International development of a patient-centered core outcome set for assessing health-related quality of life in metastatic breast cancer patients.

PURPOSE: For patients living with metastatic breast cancer (MBC), achieving best possible health-related quality of life, along with maximizing survival, is vital. Yet, we have no systemic way to determine if we achieve these goals. A Core Outcome Set (COS) that allows standardized measurement of outcomes important to patients, but also promotes discussing these outcomes during clinical encounters, is long overdue. METHODS: An international expert group (EG) of patient advocates, researchers, medical specialists, nurse specialists, and pharmaceutical industry representatives (n = 17) reviewed a list of relevant outcomes retrieved from the literature. A broader group (n = 141: patients/patient advocates (n = 45), health care professionals/researchers (n = 64), pharmaceutical industry representatives (n = 28), and health authority representatives (n = 4)) participated in a modified Delphi procedure, scoring the relevance of outcomes in two survey rounds. The EG finalized the COS in a consensus meeting. RESULTS: The final MBC COS includes 101 variables about: (1) health-related quality of life (HRQoL, n = 26) and adverse events (n = 24); (2) baseline patient characteristics (n = 9); and (3) clinical variables (n = 42). Many outcome that cover aspects of HRQoL relevant to MBC patients are included, e.g. daily functioning (including ability to work), psychosocial/emotional functioning, sexual functioning, and relationship with the medical team. CONCLUSION: The COS developed in this study contains important administrative data, clinical records, and clinician-reported measures that captures the impact of cancer. The COS is important for standardization of clinical research and implementation in daily practice and has received accreditation by the International Consortium for Health Outcomes Measurement (ICHOM).

Priority recommendations for the implementation of patient-reported outcomes in clinical cancer care: a Delphi study.

PURPOSE: The aim of this study was to develop priority recommendations for the service level implementation of patient-reported outcomes (PROs) into clinical cancer care. METHODS: Development of draft guidance statements was informed by a literature review, the Knowledge to Action (KTA) implementation framework, and discussion with PRO experts and cancer survivors. A two-round modified Delphi survey with key stakeholders including cancer survivors, clinical and research experts, and Information Technology specialists was undertaken. Round 1 rated the importance of the statements and round 2 ranked statements in order of priority. RESULTS: Round 1 was completed by 70 participants with round 2 completed by 45 participants. Forty-seven statements were rated in round 2. In round 1, the highest agreement items (>90% agreement) included those that focused on the formation of strong stakeholder partnerships, ensuring ongoing communication within these partnerships, and the use of PROs for improvement and guidance in clinical care. Items ranked as the highest priorities in round 2 included assessment of current staff capabilities and service requirements, mapping of workflows and processes to enable collection, and using collected PROs to guide improved health outcomes. CONCLUSIONS: This stakeholder consultation process has identified key priorities in PRO implementation into clinical cancer care that include clinical relevance, stakeholder engagement, communication, and integration within the existing processes and capabilities. IMPLICATION FOR CANCER SURVIVORS: Routine adoption of PRO collection by clinical cancer services requires multiple implementation steps; of highest priority is strong engagement and communication with key stakeholders including cancer survivors.

The implementation of a decision aid for women with early-stage breast cancer considering contralateral prophylactic mastectomy: A pilot study.

OBJECTIVE: Despite little survival benefit and potential for harm, contralateral prophylactic mastectomy (CPM) rates are increasing amongst early-stage breast cancer patients at low contralateral breast cancer risk. We developed a CPM decision aid (DA) and conducted a pilot implementation. METHODS: Surgeons and oncologists recruited eligible patients considering CPM. Consenting patients received the DA, completed a questionnaire and participated in a semi-structured interview. Clinicians were interviewed at study close. RESULTS: Eleven clinicians and 31 patients participated. Three themes emerged: perceived utility and impact of the DA, disagreement regarding timing of delivery and target population, and implementation strategies. Both women and clinicians found the DA valuable, indicating it confirmed rather than changed preferences. Women (all of whom raised CPM themselves), preferred offering the DA early in treatment discussions whilst clinicians favoured targeting women who enquired about CPM. CONCLUSION: A DA about CPM is feasible and acceptable, but questions remain about the role of DAs in these types of decisions where one option has limited medical benefit. PRACTICE IMPLICATIONS: Some women have a high need to make an informed choice about CPM. Tools to support this could include a DA with a clear recommendation against CPM and an explanation why.

Telemedicine and cystic fibrosis: Do we still need face-to-face clinics?

There has been growing interest in telemedicine for cystic fibrosis over recent years based largely on convenience for patients and/or increasing the frequency of surveillance and early detection which, it is assumed, could improve treatment outcomes. During 2020, the covid-19 pandemic catalysed the pace of development of this field, as CF patients were presumed to be at high risk of infection. Most clinics adapted to digital platforms with provision of lung function monitoring and sample collection systems. Here, we present the views of multidisciplinary team members at a large paediatric CF centre on what has worked well and what requires further optimisation in the future. In response to the question posed, 'Do we still need face to face clinics?' our answer is 'Yes, but not every time, and not for everyone'.

Guiding the rational design of patient-centred drug trials in Cystic Fibrosis: A Delphi study.

BACKGROUND: Making trials more patient-centred improves recruitment and retention, patient satisfaction and makes research accessible to a more representative population. We aimed to understand the factors that influence participation and engagement in clinical trials in cystic fibrosis (CF) trials to guide the rational design and delivery of patient-centred trials. METHODS: We used a Delphi process, supported by extensive literature review and 3 workshops, to determine which factors stakeholders think exert significant influence in participation and engagement in CF trials. Panellists were recruited from across the UK and the study was administered online. RESULTS: We had representation from 19 CF centres; 28 people with CF (pwCF), 26 parents and 30 healthcare professionals (HCPs). Panels were presented with a shortlist of 104 factors and asked which they thought influence participation and engagement in CF trials. After 3 iterations, 43 statements met consensus for pwCF, 48 for the parents and 69 for the HCPs. CONCLUSIONS: We identified many targets to make trials more patient-centred. Whilst some require an overhaul of trial delivery, many are relatively easy to implement. We outline a list of 'dos and don'ts' for sponsors and research teams including: focus on good communication; recognise that lack of time is the greatest barrier to trial participation so minimise the frequency and length of visits; help participants fit trials around busy lives; remember trial participation can be a major life-event and support participants accordingly; and don't underestimate the impact of simple strategies e.g. on-site access to Wifi and cups of tea.

Cost-effectiveness of radioguided occult lesion localization using 125I seeds versus hookwire localization before breast-conserving surgery for non-palpable breast cancer.

BACKGROUND: The aim was to determine the cost-effectiveness of radioguided occult lesion localization using 125I-labelled seeds (125I seeds) versus hookwire localization in terms of incremental cost per reoperation avoided for women with non-palpable breast cancer undergoing breast-conserving surgery. METHODS: This study was based on a multicentre RCT with eight study sites comprising seven public hospitals and one private hospital. An Australian public health system perspective was taken. The primary effectiveness outcome for this study was reoperations avoided. Cost-effectiveness was expressed as an incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were used to explore uncertainty. The willingness to pay (additional cost of localization using 125I seeds justified by reoperation cost avoided) was set at the weighted, top-down cost of reoperation. Costs were in 2019 Australian dollars ($1 was equivalent to €0.62). RESULTS: The reoperation rate was 13.9 (95 per cent confidence interval 10.7 to 18.0) per cent for the 125I seed group and 18.9 (14.8 to 23.8) per cent for the hookwire localization group. The ICER for 125I seed versus hookwire localization was $4474 per reoperation averted. The results were most sensitive to uncertainty around the probability of reoperation. Accounting for transition probability and cost uncertainty for 125I seed localization, there was a 77 per cent probability that using 125I seeds would be cost-effective, with a willingness to pay of $7693 per reoperation averted. CONCLUSION: Radioguided occult lesion localization using 125I seeds is likely to be cost-effective, because the marginal (additional) cost compared with hookwire localization is less than the cost of reoperations avoided.

Surgical outcomes after radioactive 125I seed versus hookwire localization of non-palpable breast cancer: a multicentre randomized clinical trial.

BACKGROUND: Previous studies have suggested improved efficiency and patient outcomes with 125I seed compared with hookwire localization (HWL) in breast-conserving surgery, but high-level evidence of superior surgical outcomes is lacking. The aim of this multicentre pragmatic RCT was to compare re-excision and positive margin rates after localization using 125I seed or hookwire in women with non-palpable breast cancer. METHODS: Between September 2013 and March 2018, women with non-palpable breast cancer eligible for breast-conserving surgery were assigned randomly to preoperative localization using 125I seeds or hookwires. Randomization was stratified by lesion type (pure ductal carcinoma in situ (DCIS) or other) and study site. Primary endpoints were rates of re-excision and margin positivity. Secondary endpoints were resection volumes and weights. RESULTS: A total of 690 women were randomized at eight sites; 659 women remained after withdrawal (125I seed, 327; HWL, 332). Mean age was 60.3 years in the 125I seed group and 60.7 years in the HWL group, with no difference between the groups in preoperative lesion size (mean 13.2 mm). Lesions were pure DCIS in 25.9 per cent. The most common radiological lesion types were masses (46.9 per cent) and calcifications (28.2 per cent). The localization modality was ultrasonography in 65.5 per cent and mammography in 33.7 per cent. The re-excision rate after 125I seed localization was significantly lower than for HWL (13.9 versus 18.9 per cent respectively; P = 0.019). There were no significant differences in positive margin rates, or in specimen weights and volumes. CONCLUSION: Re-excision rates after breast-conserving surgery were significantly lower after 125I seed localization compared with HWL. Registration number: ACTRN12613000655741 (http://www.ANZCTR.org.au/).

Correction: External validation of risk prediction models for incident colorectal cancer using UK Biobank.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Malnutrition associated with nutrition impact symptoms and localization of the disease: Results of a multicentric research on oncological nutrition.

BACKGROUND & AIMS: Malnutrition in cancer is an independent factor associated with negative clinical outcomes. The aim was to evaluate the prevalence and independent risk factors for malnutrition in hospitalized cancer patients using the Patient-Generated Subjective Global Assessment (PG-SGA). METHODS: We evaluated 4783 cancer patients, aged ≥20 years, in a hospital-based, multicenter, cross-sectional study. Patients were classified as well-nourished (PG-SGA Stage A), moderate/suspected malnutrition (PG-SGA Stage B), or severely malnourished (PG-SGA Stage C), and provided a score to define required nutritional interventions. Multivariate analysis was composed of the odds ratio (OR) estimated by ordinal polytomous logistic regression. RESULTS: 45.3% were classified as Stage B and 11.8% as Stage C. Moreover, 45.3% of the patients presented a need for nutritional intervention. The variables that presented the highest ORs for Stage B or Stage C were: problems with swallowing (OR 2.8, 95% confidence interval (CI) 2.2-3.4, p < 0.001), loss of appetite (OR 1.9, 95% CI 1.6-2.3, p < 0.001), vomiting (OR 1.8, 95% CI 1.5-2.3, p < 0.001), presence of more than 3 nutrition impact symptoms (OR 8.3, 95% CI 5.8-12, p < 0.001), and cancer site: lung (OR 4.6, 95% CI 3.2-6.6, p < 0.001), upper digestive cancer (OR 3.7, 95% CI 2.7-5.2, p < 0.001), and head and neck cancer (OR 3.7, 95% CI 2.7-5.2, p < 0.001). The score for Worksheet 4 on the PG-SGA had a higher association with malnutrition (OR 7.3, 95% CI 6.6-8.2, p < 0.001). CONCLUSIONS: Malnutrition is highly prevalent in cancer patients in Brazil, and is associated with nutritional impact symptoms, cancer site and age ≥65 years.

Systematic review of the impact of breast-conserving surgery on cancer outcomes of multiple ipsilateral breast cancers.

BACKGROUND: The clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast-conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC). METHODS: Comprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle-Ottawa Scale. The characteristics and results of identified studies were summarized. RESULTS: Twenty-four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2-23 per cent after BCS at median follow-up of 59·5 (i.q.r. 56-81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2-40 per cent after BCS at a median follow-up of 64 (i.q.r. 57-73) months. One high-quality study reported 10-year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women. CONCLUSION: The available studies were mainly of moderate quality, historical and underpowered, with limited follow-up and biased case selection favouring BCS rather than mastectomy for low-risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

Genetic characterisation of molecular targets in carcinoma of unknown primary.

BACKGROUND: Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Prognosis for patients with CUP is poor because treatment options are generally limited to broad spectrum chemotherapy. A shift towards personalised cancer management based on mutation profiling offers the possibility of new treatment paradigms. This study has explored whether actionable, oncogenic driver mutations are present in CUP that have potential to better inform treatment decisions. METHODS: Carcinoma of unknown primary cases (n = 21) were selected and DNA was isolated from formalin-fixed paraffin embedded sections prior to amplification and sequencing. Two distinct yet complementary targeted gene panels were used to assess variants in up to 76 known cancer-related genes for the identification of biologically relevant and actionable mutations. RESULTS: Variants were detected in 17/21 cases (81%) of which 11 (52%) were potentially actionable with drugs currently approved for use in known primary cancer types or undergoing clinical trials. The most common variants detected were in TP53 (47%), KRAS (12%), MET (12%) and MYC (12%). Differences at the molecular level were seen between common CUP histological subtypes. CUP adenocarcinomas and poorly differentiated carcinomas harboured the highest frequency of variants in genes involved in signal transduction pathways (e.g. MET, EGFR, HRAS, KRAS, and BRAF). In contrast, squamous cell carcinoma exhibited a higher frequency of variants in cell cycle control and DNA repair genes (e.g. TP53, CDKN2A and MLH1). CONCLUSION: Taken together, mutations in biologically relevant genes were detected in the vast majority of CUP tumours, of which half provided a potentially novel treatment option not generally considered in CUP.

Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings.

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disorder characterized by lesions and benign tumors in multiple organ systems including the brain, skin, heart, eyes, kidneys, and lungs. The phenotype is highly variable, although penetrance is reportedly complete. We report the molecular diagnosis of TSC in individuals exhibiting extreme intra-familial variability, including the incidental diagnosis of asymptomatic family members. Exome sequencing was performed in three families, with probands referred for epilepsy, autism, and absent speech (Family 1); epileptic spasms (Family 2); and connective tissue disorders (Family 3.) Pathogenic variants in TSC1 or TSC2 were identified in nine individuals, including relatives with limited or no medical concerns at the time of testing. Of the nine individuals reported here, six had post-diagnosis examinations and three met clinical diagnostic criteria for TSC. One did not meet clinical criteria for a possible or definite diagnosis of TSC, and two had only a possible clinical diagnosis following post-diagnosis workup. These individuals as well as their mothers demonstrated limited features that would not raise concern for TSC in the absence of molecular results. In addition, three individuals exhibited epilepsy with normal brain MRIs, and two without seizures or intellectual disability had MRI findings fulfilling major criteria for TSC highlighting the difficulty providers face when relying on clinical criteria to guide genetic testing. Given the importance of a timely TSC diagnosis for clinical management, such cases demonstrate a potential benefit for clinical criteria to include seizures and an unbiased molecular approach to genetic testing.

External validation of risk prediction models for incident colorectal cancer using UK Biobank.

BACKGROUND: This study aimed to compare and externally validate risk scores developed to predict incident colorectal cancer (CRC) that include variables routinely available or easily obtainable via self-completed questionnaire. METHODS: External validation of fourteen risk models from a previous systematic review in 373 112 men and women within the UK Biobank cohort with 5-year follow-up, no prior history of CRC and data for incidence of CRC through linkage to national cancer registries. RESULTS: There were 1719 (0.46%) cases of incident CRC. The performance of the risk models varied substantially. In men, the QCancer10 model and models by Tao, Driver and Ma all had an area under the receiver operating characteristic curve (AUC) between 0.67 and 0.70. Discrimination was lower in women: the QCancer10, Wells, Tao, Guesmi and Ma models were the best performing with AUCs between 0.63 and 0.66. Assessment of calibration was possible for six models in men and women. All would require country-specific recalibration if estimates of absolute risks were to be given to individuals. CONCLUSIONS: Several risk models based on easily obtainable data have relatively good discrimination in a UK population. Modelling studies are now required to estimate the potential health benefits and cost-effectiveness of implementing stratified risk-based CRC screening.

Health care experiences among women diagnosed with gestational breast cancer.

Gestational breast cancer (GBC) presents many challenges for women and the clinicians who care for them. The aim of this study was to explore the health care experiences of women diagnosed with GBC to inform and improve clinical care of women in this predicament. Semi-structured interviews were conducted with 17 women who had been diagnosed with GBC in the previous 5 years. The overarching themes for perceived quality of care were "communication" and "comprehensive care." "Communication" had two sub themes: "interdisciplinary communication" (the way health professionals from different disciplines communicated with each other about the management of the woman's care) and "patient communication" (how they communicated this to the woman). The "comprehensive care" theme incorporated three sub themes: "the spirit" (psychological care); "the mind" (information provision); and "the body" (management of treatment side effects). Women's own accounts of positive and negative experiences of GBC care provide unique and specific insights which improve understanding of their concerns and needs. The findings can inform advances in quality and efficacy of clinical care; offer guidance for obstetricians, oncologists and allied health professionals about the needs of women diagnosed with GBC and how care can be optimised; and inform the development of resources to assist women and their families.

Exercise following breast cancer: exploratory survival analyses of two randomised, controlled trials.

PURPOSE: The Exercise for Health trials were randomised, controlled trials designed to evaluate an 8-month pragmatic exercise intervention, commencing 6 weeks post-surgery for women with newly diagnosed breast cancer residing in urban or rural/regional Australia. For these exploratory analyses, the primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively. METHODS: Consenting urban- (n = 194) and rural/regional-residing women (n = 143) were randomised to exercise (intervention delivered face-to-face or by telephone) or usual care. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for survival outcomes (exercise group, n = 207, 65% urban women; usual care group, n = 130, 46% urban women). RESULTS: After a median follow-up of 8.3 years, there were 11 (5.3%) deaths in the exercise group compared with 15 (11.5%) deaths in the usual care group (OS HR for the exercise group: 0.45, 95% CI 0.20-0.96; p = 0.04). DFS events for the exercise versus usual care group were 25 (12.1%) and 23 (17.7%), respectively (HR: 0.66, 95% CI 0.38-1.17; p = 0.16). HRs for OS favoured exercise irrespective of age, body mass index, stage of disease, intervention compliance, and physical activity levels at 12 months post-diagnosis, although were stronger (p < 0.05) for younger women, women with stage II + disease, women with 1 + comorbidity at time of diagnosis, higher intervention compliance and for those who met national physical activity guidelines at 12 months post-diagnosis. CONCLUSION: An exercise intervention delivered during and beyond treatment for breast cancer, and that was designed to cater for all women irrespective of place of residence and access to health services, has clear potential to benefit survival. Trial numbers: ACT RN: 012606000233527; ACT RN: 12609000809235.

Correction to: Exercise following breast cancer: exploratory survival analyses of two randomised, controlled trials.

In the original publication of the article, under the heading Discussion, 1st paragraph, the sentence that reads as, "Nonetheless, our observed improvements of over 50% for OS and over 30% for DFS (HRs: 0.45 and 0.66, respectively) are consistent with results from other available studies" should read as "Nonetheless, our observed improvements of over 50% for OS and DFS (HRs: 0.45 and 0.66, respectively) are consistent with results from other available studies." Under the heading Discussion, 3rd paragraph, the sentence that reads as "We cannot discount the possibility …such as education, income and access to care [1, 7]" should read as "We cannot discount the possibility…such as education, income and access to care, which ultimately have on survival outcomes [1, 7]."

Mucocoele-like lesions: is surgical excision still necessary?

AIM: To assess the rate of upgrade in our screening population to determine whether open excision biopsy of mucocoele-like lesions (MLL) is still required. MATERIALS AND METHODS: A retrospective review of the breast screening database from 1999-2014 was performed. RESULTS: MLL were identified on core biopsy in 113 women (0.6% of those recalled for a core biopsy). The majority (n=100, 88%) had a localised cluster of calcification prompting screening recall. Eighty-seven percent (n=99) underwent an excision biopsy; there was a 5% upgrade rate to malignancy (all low/intermediate ductal carcinoma in situ [DCIS]) and 15 women (15%) were found to have an additional "B3" lesion. Fourteen women did not undergo excision biopsy; none of these women had a subsequent cancer at an average of 5-years follow-up. Within the follow-up period, five additional cancers were identified, one of these was in the ipsilateral breast and location, albeit 9-years later. CONCLUSION: This is the largest study of MLL in the literature to date. The present findings show a 5% upgrade rate to DCIS. As long as the current management of low-risk DCIS remains surgical excision, the present results support continued excision of MLLs, either surgically or by vacuum-assisted biopsy.

Rapid Analysis of Outcomes Using the Systemic Anti-Cancer Therapy (SACT) Dataset.

We audited the accuracy of the Systemic Anti-Cancer Therapy dataset as a resource for rapid analysis of outcomes for patients, in this example, receiving Cancer Drug Fund funded monoclonal antibodies to treat metastatic colorectal cancer. We concluded that the Systemic Anti-Cancer Therapy dataset is a potentially valuable resource for rapidly determining survival outcome for patients treated with chemotherapy.

Liver transplantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment.

UNLABELLED: The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that "very early" iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with "very early" iCCA and those with "advanced" disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the "very early" iCCA group and 33/48 (69%) the "advanced" group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the "advanced" group (3.1 [2.5-4.4] versus 1.6 [1.5-1.8]). After a median follow-up of 35 (13.5-76.4) months, the 1-year, 3-year, and 5-year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1-year, 3-year, and 5-year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. CONCLUSION: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178-1188).