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. 2020 Jun 17;15(6):e0232371. doi: 10.1371/journal.pone.0232371

Sarcopenia as a predictor of survival in patients undergoing bland transarterial embolization for unresectable hepatocellular carcinoma

Ezio Lanza 1,*,#, Chiara Masetti 2,#, Gaia Messana 3,#, Riccardo Muglia 1,2,3, Nicola Pugliese 2,3, Roberto Ceriani 2, Ana Lleo de Nalda 2,3, Lorenza Rimassa 3,4, Guido Torzilli 5, Dario Poretti 1, Felice D’Antuono 1, Letterio Salvatore Politi 3,4,5,6, Vittorio Pedicini 1,, Alessio Aghemo 2,3,; on behalf of the Humanitas HCC Multidisciplinary Group
Editor: Gianfranco D Alpini7
PMCID: PMC7299358  PMID: 32555707

Abstract

Sarcopenia has been associated with lower overall survival in patients with cirrhosis and hepatocellular carcinoma (HCC) undergoing surgical resection, TACE, TARE, or transplantation. This monocentric study evaluated the prognostic significance of sarcopenia in patients affected by HCC who received bland transarterial embolization (TAE) therapy, by analyzing its impact on survival and treatment-related complications. All consecutive patients who underwent the 1st TAE between March 1st 2011 and July 1st 2019 in our Institution were retrospectively studied. To evaluate sarcopenia, the skeletal muscle index (SMI) was calculated by normalizing the cross-sectional muscle area at the level of L3 on an abdominal CT scan prior to embolization (cm2) by patient height (m2). SMI cut-off values for sarcopenia were considered ≤ 39 cm2/m2 for women and ≤55 cm2/m2 for men. Data about age, gender, body mass index (BMI), underlying liver disease, liver function, MELD score, Child-Pugh score, multifocal disease, performance status, previous interventions, length of stay (LOS), complications after the procedure, readmission rate within 30 days, survival time from TAE and total number and type of TAE received following the first procedure were collected. From 2011 to 2019, 142 consecutive patients underwent 305 TAEs. Observation time ranged from 1.4 to 100.5 months (median 20.1 SD = 22). Sarcopenia at baseline was present in 121 (85%) patients. Overall 87 (61.2%) patients died during follow-up with survival rates at 1-, 2-, 3-, 4-, and 5-year of 71%, 41%, 22%, 16% and 11% respectively. After multivariate analysis sarcopenia (HR = 2.22, p = 0.046), previous ablation/resection (HR = 0.51, p = 0.005) and multifocal disease (HR = 1.84, p = 0.02) were associated with reduced survival. Sarcopenia did not influence the safety of TAE in terms of LOS (2 days vs 1.5 days, p = 0.2), early complications rate (8% vs 5%, p = 0.5) and readmission rate within 30 days (7% vs 5%, p = 0.74). Sarcopenia, estimated by the L3SMI method, is an emerging prognostic factor in patients with HCC undergoing bland TAE therapy as it is associated with increased mortality, without impairing the safety of the locoregional treatment. Measures to ameliorate the SMI, such as nutritional support and physical exercise, should be evaluated in clinical trials for HCC patients receiving liver embolization to determine their impact on overall survival.

Introduction

Patients affected by Hepatocellular Carcinoma (HCC) are often unfit for curative surgery due to advanced disease at diagnosis, portal hypertension, reduced liver function, multinodular disease and concomitant comorbidities [1,2]. As a consequence, according to the Barcelona Clinic Liver Cancer (BCLC) staging system, they are frequently referred for intra-arterial therapies including transarterial embolization (TAE) for local disease control, before resorting to systemic treatments when they are no longer responsive to locoregional treatments or when they progress to BCLC stage C [3,4]. Among the different techniques, bland transarterial embolization (TAE) has been shown to improve patient survival and tumor response with similar efficacy when compared to transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) [4,5]. Relying only on the ischemic effect of small microparticles, TAE does not cause the side effects known to TACE and it is less expensive and less invasive than TARE [6]. Survival rates following TAE are extremely heterogeneous as patients who undergo TAE vary significantly in terms of liver function, age and concomitant comorbidities. On top of these differences, HCC burden (number of nodules and vascular invasion) and its molecular features play a significant role in the survival post-TAE [7]. Sarcopenia, defined as loss of skeletal muscle mass, has emerged as a negative prognostic factor in patients with HCC undergoing surgical resection, TACE, Sorafenib therapy and liver transplantation, as well as in patients with other solid tumors [811]. However, data regarding the impact of sarcopenia in patients receiving TAE monotherapy are lacking.

The objectives of this study were to assess the impact of sarcopenia estimated by skeletal muscle index (SMI) on overall survival and the incidence of postprocedural complications in patients with HCC who underwent TAE in a single center (Humanitas Research Hospital IRCCS).

Materials and methods

Design of the study

This retrospective analysis aimed to evaluate if sarcopenia could be a predictor of overall survival (OS) in a cohort of patients who received TAE for HCC. The study was approved by the Ethics Committee of the Humanitas Research Hospital IRCCS and was conducted in accordance with the ethical standards laid down in the Declaration of Helsinki. Informed written consent was obtained before every treatment from all patients.

Indication to TAE was given by a multidisciplinary team comprising liver surgeons, oncologists, interventional radiologists, radiotherapists, and hepatologists [12]. All patients underwent a full disease staging before being referred to TAE and they were followed up with CT imaging 1 month after TAE. In the event of disease recurrence or partial response to treatment, the cases were re-discussed; otherwise, a 3 months follow-up interval was established.

Patients with a diagnosis of HCC who underwent the first TAE in our Institute between March 1st, 2011 and July 1st, 2019 and who had an abdominal CT scan performed up to two months before the procedure were included; those who had only an abdominal MRI were excluded due to the impossibility of calculating the SMI. The end date of the observation period was set to January 17th, 2020.

All TAEs were performed without the use of intra-arterial chemotherapeutic drugs. Technical variations included microparticles TAE (P-TAE), microparticles plus cyanoacrylate glue TAE (G-TAE) and Lipiodol TAE (L-TAE), as previously reported by our group [6]. All procedures were performed by two senior operators and two junior interventional radiologists with at least three years’ experience in an angiographic suite (V5000 Philips Medical System, Amsterdam, The Netherlands), equipped with cone-beam CT (Siemens Artis-Zee, Munich, Germany).

We collected the following data for each patient: age, gender, BMI, underlying liver disease (HCV, HBV, HDV, alcohol abuse, NASH), liver function tests (ALT, AST, AFP, PLTs, INR, albumin, bilirubin), MELD score, Child-Pugh score, number of HCC nodules, performance status, previous interventions (surgery, stereotactic body radiation therapy -SBRT- or thermal ablation), LOS, early complications rate, readmission rate within 30 days and survival time from TAE. We also considered the total number and type of TAE received following the first procedure.

Assessment of sarcopenia

Sarcopenia was assessed using the L3-SMI method [13,14]. On the latest available abdominal CT scan performed before the first TAE procedure, we segmented the lean muscle mass at an axial plane located at the level of the third lumbar vertebra (L3), in which both transverse processes were visible (Fig 1).

Fig 1. SMI measurement at the level of the L3 lumbar vertebra.

Fig 1

A. The red area highlights the abdominal muscles in a female patient aged 84 years, highly sarcopenic (SMI = 21,1) who survived only 21 days from the first TAE B. The green area highlights the same muscles in a highly muscular male patient aged 60 years (SMI = 64,6, survival 45 months and alive at the end of the study).

This included psoas, rectus and transversus abdominis, internal and external oblique, quadratus lumborum, longissimus thoracis, iliocostalis lumborum and spinalis thoracis muscles. Images were analyzed using dedicated software (Medstation, Exprivia, Italy) to calculate the total cross-sectional muscular area from pixels in the density range of -29 to +150 Hounsfield Units (HUs). Manual corrections to subtract areas with HU values -30 were performed in order to avoid overestimation of muscular tissue or erroneous inclusion of adjacent visceral, subcutaneous or intramuscular adipose tissue.

Then, we obtained the SMI normalizing the cross-sectional muscle area (cm2) by patient height (m2) [14], SMI cut-off values for sarcopenia were set at ≤ 39 cm2/m2 for women and ≤55 cm2/m2 for men [15].

Statistical analysis

Stata 13 (StataCorp LP, Texas, USA) was used for all calculations. Survival analysis was performed by E. L. who has five years of experience in medical statistics. Multivariate analyses were conducted using Cox regression. Death was considered the primary outcome and was ascertained using the regional registry. T-test and Wilcoxon Rank-sum test were used to analyze differences between sarcopenic and non-sarcopenic patients for specific instances.

Predictors of survival were estimated using univariate analyses and log-rank tests for categorical variables. We tested the following potential interactions: TAE-related complications and number of treatments; previous treatments and number of HCC nodules. Kaplan-Meier curves were also generated (Fig 2).

Fig 2. Kaplan meier curves.

Fig 2

Survival curves of patients with sarcopenia (dashed line, SMI ≤ 39 cm2/m2 for women and ≤55 cm2/m2 for men) versus non-sarcopenic patients (continuous line). Curves were generated also according to HCC stage (BCLC 0-A, B and C-D).

Results

Descriptive data of the study population

From 2011 to 2019, we included 142 patients (32 F, 110 M). Patient characteristics are shown in Table 1.

Table 1. Comparison between sarcopenic and non-sarcopenic patients according to different variables.

Variable (mean) Sarcopenic Non-sarcopenic p-value
Age 73 (40–88) 73 (48–84) 0.76
Unifocal disease 29 7 0.36
Multifocal disease 92 14
Largest lesion size 34mm (7–115) 29mm (10–86) 0.3
Gender female 24 8 0.06
HCV+ 58 7 0.21
HBV+ 7 0 0.25
Alcohol abuse 29 4 0.62
NASH 14 7 0.01
Diabetes 40 8 0.65
Child-Pugh A 93 16 0.26
Child-Pugh B 20 1 0.18
Child-Pugh C 1 0 0.67

At baseline, the mean age was 73 year old (median = 75, SD = 9.5, range 40–88).

The most common liver diseases were HCV infection in 65 cases (46%) and alcohol abuse in 33 (23%); 9 patients (6%) had an unknown cause of liver disease. One-hundred-six patients (75%) had a multifocal disease (mean number of nodules = 2 range 1–3) with the largest tumor measuring averagely 34mm (SD = 22; median = 28mm, range 7–115).

The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 57 patients (40%), 1 in 68 patients (48%), 2 in 16 patients (11%) and in one patient it could not be assessed.

The MELD score was in average 10 (SD = 3; median = 9, range 6–29); Child-Pugh score was class A in 93 patients (81.5%), class B in 20 (17.5%) and class C in 1 patient (1%).

BCLC was very early stage (0) in seven patients (5%); early stage (A) in 31 patients (21.4%); intermediate stage (B) in 81 patients (57%); advanced stage (C) in 21 patients (14.8%); terminal stage (D) in one patient (0.7%) and in one patient it could not be assessed.

Eighty-six patients (61%) had not undergone previous treatment for HCC while fifty-six patients (39%) had a history of previous percutaneous ablation or liver resection. Overall, 305 TAEs were performed (average 2.2, SD = 1.4): in detail, 143 G-TAEs (47%), 123 P-TAEs (40%) and 39 L-TAEs (13%) (Table 2).

Table 2. Number and types of TAE procedures performed.

TOT Patients n° of TAE for each patient G-TAE P-TAE L-TAE
59 1 25 22 12
41 2 43 31 8
19 3 31 21 5
13 4 19 24 9
7 5 14 18 3
2 6 7 4 1
1 8 4 3 1
142 - 143 123 39

The average BMI was 25.8 (SD = 4.9; median 25.5, range 16.7–53); the mean SMI was 41 (SD = 8.9; median 41, range 21.1–64.8).

Sarcopenia, defined as SMI cut-off values ≤ 39 cm2/m2 for women and ≤55 cm2/m2 for men, was present in 121 (85%) patients. The prevalence of sarcopenia was not significantly different between patients with single or multiple HCC nodules.

Impact of sarcopenia on the safety of TAE

Mean LOS after TAE was 2 days (SD = 1.7, range 1–15). After the procedure, 11 patients (8%) had early complications (6 had digestive bleeding, 3 had sepsis and 2 had liver decompensation) and 9 (6%) had unplanned readmission within 30 days. No statistically significant differences were found between sarcopenic and non-sarcopenic patients concerning the following: LOS (2 days vs 1.5 days, p = 0.2), early complications rate (8% vs 5%, p = 0.5) and rate of readmission within 30 days (7% vs 5%, p = 0.74).

Impact of sarcopenia on survival

Patients were followed up regularly for a mean of 27 months (1.4–100.5 months: median 20.1; SD = 22).

Eighty-seven (61.2%) patients died during the follow-up period; with survival rates at 1-, 2-, 3-, 4-, and 5-year being 71%, 41%, 22%, 16% and 11% respectively. (Table 3, Fig 3).

Table 3. Patients overall survival and subgroup analysis.

Overall Survival
n 1yr 2yrs 3yrs 4yrs 5yrs
PATIENTS 101 58 32 23 16
71% 41% 22% 16% 11%
Sarcopenic 121 83 47 26 20 14
69% 39% 21% 17% 12%
Non-sarcopenic 21 18 11 6 3 2
86% 52% 29% 14% 10%

Fig 3. Survival rates of the population grouped by the presence of sarcopenia.

Fig 3

When testing OS prediction, the univariate analysis (Table 4) resulted in the inclusion of the following variables: being sarcopenic, performance status, multifocal disease, history of previous surgical or ablative treatments, MELD score and patient weight. After multivariate analysis (Table 5), the following were predictors of lower OS: sarcopenia (HR = 2.22, p = 0.046), previous ablation/resection (HR = 0.52, p = 0.005) and multifocal disease (HR = 1.84, p = 0.02). The potential interactions proved non-significant and were not included in the final model.

Table 4. Variables tested in the univariate survival analysis (n = 87).

Variable Y N p-value
Sarcopenia 80 7 0.03*
Performance status = 0 31 56 0.03*
Performance status > 2 12 75 0.05*
Multifocal disease 67 20 0.01*
Previous treatments 30 57 0.03*
MELD score 0–9 40 47 0.59
MELD score 10–19 44 43 0.64
MELD score >19 0 87 0.57
Weight mean = 73 kg SD = 16 0.599
Age at diagnosis M = 74 (40–88)
F = 76 (42–88)
0.886

*included in the multivariate analysis

P <0.2 allows for inclusion in the multivariate.

Table 5. Variables tested in the multivariate analysis.

Variable HR SD z p C.I. 95%
Sarcopenia * 2.22 0.88 2.14 0.046 1.01 4.86
Performance status = 0 0.73 0.17 -1.26 0.21 0.46 1.18
Performance status > 2 1.67 0.6 1.79 0.07 0.95 3.50
Previous treatments * 0.51 0.12 -2.79 0.005 0.32 0.81
Multifocal disease * 1.84 0.48 2.31 0.02 1.09 3.10

*predictor of survival

P < 0.05 is considered significant.

Discussion

The European Working Group on Sarcopenia in Older People (EWGSOP) defines sarcopenia as “a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death” [16]. Sarcopenia has been recently associated with increased mortality in patients with HCC or cirrhosis, regardless of the treatment received [17]. Particularly, its prognostic value has been analyzed in patients with HCC undergoing surgical resection, TACE therapy, Sorafenib therapy, or transplantation. In our Institution, however, TAE is preferred over TACE in patients with unresectable HCC as it provides similar survival rates without the side effects related to arterial chemotherapy [6,18]. Briefly, the aim of TAE therapy, as opposed to TACE, is to deploy the embolizing agent from a distal stance, in close proximity to the tumor, to achieve the maximum ischemic effect and promote necrosis of tumoral cells.

Of note, the advantage of adding chemotherapy to bland embolization is a controversial topic [18]. In this retrospective survival analysis conducted in consecutive patients who underwent TAE at our center, we observed that sarcopenia is a negative prognostic factor also for HCC patients receiving TAE monotherapy, highlighting its role as a potential determinant for patient stratification and selection of candidates. Other factors affected OS: first, a history of surgical resection or percutaneous ablation prior to TAE, which may have implied a long-standing disease; second, the presence of multiple as opposed to a single unresectable nodules (Fig 4), indicator of a greater disease burden, which may account for a poorer life expectancy [19].

Fig 4. Survival curves of HCC patients with a single nodule (continuous line) versus patients with a multinodular disease (dashed line).

Fig 4

Survival rates in non-sarcopenic patients were slightly lower at 4- and 5-year compared to sarcopenic patients (14% vs 17%; 10% vs 12%). However, this did not impact the statistical significance of our results, hence no correlation with sarcopenia may be assumed.

Sarcopenia was not associated with higher rates of post-procedural complications nor impaired safety of TAE, thus indicating that the increased mortality in sarcopenic patients was not the consequence of technical complications of TAE. This finding has important clinical implications as it highlights that pre-TAE sarcopenia should not be considered an exclusion criterion for the procedure; on the contrary, it should prompt an effort to increase SMI aimed to OS improvement. Among the strategies studied for the management and prevention of sarcopenia, only physical exercise [20,21] has shown significant positive effects. A potential role for Creatine and Leucine supplementation has been suggested but remains yet to be proven [22,23]. Thus, further well-designed ad-hoc studies are needed [24], even if it might be difficult to conduct them in patients with advanced liver disease, older age and significant extrahepatic comorbidities who are usually the subgroups receiving TAE. Most importantly, given that sarcopenia was not the only factor associated with mortality and that the other variables correlated to reduced survival are mostly non-modifiable and intrinsically associated with late HCC diagnosis, it remains to be proven that the exclusive correction of sarcopenia will have a positive effect in patients undergoing TAE.

There were some limitations to this study. Firstly, due to its retrospective nature, we could not acquire information on the patient’s daily activities and diet, which may have influenced the prevalence of sarcopenia. Secondly, data about the specific cause of patients’ death during the follow-up period were not covered by our study; thus external factors may have influenced the OS. Thirdly, only a small percentage of patients were not sarcopenic (15%), reflecting the fact that sarcopenia is common in patients affected by advanced-stage HCC who are usually the ideal candidates for TAE, but reducing the comparability of the two groups. Also, the treatment history differed in the cohort we studied, thus potentially influencing the OS. However, this should be considered representative of HCC patients who undergo embolization, as they are frequently diagnosed at different stages, with TAE often being their first therapeutic option before systemic therapy.

Noteworthy, the strengths of this study are the large cohort managed by the same group of physicians, and the exclusion of patients who underwent any other HCC treatment during the observation window, limiting the confounding effect on OS of other therapeutic interventions.

Conclusions

Sarcopenia, estimated by the L3SMI method, is an emerging prognostic factor in patients with HCC undergoing bland TAE therapy as it is associated with increased mortality, without impairing the safety of the locoregional treatment. Measures to ameliorate the SMI, such as nutritional support and physical exercise, should be evaluated in clinical trials for HCC patients receiving liver embolization to determine their impact on overall survival.

Supporting information

S1 File. STATA database containing all data used for the statistical analysis.

(ZIP)

Acknowledgments

Humanitas HCC Multidisciplinary Group

Lead Author: Prof. Guido Torzilli (guido.torzilli@humanitas.it)

Members:

Alessio Aghemo
Luca Balzarini
Ilaria Bianchi
Isabella Bolengo
Silvia Bozzarelli
Savino Bruno
Michele Carvello
Roberto Ceriani
Silvia Chiola
Arturo Chiti
Matteo Maria Cimino
Francesca Colapietro
Massimo Colombo
Tiziana Comito
Nadia Cordua
Guido Costa
Giovanni Covini
Luca Cozzaglio
Antonio D’Alessio
Federica D’Antonio
Daniele Del Fabbro
Luca Di Tommaso
Angelo Dipasquale
Roberto Doci
Matteo Donadon
Ciro Franzese
Roberto Gabbiadini
Silvia Garlaschi
Elena Generali
Nicolò Gennaro
Luigi Laghi
Ezio Lanza
Ana Lleo De Nalda
Egesta Lopci
Fabio Romano Lutman
Paola Magnoni
Alberto Malesci
Arianna Marinello
Chiara Masetti
Francesca Meda
Marco Montorsi
Riccardo Muglia
Angela Palmisano
Vittorio Pedicini
Nicola Personeni
Francesca Piccoli
Laura Poliani
Dario Poretti
Tiziana Pressiani
Maria Prete
Vittorio Quagliuolo
Alessandro Repici
Lorenza Rimassa
Marcello Rodari
Massimo Roncalli
Matteo Sacchi
Marta Scorsetti
Carlo Selmi
Valeria Smiroldo
Martina Sollini
Antonino Spinelli
Maurizio Tommasini
Guido Torzilli
Simona Verlingieri
Edoardo Vespa
Luca Viganò
Giuseppe Ferrillo
Fabio Procopio

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Gianfranco D Alpini

9 Apr 2020

PONE-D-20-08174

Sarcopenia as a predictor of survival in patients undergoing bland transarterial embolization for unresectable Hepatocellular Carcinoma

PLOS ONE

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PLOS ONE

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1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

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3. One of the noted authors is a group or consortium "Humanitas HCC Multidisciplinary Group" In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address.

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Comments to the Author

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript is a mono-centric study by the Humanitas HCC Multidisciplinary Group in Milan (Italy). It is a retrospective study aiming to evaluate the prognostic significance of sarcopenia in patients affected by HCC who received bland transarterial embolization (TAE) therapy. The manuscript is interesting and well-written. I have only few minor points.

- In table 1, authors could include also alcohol abuse and NAFLD diagnosis as variables.

- Line 179. Authors stated “No specific liver disease was associated with sarcopenia (Table 4); non-NASH liver disease showed the highest incidence (p < 0.01)”. However, table 4 reports variables tested in the multivariate analysis.

Reviewer #2: The authors provide insight on an important factor determining HCC TAE outcome, however there are some issues that must be addressed prior to publication:

1. Ranges must be included along with the mean in the various tables provided with this manuscript. Additionally, subcategories of underlying diseases of sarcopenic and non-sarcopenic patients must be added in additional rows in the appropriate table.

2. There must a table with the TAE data that was listed in the manuscript.

3. Results should be rewritten for a more cohesive presentation of the data collected.

4. Correlation analysis should be performed between sarcopenia and the following:

a. Previous treatment and HCC nodule #

b. TAE complication and TAE #

5. Additionally, there should be analysis that separates the OS of sarcopenic/non-sarcopenic patients for the various stages. This data will likely be weaker due to the lower N, but it will help lend evidence to the idea that sarcopenia may influence OS and early intervention will help depending on HCC stage.

6. The authors should discuss the lower OS in non-sarcopenic patients in years 3 and 4 compared to sarcopenic patients.

**********

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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PLoS One. 2020 Jun 17;15(6):e0232371. doi: 10.1371/journal.pone.0232371.r002

Author response to Decision Letter 0


10 Apr 2020

Response to Reviewers

Dear Professor Alpini,

Thank you for giving us the opportunity to submit a revised draft of the manuscript “Sarcopenia as a predictor of survival in patients undergoing bland transarterial embolization for unresectable hepatocellular carcinoma”. We appreciate the constructive suggestions and the attentive comments you and the reviewers have made. We have incorporated most of them; changes are marked-up within the file “Revised Manuscript with Track Changes”.

Our response follows (Editor’s and reviewers’ comments are in italics).

Journal requirements

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Reply: The corrections have been made.

2. Please amend your current ethics statement to address the following concerns: Please state whether informed consent was written or verbal. If written consent was not obtained, please describe how you recorded/documented participant consent, and if the ethics committees/IRBs approved this consent procedure.

Reply: We specified in the text that informed consent was written. Thank you for pointing this out.

3. One of the noted authors is a group or consortium "Humanitas HCC Multidisciplinary Group" In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgements section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address.

Reply: We added the members list of Humanitas HCC Multidisciplinary Group in the Acknowledgments section.

4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Reply: We added captions for our Supporting Information.

Review Comments to the Author

Reviewer #1: This manuscript is a mono-centric study by the Humanitas HCC Multidisciplinary Group in Milan (Italy). It is a retrospective study aiming to evaluate the prognostic significance of sarcopenia in patients affected by HCC who received bland transarterial embolization (TAE) therapy. The manuscript is interesting and well-written. I have only few minor points.

- In table 1, authors could include also alcohol abuse and NAFLD diagnosis as variables.

- Line 179. Authors stated “No specific liver disease was associated with sarcopenia (Table 4); non-NASH liver disease showed the highest incidence (p < 0.01)”. However, table 4 reports variables tested in the multivariate analysis.

Reply: We included in Table 1 the variables “Alcohol abuse” and “NASH” as suggested. We removed the reported sentence because there was an error, thank you for pointing this out.

Reviewer #2: The authors provide insight on an important factor determining HCC TAE outcome, however there are some issues that must be addressed prior to publication:

1. Ranges must be included along with the mean in the various tables provided with this manuscript. Additionally, subcategories of underlying diseases of sarcopenic and non-sarcopenic patients must be added in additional rows in the appropriate table.

Reply: Ranges were included in the tables for continuous variables. HBV+, NASH and alcohol abuse were added as variables in Table 1.

2. There must a table with the TAE data that was listed in the manuscript.

Reply: We created a table with the TAE data, specifying the number and types of TAE procedures performed (Table 2).

3. Results should be rewritten for a more cohesive presentation of the data collected.

Reply: We reorganized the data included in the Results in three main paragraphs: “Descriptive data of the study population”, “Impact of sarcopenia on the safety of TAE”, “Impact of sarcopenia on survival”. We believe that details are necessary for the deep comprehension of the study and should be included in the text. Instead, to have a general schematic view, Tables should be used.

4. Correlation analysis should be performed between sarcopenia and the following: a. Previous treatment and HCC nodule # b. TAE complication and TAE #

Reply: We have tested the interactions and both proved non-significant (previous treatments#HCC, p = 0.070; TAE complication#number of TAE, p = 0.65). We have added these data in the “Materials and Methods” and “Results” section. The sentences read:

“We tested the following potential interactions: TAE-related complications and number of treatments; previous treatments and number of HCC nodules.” (Materials and methods)

“The potential interactions proved non-significant and were not included in the final model.” (Results)

5. Additionally, there should be analysis that separates the OS of sarcopenic/non-sarcopenic patients for the various stages. This data will likely be weaker due to the lower N, but it will help lend evidence to the idea that sarcopenia may influence OS and early intervention will help depending on HCC stage.

Reply: We generated Kaplan-Meier curves according to disease stage (BCLC), distinguishing sarcopenic patients from non-sarcopenic patients. They are incorporated in Fig 2.

6. The authors should discuss the lower OS in non-sarcopenic patients in years 3 and 4 compared to sarcopenic patients.

Reply: The lower OS at 4- and 5-years in the non-sarcopenic group with respect to the sarcopenic group was examined in the Discussion.

Attachment

Submitted filename: Response to Reviewers.docx

Decision Letter 1

Gianfranco D Alpini

14 Apr 2020

Sarcopenia as a predictor of survival in patients undergoing bland transarterial embolization for unresectable Hepatocellular Carcinoma

PONE-D-20-08174R1

Dear Dr. Ezio Lanza,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Gianfranco D. Alpini

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have either addressed the reviewer critiques or explained as to why text should not be changed. There are no further comments or recommendations.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Acceptance letter

Gianfranco D Alpini

24 Apr 2020

PONE-D-20-08174R1

Sarcopenia as a predictor of survival in patients undergoing bland transarterial embolization for unresectable Hepatocellular Carcinoma

Dear Dr. Lanza:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Gianfranco D. Alpini

Academic Editor

PLOS ONE

Associated Data

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    Supplementary Materials

    S1 File. STATA database containing all data used for the statistical analysis.

    (ZIP)

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    Submitted filename: Response to Reviewers.docx

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.


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