IU/mL and persistently normal alanine aminotransferase levels were randomized to 56 weeks of antiviral therapy with an oral nucleoside analogue [entecavir or lamivudine], combined with subcutaneous peginterferon alfa-2a from week 8, or 80 weeks of untreated observation. The primary efficacy outcome was hepatitis B surface antigen loss 24 weeks post-treatment in the antiviral therapy group or at the end of observation in the control group. RESULTS: Enrollment was terminated after the results of two similar studies showed that similar antiviral regimens were ineffective in children and adults with immune-tolerant CHB. At 24 weeks post-treatment, 1 of 26 patients in the antiviral treatment group experienced HBsAg loss (vs none of 33 patients in the control group). No serious treatment-related adverse events were reported, and no patients discontinued treatment because of adverse events. CONCLUSIONS: The antiviral regimen evaluated in this trial had an acceptable tolerability profile, but was ineffective in children and adolescents with immune-tolerant CHB.

Persistent Hepatitis E virus infection across England and Wales 2009-2017: Demography, virology and outcomes.

The first clinical case of persistent HEV infection in England was reported in 2009. We describe the demography, virology and outcomes of patients identified with persistent HEV infection in England and Wales between 2009 and 2017. A series of 94 patients with persistent HEV infection, defined by HEV viraemia of more than 12 weeks, was identified through routine reference laboratory testing. Virology, serology and clinical data were recorded through an approved PHE Enhanced Surveillance System. Sixty-six cases (70.2%) were transplant recipients, 16 (17.0%) had an underlying haematological malignancy without stem cell transplantation, six (6.4%) had advanced HIV infection, five (5.3%) were otherwise immunosuppressed, and one patient (1.1%) had no identified immunosuppression. Retrospective analysis of 46 patients demonstrated a median 38 weeks of viraemia before diagnostic HEV testing. At initial diagnosis, 16 patients (17.0%) had no detectable anti-HEV serological response. Of 65 patients treated with ribavirin monotherapy, 11 (16.9%) suffered virological relapse despite undetectable RNA in plasma or stool at treatment cessation. Persistent HEV infection remains a rare diagnosis, but we demonstrate that a broad range of immunocompromised patients are susceptible. Both lack of awareness and the pauci-symptomatic nature of persistent HEV infection likely contribute to significant delays in diagnosis. Diagnosis should rely on molecular testing since anti-HEV serology is insufficient to exclude persistent HEV infection. Finally, despite treatment with ribavirin, relapses occur even after cessation of detectable faecal shedding of HEV RNA, further emphasising the requirement to demonstrate sustained virological responses to treatment.

Management of Hepatitis B Virus Infection and Prevention of Hepatitis B Virus Reactivation in Children With Acquired Immunodeficiencies or Undergoing Immune Suppressive, Cytotoxic, or Biological Modifier Therapies.

Reactivation of hepatitis B virus (HBV) is a known complication of immune-suppressive, cytotoxic, and biological modifier therapies in patients currently infected with HBV or who have had past exposure to HBV. Nowadays, newer and emerging forms of targeted biologic therapies are available for the management of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions and solid-organ, bone marrow, or haematologic stem cell transplant but there is currently a lack of a systematic approach to the care of patients with or at risk of HBV reactivation. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) together with a working group of ESPGHAN members with clinical and research expertise in viral hepatitis developed an evidence-based position paper on reactivation of HBV infection in children identifying pertinent issues addressing the diagnosis, prevention, and treatment of this condition. Relevant clinical questions were formulated and agreed upon by all the members of the working group. Questions were answered and positions were based on evidence resulting from a systematic literature search on PubMed and Embase from their inception to July 1, 2019. A document was produced and the working group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique. A recommendation was accepted provided upon agreement by at least 75% of the working group members. This position paper provides a comprehensive update on the diagnosis, prevention and treatment of HBV reactivation in children.

Ledipasvir-Sofosbuvir for 12 Weeks in Children 3 to <6 Years Old With Chronic Hepatitis C.

For children under 12 years of age who have chronic hepatitis C virus (HCV) infection, there are currently no approved treatments with direct-acting antiviral agents. We therefore evaluated the safety and efficacy of ledipasvir-sofosbuvir in HCV-infected children aged 3 to <6 years. In an open-label study, patients 3 to <6 years old chronically infected with HCV genotype 1 (n = 33) or 4 (n = 1) received weight-based doses of combined ledipasvir-sofosbuvir as granules (33.75 mg/150 mg for weights <17 kg or 45 mg/200 mg for weights ≥17 kg) for 12 weeks. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12). For the first 14 patients, intensive pharmacokinetic sampling was done on day 10 of treatment. All patients had been infected through perinatal transmission and were treatment naïve. No patients had known cirrhosis. Ten patients (29%) weighed <17 kg. SVR12 was achieved in 97% of patients (33 of 34); the patient who did not achieve SVR12 was 3 years old and discontinued treatment after 5 days because of an adverse event "abnormal drug taste." The most common adverse events were vomiting (24% of patients), cough (21%), and pyrexia (21%). No patients experienced a serious adverse event. Intensive pharmacokinetic analysis of 13 patients for whom data were evaluable confirmed that the doses selected were appropriate. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 3 to <6 years old with chronic HCV infection.

Sofosbuvir and Ribavirin Therapy for Children Aged 3 to <12 Years With Hepatitis C Virus Genotype 2 or 3 Infection.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged <12 years is pegylated interferon plus ribavirin. In an open-label study, we evaluated the safety and efficacy of sofosbuvir plus ribavirin for 12 weeks in children aged 3 to <12 years chronically infected with genotype 2 or for 24 weeks in patients with genotype 3. Patients aged 3 to <6 years weighing <17 kg received sofosbuvir 150 mg, and patients aged 3 to <6 years weighing ≥17 kg and all patients aged 6 to <12 years received sofosbuvir 200 mg once daily. Intensive pharmacokinetic sampling conducted in each age group confirmed the appropriateness of sofosbuvir doses. For all patients, ribavirin dosing was determined by baseline weight (up to 1,400 mg/day, two divided doses). The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Fifty-four patients were enrolled (41 aged 6 to <12 years and 13 aged 3 to <6 years). Most were treatment naïve (98%) and infected perinatally (94%). All but one patient achieved SVR12 (53/54, 98%; 95% confidence interval, 90%-100%). The patient who did not achieve SVR12 was a 4-year-old who discontinued treatment after 3 days because of "abnormal drug taste." The most commonly reported adverse events in patients aged 6 to <12 years were vomiting (32%) and headache (29%), and those in patients aged 3 to <6 years were vomiting (46%) and diarrhea (39%). One 3-year-old patient had a serious adverse event of accidental ribavirin overdose requiring hospitalization for monitoring; this patient completed treatment and achieved SVR12. Conclusion: Sofosbuvir plus ribavirin was well tolerated and highly effective in children aged 3 to <12 years with chronic HCV genotype 2 or 3 infection.

Alginate microencapsulated human hepatocytes for the treatment of acute liver failure in children.

BACKGROUND & AIMS: Liver transplantation (LT) is the most effective treatment for patients with acute liver failure (ALF), but is limited by surgical risks and the need for life-long immunosuppression. Transplantation of microencapsulated human hepatocytes in alginate is an attractive option over whole liver replacement. The safety and efficacy of hepatocyte microbead transplantation have been shown in animal models. We report our experience of this therapy in children with ALF treated on a named-patient basis. METHODS: Clinical grade human hepatocyte microbeads (HMBs) and empty microbeads were tested in immunocompetent healthy rats. Subsequently, 8 children with ALF, who were awaiting a suitable allograft for LT, received intraperitoneal transplantation of HMBs. We monitored complications of the procedure, assessing the host immune response and residual function of the retrieved HMBs, either after spontaneous native liver regeneration or at the time of LT. RESULTS: Intraperitoneal transplantation of HMBs in healthy rats was safe and preserved synthetic and detoxification functions, without the need for immunosuppression. Subsequently, 8 children with ALF received HMBs (4 neonatal haemochromatosis, 2 viral infections and 2 children with unknown cause at time of infusion) at a median age of 14.5 days, range 1 day to 6 years. The procedure was well tolerated without complications. Of the 8 children, 4 avoided LT while 3 were successfully bridged to LT following the intervention. HMBs retrieved after infusions (at the time of LT) were structurally intact, free of host cell adherence and contained viable hepatocytes with preserved functions. CONCLUSION: The results demonstrate the feasibility and safety of an HMB infusion in children with ALF. LAY SUMMARY: Acute liver failure in children is a rare but devastating condition. Liver transplantation is the most effective treatment, but it has several important limitations. Liver cell (hepatocyte) transplantation is an attractive option, as many patients only require short-term liver support while their own liver recovers. Human hepatocytes encapsulated in alginate beads can perform the functions of the liver while alginate coating protects the cells from immune attack. Herein, we demonstrated that transplantation of these beads was safe and feasible in children with acute liver failure.

Resolution by deep sequencing of a dual hepatitis E virus infection transmitted via blood components.

Hepatitis E virus (HEV) is a zoonotic infection, with consumption of processed pork products thought to be the major route of transmission in England. The clinical features of HEV infection range from asymptomatic infection to mild hepatitis to fulminant liver failure. Persistent, chronic hepatitis is increasingly recognized in immunocompromised patients. Infection via HEV-containing blood components and organs has been reported and measures to reduce this transmission risk were introduced into the blood service in England in 2016. We report here the sequence and phylogenetic findings from investigations into a transmission event from an HEV-infected donor to two recipients. Phylogenetic analysis of HEV genome sequence fragments obtained by Sanger sequencing showed that, whilst most of the sequences from both recipients' samples grouped with the sequence from the blood donor sample, the relationship of five sequences from recipient 2 were unresolved. Analysis of Illumina short-read deep sequence data demonstrated the presence of two divergent viral populations in the donor's sample that were also present in samples from both recipients. A clear phylogenetic relationship was established, indicating a probable transmission of both populations from the donor to each of the immunocompromised recipients. This study demonstrates the value of the application of new sequencing technologies combined with bioinformatic data analysis when Sanger sequencing is not able to clarify a proper phylogenetic relationship in the investigation of transmission events.

Contrast-enhanced US in Local Ablative Therapy and Secondary Surveillance for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has a high incidence of recurrence following therapy. Therefore, secondary surveillance (scheduled follow-up imaging after treatment) is an important part of disease management. The recent approval in the United States for use of a microbubble-based contrast agent for US liver imaging promotes the increased use of contrast-enhanced US (CEUS) in patients with HCC. Although the criteria for the diagnosis of HCC at CEUS are well described, there is a paucity of published literature describing the role of CEUS in ablative therapy and secondary surveillance. In the setting of ablative therapy, CEUS can have vital roles, including patient selection, intraprocedural guidance, and immediate postprocedural assessment. Although CEUS is not widely used, the authors found that it can be used to accurately detect residual or recurrent tumor, characterize the geographic pattern of recurrence (intrazonal, extrazonal, segmental, or remote), and assess for tumor in vein. In addition, similar to primary surveillance, secondary surveillance includes assessment of the entire liver for evaluation of new nodules. Arterial phase hyperenhancement is the reference standard characteristic of disease recurrence at secondary surveillance with CEUS. ©RSNA, 2019 See discussion on this article by Rodgers.

TP53 Status as a Determinant of Pro- vs Anti-Tumorigenic Effects of Estrogen Receptor-Beta in Breast Cancer.

BACKGROUND: Anti-tumorigenic vs pro-tumorigenic roles of estrogen receptor-beta (ESR2) in breast cancer remain unsettled. We investigated the potential of TP53 status to be a determinant of the bi-faceted role of ESR2 and associated therapeutic implications for triple negative breast cancer (TNBC). METHODS: ESR2-TP53 interaction was analyzed with multiple assays including the in situ proximity ligation assay. Transcriptional effects on TP53-target genes and cell proliferation in response to knocking down or overexpressing ESR2 were determined. Patient survival according to ESR2 expression levels and TP53 mutation status was analyzed in the basal-like TNBC subgroup in the Molecular Taxonomy of Breast Cancer International Consortium (n = 308) and Roswell Park Comprehensive Cancer Center (n = 46) patient cohorts by univariate Cox regression and log-rank test. All statistical tests are two-sided. RESULTS: ESR2 interaction with wild-type and mutant TP53 caused pro-proliferative and anti-proliferative effects, respectively. Depleting ESR2 in cells expressing wild-type TP53 resulted in increased expression of TP53-target genes CDKN1A (control group mean [SD] = 1 [0.13] vs ESR2 depletion group mean [SD] = 2.08 [0.24], P = .003) and BBC3 (control group mean [SD] = 1 [0.06] vs ESR2 depleted group mean [SD] = 1.92 [0.25], P = .003); however, expression of CDKN1A (control group mean [SD] = 1 [0.21] vs ESR2 depleted group mean [SD] = 0.56 [0.12], P = .02) and BBC3 (control group mean [SD] = 1 [0.03] vs ESR2 depleted group mean [SD] = 0.55 [0.09], P = .008) was decreased in cells expressing mutant TP53. Overexpressing ESR2 had opposite effects. Tamoxifen increased ESR2-mutant TP53 interaction, leading to reactivation of TP73 and apoptosis. High levels of ESR2 expression in mutant TP53-expressing basal-like tumors is associated with better prognosis (Molecular Taxonomy of Breast Cancer International Consortium cohort: log-rank P = .001; hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.84, univariate Cox P = .02). CONCLUSIONS: TP53 status is a determinant of the functional duality of ESR2. Our study suggests that ESR2-mutant TP53 combination prognosticates survival in TNBC revealing a novel strategy to stratify TNBC for therapeutic intervention potentially by repurposing tamoxifen.