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Grafts of spinal-cord-derived neural progenitor cells (NPCs) enable the robust regeneration of corticospinal axons and restore forelimb function after spinal cord injury1; however, the molecular mechanisms that underlie this regeneration are unknown. Here we perform translational profiling specifically of corticospinal tract (CST) motor neurons in mice, to identify their 'regenerative transcriptome' after spinal cord injury and NPC grafting. Notably, both injury alone and injury combined with NPC grafts elicit virtually identical early transcriptomic responses in host CST neurons. However, in mice with injury alone this regenerative transcriptome is downregulated after two weeks, whereas in NPC-grafted mice this transcriptome is sustained. The regenerative transcriptome represents a reversion to an embryonic transcriptional state of the CST neuron. The huntingtin gene (Htt) is a central hub in the regeneration transcriptome; deletion of Htt significantly attenuates regeneration, which shows that Htt has a key role in neural plasticity after injury.
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Proliferación Celular/genética , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Regeneración Nerviosa/genética , Células-Madre Neurales/citología , Neuronas/metabolismo , Neuronas/patología , Transcripción Genética , Animales , Axones/patología , Axones/fisiología , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Proteína Huntingtina/genética , Ratones , Células-Madre Neurales/trasplante , Plasticidad Neuronal , Neuronas/citología , Neuronas/trasplante , Biosíntesis de Proteínas , Tractos Piramidales/citología , Tractos Piramidales/metabolismo , Tractos Piramidales/patología , RNA-Seq , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/patología , TranscriptomaRESUMEN
Since 2010, US life expectancy growth has stagnated. Much research on US mortality has focused on working-age adults given adverse trends in drug overdose deaths, other external causes of death, and cardiometabolic deaths in midlife. We show that the adverse mortality trend at retirement ages (65+ y) has in fact been more consequential to the US life expectancy stagnation since 2010, as well as excess deaths and years of life lost in 2019, than adverse mortality trends at working ages. These results reveal that the United States is experiencing a "double jeopardy" that is driven by both mid-life and older-age mortality trends, but more so by older-age mortality. Understanding and addressing the causes behind the worsening mortality trend in older ages will be essential to returning to the pace of life expectancy improvements that the United States had experienced for decades.
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Sobredosis de Droga , Esperanza de Vida , Adulto , Humanos , Estados Unidos/epidemiología , Teoría Ética , Jubilación , Mortalidad , Causas de MuerteRESUMEN
Immunotherapy has revolutionised the treatment of advanced hepatocellular carcinoma (HCC). In addition, several phase III trials of immunotherapy in combination with surgical or locoregional therapies for early-to intermediate-stage HCC have recently reported positive results, and other phase III trials in the same patient population are currently in progress. As the application of immunotherapy is shifting to include patients with earlier stages of HCC, one looming question now emerges: What is the role of immunotherapy in the pre-liver transplant population? Liver transplantation is a potentially curative therapy for HCC and confers the additional advantage of restoring a normal, healthy liver. In pre-transplant patients, immunotherapy may improve downstaging success and tumour control at the cost of some immunologic risks. These include immune-related toxicities, which are particularly relevant in a uniquely vulnerable population with chronic liver disease, and the possibility of acute rejection after transplantation. Ultimately, the goal of immunotherapy in this population will be to effectively expand access to liver transplantation while preserving pre- and post-transplant outcomes. In this review, we discuss the mechanisms supporting combination immunotherapy, summarise key recent clinical data from major immunotherapy trials, and explore how immunotherapy can be applied in the neoadjuvant setting prior to liver transplantation in selected high-risk patients.
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BACKGROUND AND AIM: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. MATERIALS AND METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.
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OBJECTIVE: To evaluate long-term oncologic outcomes of patients post-living donor liver transplantation (LDLT) within and outside standard transplantation selection criteria and the added value of the incorporation of the New York-California (NYCA) score. BACKGROUND: LDLT offers an opportunity to decrease the liver transplantation waitlist, reduce waitlist mortality, and expand selection criteria for patients with hepatocellular carcinoma (HCC). METHODS: Primary adult LDLT recipients between October 1999 and August 2019 were identified from a multicenter cohort of 12 North American centers. Posttransplantation and recurrence-free survival were evaluated using the Kaplan-Meier method. RESULTS: Three hundred sixty LDLTs were identified. Patients within Milan criteria (MC) at transplantation had a 1, 5, and 10-year posttransplantation survival of 90.9%, 78.5%, and 64.1% versus outside MC 90.4%, 68.6%, and 57.7% ( P = 0.20), respectively. For patients within the University of California San Francisco (UCSF) criteria, respective posttransplantation survival was 90.6%, 77.8%, and 65.0%, versus outside UCSF 92.1%, 63.8%, and 45.8% ( P = 0.08). Fifty-three (83%) patients classified as outside MC at transplantation would have been classified as either low or acceptable risk with the NYCA score. These patients had a 5-year overall survival of 72.2%. Similarly, 28(80%) patients classified as outside UCSF at transplantation would have been classified as a low or acceptable risk with a 5-year overall survival of 65.3%. CONCLUSIONS: Long-term survival is excellent for patients with HCC undergoing LDLT within and outside selection criteria, exceeding the minimum recommended 5-year rate of 60% proposed by consensus guidelines. The NYCA categorization offers insight into identifying a substantial proportion of patients with HCC outside the MC and the UCSF criteria who still achieve similar post-LDLT outcomes as patients within the criteria.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Adulto , Humanos , Trasplante de Hígado/métodos , Donadores Vivos , Recurrencia Local de Neoplasia/etiología , Selección de Paciente , América del Norte , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Noninvasive variceal risk stratification systems have not been validated in patients with hepatocellular carcinoma (HCC), which presents logistical barriers for patients in the setting of systemic HCC therapy. We aimed to develop and validate a noninvasive algorithm for the prediction of varices in patients with unresectable HCC. METHODS: We performed a retrospective cohort study in 21 centers in the United States including adult patients with unresectable HCC and Child-Pugh A5-B7 cirrhosis diagnosed between 2007 and 2019. We included patients who completed an esophagogastroduodonoscopy (EGD) within 12 months of index imaging but before HCC treatment. We divided the cohort into a 70:30 training set and validation set, with the goal of maximizing negative predictive value (NPV) to avoid EGD in low-risk patients. RESULTS: We included 707 patients (median age, 64.6 years; 80.6% male; 74.0% White). Median time from HCC diagnosis to EGD was 47 (interquartile range, 114) days, with 25.0% of patients having high-risk varices. A model using clinical variables alone achieved an NPV of 86.3% in the validation cohort, whereas a model integrating clinical and imaging variables had an NPV 97.4% in validation. The clinical and imaging model would avoid EGDs in more than half of low-risk patients while misclassifying 7.7% of high-risk patients. CONCLUSIONS: A model incorporating clinical and imaging data can accurately predict the absence of high-risk varices in patients with HCC and avoid EGD in many low-risk patients before the initiation of systemic therapy, thus expediting their care and avoiding treatment delays.
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Immune checkpoint inhibitors are becoming a mainstay of cancer treatment. While first studied and approved for patients with unresectable disease, due to their efficacy, they are becoming increasingly used in the perioperative period across many cancer types. In patients with HCC, immune checkpoint inhibitors have now become the standard of care in the advanced setting and have shown promising results in the adjuvant setting after liver resection. While these drugs continue to show promise, their role in the peritransplant setting still remains a question. In this review, we explore the current use of this class of medications in patients with HCC, as well as the immunologic role of the pathways that they inhibit. We also identify potential for future research opportunities to better understand the role of these medications.
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Carcinoma Hepatocelular , Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Trasplante de Hígado/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/tratamiento farmacológico , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/tratamiento farmacológico , Resultado del Tratamiento , Hepatectomía , Quimioterapia Adyuvante/métodosRESUMEN
Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are the 2 most used modalities for patients with HCC while awaiting liver transplant. The purpose of this study is to perform a cost-effectiveness analysis comparing TACE and TARE for downstaging (DS) patients with HCC. A cost-effectiveness analysis was performed comparing TACE and TARE in DS HCC over a 5-year time horizon from a payer's perspective. The clinical course, including those who achieved successful DS leading to liver transplant and those who failed DS with possible disease progression, was obtained from the United Network for Organ Sharing. Costs and effectiveness were measured in US dollars and quality-adjusted life years (QALYs). Probabilistic and deterministic sensitivity analyses were performed. TARE achieved a higher effectiveness of 2.51 QALY (TACE: 2.29 QALY) at a higher cost of $172,162 (TACE: $159,706), with the incremental cost-effectiveness ratio of $55,964/QALY, making TARE the more cost-effective strategy. The difference in outcome was equivalent to 104 days (nearly 3.5 months) in compensated cirrhosis state. Probabilistic sensitivity analyses showed that TARE was more cost-effective in 91.69% of 10,000 Monte Carlo simulations. TARE was more effective if greater than 48.2% of patients who received TACE or TARE were successfully downstaged (base case: 74.6% from the pooled analysis of multiple published cohorts). TARE became more cost-effective when the cost of TACE exceeded $4,831 (base case: $12,722) or when the cost of TARE was lower than $43,542 (base case: $30,609). Subgroup analyses identified TARE to be the more cost-effective strategy if the TARE cohort required 1 fewer locoregional therapy than the TACE cohort. TARE is the more cost-effective DS strategy for patients with HCC exceeding Milan criteria compared to TACE.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Análisis de Costo-Efectividad , Trasplante de Hígado/efectos adversos , Resultado del TratamientoRESUMEN
For many cancers, biomarkers have served as an important tool across the cancer care continuum from risk stratification and early detection to diagnosis and treatment. Alpha-fetoprotein (AFP) remains one of the few validated biomarkers for patients with HCC. Although AFP has shown potential for each of these steps, its performance, when used alone, has often been suboptimal. There continue to be discordant recommendations about AFP's value when combined with ultrasound for surveillance, as well as its role in diagnostic algorithms. Conversely, high AFP levels are associated with aggressive tumor biology and survival, so it remains a key factor for the selection of candidates for liver transplant. There have been immense efforts to identify and validate additional biomarkers for each of these steps in the HCC care continuum. Indeed, biomarker panels have shown promising data for HCC risk stratification and surveillance among patients with cirrhosis, as well as prognostication and detection of minimal residual disease in patients undergoing HCC treatment. Several large prospective studies are currently ongoing to evaluate the role of these emerging biomarkers in clinical practice.
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Safety net systems care for patients with a high burden of liver disease yet experience many barriers to liver transplant (LT) referral. This study aimed to assess safety net providers' perspectives on barriers to LT referrals in the United States. We conducted a nationwide anonymous online survey of self-identified safety net gastroenterologists and hepatologists from March through November 2022. This 27-item survey was disseminated via e-mail, society platforms, and social media. Survey sections included practice characteristics, transplant referral practices, perceived multilevel barriers to referral, potential solutions, and respondent characteristics. Fifty complete surveys were included in analysis. A total of 60.0% of respondents self-identified as White and 54.0% male. A total of 90.0% practiced in an urban setting, 82.0% in tertiary medical centers, and 16.0% in community settings, with all 4 US regions represented. Perceived patient-level barriers ranked as most significant, followed by practice-level, then provider-level barriers. Patient-level barriers such as lack of insurance (72.0%), finances (66.0%), social support (66.0%), and stable housing/transportation (64.0%) were ranked as significant barriers to referral, while medical mistrust and lack of interest were not. Limited access to financial services (36.0%) and addiction/mental health resources (34.0%) were considered important practice-level barriers. Few reported existing access to patient navigators (12.0%), and patient navigation was ranked as most likely to improve referral practices, followed by an expedited/expanded pathway for insurance coverage for LT. In this national survey, safety net providers reported the highest barriers to LT referral at the patient level and practice level. These data can inform the development of multilevel interventions in safety net settings to enhance equity in LT access for vulnerable patients.
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Accesibilidad a los Servicios de Salud , Trasplante de Hígado , Derivación y Consulta , Proveedores de Redes de Seguridad , Humanos , Trasplante de Hígado/estadística & datos numéricos , Derivación y Consulta/estadística & datos numéricos , Derivación y Consulta/organización & administración , Proveedores de Redes de Seguridad/estadística & datos numéricos , Proveedores de Redes de Seguridad/organización & administración , Masculino , Estados Unidos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/organización & administración , Femenino , Gastroenterólogos/estadística & datos numéricos , Gastroenterólogos/psicología , Gastroenterólogos/organización & administración , Encuestas y Cuestionarios/estadística & datos numéricos , Actitud del Personal de Salud , Persona de Mediana Edad , Pautas de la Práctica en Medicina/estadística & datos numéricos , Enfermedad Hepática en Estado Terminal/cirugía , Enfermedad Hepática en Estado Terminal/diagnósticoRESUMEN
OPINION STATEMENT: Liver transplantation for hepatocellular carcinoma (HCC) remains an evolving field. Major challenges HCC transplant patients face today include liver organ donor shortages and the need for both better pre-transplant bridging/downstaging therapies and post-transplant HCC recurrence treatment options. The advent of immunotherapy and the demonstrated efficacy of immune checkpoint inhibitors in multiple solid tumors including advanced/unresectable HCC hold promise in expanding both the neoadjuvant and adjuvant HCC transplant treatment regimen, though caution is needed with these immune modulating agents leading up to and following transplant. New options for pre-transplant HCC management will expand access to this curative option as well as ensure patients have adequate control of their HCC prior to transplant to maximize the utility of a liver donor. Machine perfusion has been an active area of investigation in recent years and could expand the organ donor pool, helping address current liver donor shortages. Finally, additional HCC biomarkers such as AFP-L3 and DCP have shown promise in improving risk stratification of HCC patients. Together, these three recent advancements will likely alter HCC transplant guidelines in the coming years.
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Healthcare educators are exploring ways to integrate Large Language Models (LLMs) into the curriculum. At the same time, they are concerned about the negative impact on students' cognitive development. There is concern that the students will not learn to think and problem-solve by themselves and instead become dependent on LLMs to find answers. In addition, the students could start accepting the LLM generated responses at face value. The Illusion of Explanatory Depth (IoED) is a cognitive bias where humans believe they understand complex phenomena in more depth than they do. This illusion is caused when people rely on external sources of information rather than deeper levels of internalized knowledge. This illusion can be exposed by asking follow-up in depth questions. Using the same approach, specifically iterative prompting, can help students interact with LLM's while learning actively, gaining deeper levels of knowledge, and exposing the LLM shortcomings. The article proposes that educators encourage use of LLMs to complete assignments using a template, that promotes students' reflections on their interactions with LLMs, using iterative prompting. This process based on IoED, and iterative prompting will help educators integrate LLMs in the curriculum while mitigating the risk of students becoming dependent on these tools. Students will practice active learning and experience firsthand the inaccuracies and inconsistencies in LLM responses.
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The custom GPT is the latest powerful feature added to ChatGPT. Non-programmers can create and share their own GPTs ("chat bots"), allowing Health Professions Educators to apply the capabilities of ChatGPT to create administrative assistants, online tutors, virtual patients, and more, to support their clinical and non-clinical teaching environments. To achieve this correctly, however, requires some skills, and this 12-Tips paper provides those: we explain how to construct data sources, build relevant GPTs, and apply some basic security.
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Empleos en Salud , Humanos , Empleos en Salud/educación , InternetRESUMEN
Patients with hepatocellular carcinoma meeting united network for organ sharing (UNOS)-downstaging (DS) criteria have excellent liver transplantation (LT) outcomes after DS. However, outcomes for "all-comers" (AC) patients with tumors initially exceeding UNOS-DS are poorly understood. Patients meeting AC (n = 82) or UNOS-DS (n = 229) at 7 LT centers in 4 UNOS regions were prospectively followed from 2015-2020. AC patients had a lower probability of successful DS (67% vs 83% within 12 months; P < .001). The 3-year survival was 69% for UNOS-DS vs 58% for AC (P = .05) and reduced to 30% in patients with Child-Pugh B/C cirrhosis or alpha-fetoprotein (AFP) ≥ 500. Five-year LT probability was 42% for AC vs 74% in UNOS-DS (P = .10). Thirty-eight percent were understaged on explant, with the increasing sum of the largest tumor diameter plus the number of lesions before LT (odds ratio 1.3; P = .01) and AFP ≥ 20 (odds ratio 5.9; P = .005) associated with understaging. Post-LT 3-year survival was 91% for AC vs 81% for UNOS-DS (P = .67). In this first prospective multiregional study of AC patients from the multicenter evaluation of reduction in tumor size before liver transplantation (MERITS-LT) consortium, we observed a 65% probability of successful DS. Three-year survival in AC was nearly 60%, though AC with Child-Pugh B/C or AFP ≥ 500 had poor survival. Explant pathology and 3-year post-LT outcomes were similar between cohorts, suggesting that LT is a reasonable goal in selected AC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , alfa-Fetoproteínas , Estudios Prospectivos , Estudios Retrospectivos , Recurrencia Local de Neoplasia , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND & AIMS: Alpha-fetoprotein (AFP) predicts hepatocellular carcinoma (HCC) recurrence after liver transplant (LT) but remains an imperfect biomarker. The role of DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) in predicting HCC recurrence remains incompletely characterized. AFP-L3 and DCP could identify patients at high risk of post-transplant HCC recurrence and serve as liver transplant exclusion criteria to defer transplant until patients receive additional risk-reducing pre-transplant locoregional therapy. METHODS: This prospective cohort study included consecutive patients with HCC who underwent LT (within or down-staged to Milan criteria) between 2017 and 2022. Pre-transplant AFP, AFP-L3, and DCP measurements were obtained. The primary endpoint was the ability of biomarkers to predict HCC recurrence-free survival. RESULTS: This cohort included 285 patients with a median age of 67 (IQR 63-71). At LT, median biomarker values were AFP 5.0 ng/ml (IQR 3.0-12.1), AFP-L3 6.7% (0.5-13.2), and DCP 1.0 ng/ml (0.3-2.8). Most (94.7%) patients received pre-LT locoregional therapy. After a median post-LT follow-up of 3.1 years, HCC recurrence was observed in 18 (6.3%) patients. AFP-L3 and DCP outperformed AFP with C-statistics of 0.81 and 0.86 respectively, compared with 0.74 for AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted 61.1% of HCC recurrences, whereas HCC only recurred in 7 of 265 (2.6%) patients not meeting this threshold. The Kaplan-Meier recurrence-free survival rate at 3 years post-LT was 43.7% for patients with dual-positive biomarkers compared to 97.0% for all others (p <0.001). CONCLUSIONS: Dual-positivity for AFP-L3 ≥15% and DCP ≥7.5 strongly predicted post-LT HCC recurrence. This model could refine LT selection criteria and identify high-risk patients who require additional locoregional therapy prior to LT. IMPACT AND IMPLICATIONS: Alpha-fetoprotein (AFP) is used to predict hepatocellular carcinoma (HCC) recurrence after liver transplant, but it remains an imperfect biomarker. In this prospective study, the biomarkers DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) strongly predicted early HCC recurrence and outperformed AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted the majority of recurrences and could be used to further refine liver transplant eligibility criteria.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , alfa-Fetoproteínas/metabolismo , Estudios Prospectivos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Biomarcadores de Tumor , Biomarcadores , ProtrombinaRESUMEN
BACKGROUND & AIMS: The United Network for Organ Sharing (UNOS) grants priority listing for liver transplant for patients with hepatocellular carcinoma after successful down-staging to Milan criteria. We evaluated the national experience on down-staging by comparing 2 down-staging groups: tumor burden meeting UNOS down-staging (UNOS-DS) inclusion criteria, and all-comers (AC)-DS with initial tumor burden beyond UNOS-DS criteria vs patients always within Milan criteria. METHODS: We performed a retrospective analysis of the UNOS database of 23,398 patients listed for liver transplant who had submitted a hepatocellular carcinoma Model for End-Stage Liver Disease exception application from 2010 to 2019, classified as always within Milan (n = 20,579), UNOS-DS (n = 2151), and AC-DS (n = 668). RESULTS: The 2-year cumulative probabilities of dropout were 19% for Milan, 25% for UNOS-DS (P < .001), and 30% for AC-DS (P < .001). In multivariate analysis of the down-staging groups, factors predicting dropout included Model for End-Stage Liver Disease at listing (hazard ratio [HR], 1.06; P < .001) and initial total tumor diameter (HR, 1.04; P = .002). Compared with α-fetoprotein (AFP) level ≤20 ng/mL, AFP levels of 21 to 100, 101 to 1000, and greater than 1000 ng/mL were associated with a higher risk of dropout (HRs, 1.63, 2.06, and 4.58, respectively; P < .001). A subset of all-comers with AFP levels greater than 100 ng/mL had a 2-year probability of dropout of 52% vs 26% for all others beyond Milan criteria (P < .001). CONCLUSIONS: All-comers had a significantly higher risk for waitlist dropout compared with the UNOS-DS and Milan groups after initial successful down-staging to Milan criteria. In particular, the subgroup of AC-DS with an AFP level greater than 100 ng/mL had a greater than 50% probability of dropout in the next 2 years. These observations suggest a high likelihood of failure when expanding the indications for down-staging.
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Carcinoma Hepatocelular , Enfermedad Hepática en Estado Terminal , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , alfa-Fetoproteínas , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Recurrencia Local de NeoplasiaRESUMEN
Background The Liver Imaging Reporting and Data System version 2018 (LI-RADS) treatment response algorithm (TRA) is a high-specificity, lower-sensitivity grading system to diagnose hepatocellular carcinoma (HCC) and recurrence after local-regional therapy. However, the emphasis on specificity can result in disease understaging, potentially leading to poorer posttransplant outcomes. Purpose To determine the negative predictive value (NPV) of pretransplant CT and MRI assessment for viable HCC on a per-patient basis using the LI-RADS TRA, considering explant pathology as the reference standard. Materials and Methods Patient records from 218 consecutive adult patients from a single institution with HCC who underwent liver transplant from January 2011 to November 2017 were retrospectively reviewed. Two readers blinded to the original report reviewed immediate (within 90 days) pretransplant imaging and characterized observations according to the LI-RADS TRA. Based on this, patients with LR-4, LR-5, or LR-TR (treatment response) viable tumors were designated as viable tumor; patients with solely LR-3 or LR-TR equivocal tumors were designated as equivocal; and patients with only LR-TR nonviable lesions were designated as no viable disease. Patients were designated as within or outside the Milan criteria. These per-patient designations were compared with the presence of viable disease at explant pathology. Fisher exact test was used to compare the differences between CT and MRI. Weighted κ values were used to calculate interreader reliability. Results Final study sample consisted of 206 patients (median age, 61 years [IQR, 57-65 years]; 157 male patients and 49 female patients). Per-patient LI-RADS TRA assessment of pretransplant imaging had an NPV of 32% (95% CI: 27, 38) and 26% (95% CI: 20, 33) (readers 1 and 2, respectively) for predicting viable disease. Seventy-five percent (reader 1) and 77% (reader 2) of patients deemed equivocal had residual tumors at explant pathology. Weighted interreader reliability was substantial (κ = 0.62). Conclusion Patient-based stratification of viable, equivocal, and nonviable disease at pretransplant CT or MRI, based on LI-RADS TRA, demonstrated low negative predictive value in excluding HCC at explant pathology. © RSNA, 2023 See also the editorial by Tamir and Tau in this issue.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Humanos , Masculino , Femenino , Persona de Mediana Edad , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Reproducibilidad de los Resultados , Imagen por Resonancia Magnética/métodos , Algoritmos , Tomografía Computarizada por Rayos X/métodos , Sensibilidad y Especificidad , Medios de ContrasteRESUMEN
Since the Final Rule regarding transplantation was published in 1999, organ distribution policies have been implemented to reduce geographic disparity. While a recent change in liver allocation, termed acuity circles, eliminated the donor service area as a unit of distribution to decrease the geographic disparity of waitlisted patients to liver transplantation, recently published results highlight the complexity of addressing geographic disparity. From geographic variation in donor supply, as well as liver disease burden and differing model for end-stage liver disease (MELD) scores of candidates and MELD scores necessary to receive liver transplantation, to the urban-rural disparity in specialty care access, and to neighborhood deprivation (community measure of socioeconomic status) in liver transplant access, addressing disparities of access will require a multipronged approach at the patient, transplant center, and national level. Herein, we review the current knowledge of these disparities-from variation in larger (regional) to smaller (census tract or zip code) levels to the common etiologies of liver disease, which are particularly affected by these geographic boundaries. The geographic disparity in liver transplant access must balance the limited organ supply with the growing demand. We must identify patient-level factors that contribute to their geographic disparity and incorporate these findings at the transplant center level to develop targeted interventions. We must simultaneously work at the national level to standardize and share patient data (including socioeconomic status and geographic social deprivation indices) to better understand the factors that contribute to the geographic disparity. The complex interplay between organ distribution policy, referral patterns, and variable waitlisting practices with the proportion of high MELD patients and differences in potential donor supply must all be considered to create a national policy strategy to address the inequities in the system.
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Enfermedad Hepática en Estado Terminal , Hepatopatías , Trasplante de Hígado , Obtención de Tejidos y Órganos , Humanos , Trasplante de Hígado/efectos adversos , Enfermedad Hepática en Estado Terminal/cirugía , Listas de Espera , Índice de Severidad de la Enfermedad , Donantes de Tejidos , Disparidades en Atención de SaludRESUMEN
In patients with HCC awaiting liver transplantation (LT), there is a need to identify biomarkers that are superior to AFP in predicting prognosis. AFP-L3 and des-gamma-carboxyprothrombin (DCP) play a role in HCC detection, but their ability to predict waitlist dropout is unknown. In this prospective single-center study commenced in July 2017, 267 HCC patients had all 3 biomarkers obtained at LT listing. Among them, 96.2% received local-regional therapy, and 18.8% had an initial tumor stage beyond Milan criteria requiring tumor downstaging. At listing, median AFP was 7.0 ng/mL (IQR 3.4-21.5), median AFP-L3 was 7.1% (IQR 0.5-12.5), and median DCP was 1.0 ng/mL (IQR 0.2-3.8). After a median follow-up of 19.3 months, 63 (23.6%) experienced waitlist dropout, while 145 (54.3%) received LT, and 59 (22.1%) were still awaiting LT. Using Cox proportional hazards analysis, AFP-L3≥35% and DCP≥7.5 ng/mL were associated with increased waitlist dropout, whereas AFP at all tested cutoffs, including ≥20,≥ 100, and≥250 ng/mL was not. In a multivariable model, AFP-L3≥35% (HR 2.25, p =0.04) and DCP≥7.5 ng/mL (HR 2.20, p =0.02) remained associated with waitlist dropout as did time from HCC diagnosis to listing ≥ 1 year and increasing MELD-Na score. Kaplan-Meier probability of waitlist dropout within 2 years was 21.8% in those with AFP-L3<35% and DCP<7.5 ng/mL, 59.9% with either AFP-L3 or DCP elevated, and 100% for those with both elevated ( p <0.001). In this prospective study, listing AFP-L3% and DCP were superior to AFP in predicting waitlist dropout with the combination of AFP-L3≥35% and DCP≥7.5 ng/mL associated with a 100% risk of waitlist dropout, thus clearly adding prognostic value to AFP alone.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Biomarcadores de Tumor , Estudios Prospectivos , alfa-Fetoproteínas/análisis , Biomarcadores , ProtrombinaRESUMEN
The burden of HCC is substantial. To address gaps in HCC care, the American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) aimed to develop a standard set of process-based measures and patient-reported outcomes (PROs) along the HCC care continuum. We identified candidate process and outcomes measures for HCC care based on structured literature review. A 13-member panel with content expertise across the HCC care continuum evaluated candidate measures on importance and performance gap using a modified Delphi approach (two rounds of rating) to define the final set of measures. Candidate PROs based on a structured scoping review were ranked by 74 patients with HCC across 7 diverse institutions. Out of 135 measures, 29 measures made the final set. These covered surveillance (6 measures), diagnosis (6 measures), staging (2 measures), treatment (10 measures), and outcomes (5 measures). Examples included the use of ultrasound (± alpha-fetoprotein [AFP]) every 6 months, need for surveillance in high-risk populations, diagnostic testing for patients with a new AFP elevation, multidisciplinary liver tumor board (MLTB) review of Liver Imaging-Reporting and Data System 4 lesions, standard evaluation at diagnosis, treatment recommendations based on Barcelona Clinic Liver Cancer staging, MLTB discussion of treatment options, appropriate referral for evaluation of liver transplantation candidacy, and role of palliative therapy. PROs include those related to pain, anxiety, fear of treatment, and uncertainty about the best individual treatment and the future. The AASLD PMC has developed a set of explicit quality measures in HCC care to help bridge the gap between guideline recommendations and measurable processes and outcomes. Measurement and subsequent implementation of these metrics could be a central step in the improvement of patient care and outcomes in this high-risk population.