Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass.

Calf circumference (CC) has been established as a marker of muscle mass (MM) with good performance for predicting survival in individuals with cancer. The study aims to determine the prevalence of sarcopenia according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria and to evaluate the accuracy of sarcopenia using low CC relative to MM assessment by computed tomography (CT) at third lumbar vertebra level (L3) as a reference. Cross-sectional study with cancer patients aged ≥ 60 years. Data included socio-demographic, clinical and anthropometric variables. MM was assessed by CC and by CT images at the L3. Sarcopenia was diagnosed according to the EWGSOP2 criteria: a) low handgrip strength (HGS) + reduced MM evaluated by CT; and b) low HGS + low CC. Pearson's correlation, accuracy, sensitivity, specificity, positive predictive and negative predictive value were analyzed. A total of 108 patients were evaluated, age of 70.6 ± 7.4 years (mean ± standard deviation). The prevalence of sarcopenia was of 24.1% (low MM) and 25.9% (low CC). The Kappa test showed a substantial agreement (K = 0.704), 81% sensitivity, and 92% specificity. Although the EWGSOP2 advises that we should use CC measures in the algorithm for sarcopenia when no other MM diagnostic methods are available, the findings allow the use of CC instead of MM by CT in cancer patients.

Introduction

People worldwide are living longer. According to the World Health Organization (WHO), today, the number of people aged 60 years and older will outnumber children younger than 5 years [1]. In Brazil, “older adults” are 60 years of age or older, and it is estimated that this group will represent 18.6% in 2030 and 33.7% in 2060 of the total population [2]. The risk of cancer increases exponentially with age; about 60% of cancers occur in people of 65 years of age or older, and 70% of the deaths caused by cancers occur in this stage [3, 4].

The prevalence of malnutrition in patients with cancer varies according to the type and stage of the tumor, treatment performed, as well as age [5-7]. Chemotherapy and radiation therapy cause side effects more often and in greater severity to the elderly than to the young, and frequently they can cause loss of muscle mass (MM) [8, 9]. Moreover, older cancer patients usually present loss in physical function and disability, both associated with losses of functional reserve, which, in the presence of chemotherapy, increases the likelihood that these patients will experience toxic side effects [8]. Therefore, elderly patients with cancer are easy to become sarcopenic.

The term “Sarcopenia” has originally been proposed to describe the age-related decrease in MM, today know as primary sarcopenia [10, 11]. The European Working Group on Sarcopenia in Older People (EWGSOP) suggests that sarcopenia should be evaluated through the association between reduced MM and reduced muscle function [12-14]. Since the publication of the revised version of this document (EWGSOP2), both muscle quantity and quality are accepted in the algorithm of sarcopenia [15]. Muscle quality, best described as myosteatosis, as well as the amount of MM (quantity), can be measured by the analysis of computed tomography (CT) images [16-18], a tool usually used for diagnostic of low MM in cancer patients, also known as CT-sarcopenia. However, because of occasionally unavailable technology and equipment, MM assessment remains as a problematic variable to be measured in the clinical practice of cancer patient care and in the identification of sarcopenia in these patients.

According to the revised version of guidelines of sarcopenia in older people (EWGSOP2), calf circumference (CC) has been presented as a predictor of performance and survival in older people, and may be used as a diagnostic proxy for older adults in contexts where no other MM diagnostic methods are available [15]. However, no studies comparing these two parameters of MM (CC vs CT image) for evaluating the prevalence of sarcopenia estimated by the EWGSOP2 reference in this population were available. Thus, the present study aimed to determine the prevalence of sarcopenia by applying the EWGSOP2 algorithm and evaluating the agreement of sarcopenia based on low CC considering sarcopenia-based CT image (MM) as a reference method in patients with cancer.

Materials and methods

Design and subjects

A cross-sectional study including elderly cancer patients of both genders, aged 60 years or older, in a primary care hospital, Brazil. Patients in all cancer treatment modalities (surgical, chemotherapy, radiotherapy or combined), able to perform evaluations and who had CT images of the abdominal region in the last 30 days were included. Patients with concomitant consumptive diseases (AIDS, non-cancerous liver diseases, tuberculosis), with ascites, edema or amputation, which made it impossible to analyze their CT images or measuring CC, were excluded. The study was approved by the Research Ethics Committee of the Federal University of Rio Grande do Norte (protocol number 73315617.4.0000.5292).

Procedures

The study was conducted between January 2017 and March 2019. All eligible patients were asked about their interest in participating in the study by trained researchers at the hospital during regular consultations for cancer treatment. After verbal acceptance and signing an informed consent form, they were directed to a reserved room to assess nutritional status (anthropometry) and muscle strength. Clinical data was obtained from the digital records at the hospital and included age, sex, ethnicity, primary tumor site, treatment performed and CT images.

Anthropometric evaluation

Three trained researchers measured body weight, height and CC. Body mass and height were determined by an electronic scale (Filizola®), with a precision of 100g. Body Mass Index (BMI) was calculated as a ratio of weight (kg) and height squared (m2), using the cut-off points proposed by the WHO: underweight (< 18.5 kg/m2), normal weight (18.5 to 24.9 kg/m2), overweight (25 to 29.9 kg/m2) and obese (≥ 30 kg/m2) [19]. For CC measurement, individuals were seated with the legs positioned at a 90° angle with the thigh and the inelastic band (Sanny®) around the maximum calf muscle circumference (in both legs). The measurement was performed in triplicate, and the maximum value was used. Low CC was classified using the cutoff points purposed by Barbosa-Silva et al.: 34 cm for men and 33 cm for women [20].

Muscle strength assessment

Handgrip strength (HGS, kg) of both arms was measured using a hydraulic dynamometer (Jamar®). Patients were instructed to adjust the dynamometer and tighten it by producing as much force as possible [21]. Three attempts were made in each hand alternately, with a minimum rest period of 60 seconds for each hand [22]. The highest value recorded was used as maximum muscle strength [23]. Low HGS was determined based on the reference values of the EWGSOP2, for diagnostic of sarcopenia (HGS < 27kg and < 16kg for male and female, respectively) [15].

Muscle mass assessment

Skeletal MM analysis was performed by evaluating using CT scans at the level of third lumbar vertebra (L3), using the Slice-O-Matic version 5.0 program (Tomovision, Montreal, Canada). A single trained researcher with anatomical knowledge selected and analyzed specific tissue using Hounsfield Unit (HU) boundaries of -29 to +150 for the skeletal muscle area (SMA, including psoas, erector spinae, lumbar square, transverse abdominal, internal and external oblique, rectus abdominis) [24]. Skeletal Muscle Index (SMI) was calculated by the total cross-sectional area (cm2) divided by height squared (m2). The SMI cut-off point proposed by Caan et al. was used to define low SMI, used as a marker of muscle quantity for the diagnostic of sarcopenia: < 52.3 cm2/m2 for men and < 37.6 cm2/m2 for women with a BMI < 30 kg/m2 and < 54.3 cm2/m2 for men and < 46.6 cm2/m2 for women with BMI > 30 kg/m2 [25]. Muscle quality was assessed through skeletal muscle radiodensity (SMD) from CT images and compared to the cut-off points by Kroenke et al.: < 35.5 HU and < 32.5 HU for males and females, respectively [26].

Definition of sarcopenia

Individuals with sarcopenia were classified by two different criteria, according to the EWGSOP2; a) low HGS + reduced MM assessed by CT (including low MM quality and/or quantity, named “sarcopenia by low MM”; and b) low HGS + low CC, named “sarcopenia by low CC” [15].

Statistical analysis

Data analysis was performed in SPSS version 22.0 for Windows. The Kolmogorov-Smirnov test was performed to assess the normality of the data. Categorical variables are expressed as absolute and relative frequency, and numerical data as mean and standard deviation. Differences in general characteristics between the sex of the patients were evaluated using the Chi-square test or Fisher’s exact test for categorical variables. Differences between the quantitative variables in patients classified with sarcopenia according to the different criteria were evaluated using independent t-test. Pearson’s correlation test was performed to verify the correlation between CC and MM by CT (SMI). The Kappa coefficient between low CC and low SMI was calculated and, for its classification, the reference values considered were: < 0.20 as poor, 0.21–0.40 as fair, 0.41–0.60 as moderate, 0.61–0.80 as substantial, 0.81–0.99 as almost perfect, and 1.00 as perfect [27]. Sensitivity, specificity, positive and negative predictive values were calculated. A p value < 0.05 was considered statistically significant for all tests.

Results

A total of 208 patients were interviewed, but 21 were unable to have their CC assessed due to leg edema or amputation. After the interview, the CT image was inaccessible for analysis in 79 patients (CT exams were older than 30 days). Thus, 108 elderly cancer patients were considered eligible, with a mean age of 70.6 ± 7.4 years old. Table 1 shows the clinical variables of the sample. The sex distribution is nearly even, with a slight majority of females (52.3%). Regarding the disease characteristics, the most frequent type was of colorectal cancer, followed by gastric tumor (27.8% and 22.2%, respectively), and advanced stages (III and IV) were diagnosed in more than a half of the patients (54.6%). The majority of the evaluated patients have had previous treatment (74.1%). According to BMI categories, 47.2% of patients classified with normal BMI and 30.6% with overweight. Only the variables ethnicity and cancer site showed differences between sexes.

Table 1

General characteristics of cancer patients according to sex.

Variables	Total (n = 108)	Male (n = 51)	Female (n = 57)	p-value
Age				0.050
60–69 years	51 (47.2%)	19 (37.3%)	32 (56.1%)
≥70 years	57 (52.8%)	32 (62.7%)	25 (43.9%)
Ethnicity				0.002
Caucasian	40 (37.0%)	11 (21.6%)	29 (50.9%)
Non-caucasian	68 (63.0%)	40 (78.4%)	28 (49.1%)
Cancer site				< 0.001
Head and neck	7 (6.5%)	5 (9.8%)	2 (3.5%)
Gastric	24 (22.2%)	15 (29.4%)	9 (15.8%)
Colon and rectum	30 (27.8%)	14 (27.5%)	16 (28.1%)
Breast	15 (13.9%)	-	15 (26.3%)
Prostate	14 (13.0%)	14 (27.5%)	-
Other	18 (16.7%)	3 (5.9%)	15 (26.3%)
Staging of disease				0.078
I-II	30 (27.8%)	9 (17.6%)	21 (36.8%)
III-IV	59 (54.6%)	31 (60.8%)	28 (49.1%)
Unknown	19 (17.6%)	11 (21.6%)	8 (14.0%)
Previous Treatment 1				0.097
Yes	80 (74.1%)	34 (66.7%)	46 (80.7%)
No	28 (25.9%)	17 (33.3%)	11 (19.3%)
Nutritional status (BMI)				0.620
Underweight 2	9 (8.3%)	5 (9.8%)	4 (7.0%)
Normal 3	51 (47.2%)	26 (51.0%)	25 (43.90%)
Overweight 4	33 (30.6%)	15 (29.4%)	18 (31.6%)
Obese 5	15 (13.9%)	5 (9.8%)	10 (17.5%)

Data in absolute (n) and relative (%) frequency; p value with Chi-square test and Fisher’s exact test.

1Previous treatment including chemotherapy, radiotherapy, surgery alone or combined.

2BMI below 18.5 kg/m2.

3BMI 18.5–24.9 kg/m2.

4BMI 25.0–29.9 kg/m2.

5BMI 30 kg/m2 and above.

BMI, Body Mass Index.

Based on the EWGSOP2 criteria using CT data (sarcopenia by low MM), the prevalence of sarcopenia was of 24.1% (26 of 108 patients). When using the EWGSOP2 criteria with CC (sarcopenia by low CC), the prevalence was of 25.9% (28 of 108 patients). The overlap was observed in 21 individuals classified by both definitions of sarcopenia (Fig 1).

Fig 1

Concordance of individual cases identified by European Working Group on Sarcopenia in Older People 2 (EWGSOP2) considering muscle mass (MM) evaluated by computed tomography (sarcopenia by low MM) and by calf circumference (CC) (sarcopenia by low CC).

The prevalence of low CC, low HGS, and low MM (by SMI measure) were observed in 46.3%, 39.8%, and 24.1%, respectively. Table 2 presents the frequency of sarcopenia and related variables between the different criteria used. All variables presented differences between patients classified with and without sarcopenia regardless of the method used for classification. Patients with sarcopenia showed lower BMI, CC, SMA, SMI, SMD, and HGS.

Table 2

Frequency of sarcopenia and comparison of quantitative variables in patients classified with sarcopenia according to the different criteria (n = 108).

	Sarcopenia by low MM1			Sarcopenia by low CC2
	No	Yes	p-value	No	Yes	p-value
	(82; 75.9%)	(26; 24.1%)		(80; 74.1%)	(28; 25.9%)
Age (years)	69.2 ± 7.6	74.9 ±5.2	<0.001	69.7 ± 7.7	73.2 ± 6.3	0.033
Weight (Kg)	64.1 ± 12.2	54.4 ± 11.9	0.001	65.8 ± 11.7	50.4 ± 8.2	<0.001
BMI (kg/m2)	25.6 ± 4.4	22.6 ± 4.3	0.003	26.0 ± 4.3	21.7 ± 3.7	<0.001
CC (cm)	34.2 ± 3.4	30.6 ± 2.6	<0.001	34.6 ± 3.2	29.8 ± 1.9	<0.001
SMA (cm2)	126.0 ± 30.7	108.3 ± 23.0	0.008	127.4 ± 30.6	105.8 ± 21.1	<0.001
SMI (cm2/m2)	49.9 ± 9.2	44.9 ± 7.9	0.015	49.9 ± 9.4	45.2 ± 7.1	<0.001
SMD (HU)	40.5 ± 8.9	34.2 ± 8.6	0.002	39.6 ± 9.8	37.3 ± 7.2	0.008
HGS (kg/F)	24.8 ± 9.8	13.8 ± 6.1	<0.001	25.3 ± 9.3	13.1 ± 6.4	<0.001

p-value with independent-t test comparing patients with and without sarcopenia.

1Low MM according to Cana et al. [25].

2Low CC according to Barbosa-Silva et al. [20].

BMI, Body Mass Index; CC, Calf Circumference; SMA, Skeletal Muscle Area; SMI, Skeletal Muscle Index; SMD, Skeletal Muscle Radiodensity; HU, Hounsfield Unit; HGS, Handgrip Strength.

The correlation between measures of CC and skeletal MM measured by CT and adjusted by height (SMI) in the sample and according to sex is presented in Fig 2. CC was weak positively correlated with SMI in the sample (r = 0.3431, p < 0.001) and in females (r = 0.3001, p = 0.023), and moderate in males (r = 0.4573, p < 0.001). Nevertheless, stronger and statistically significant correlations were observed between CC and the total MM (without dividing by height squared) analyzed by CT images. The correlations for the total sample, males and females, were r = 0.4078, r = 0.6492, and r = 0.4611, respectively (all p-value <0.001). Therefore, CC is considered a good indicator of MM. Analysis of correlation between CC and SMD were performed and showed no correlation (r = -0.02624, p = 0.7875; r = -0.1371, p = 0.373; r = 0.01385, p = 0.9185 for the general sample, males and females, respectively).

Fig 2

Pearson’s correlation between skeletal muscle index (SMI) and calf circumference in total patients (A), males (B), and females (C) with cancer (n = 108).

The agreement between the sarcopenia diagnostic criteria (using CT or CC for MM evaluation) is observed in Table 3. The sensitivity, specificity, and accuracy were calculated according to sex. For the total sample was observed 81% sensitivity, and 92% specificity, with higher values in females (86% sensitivity, and 91% specificity) compared to males (75% sensitivity, and 92% specificity). The Kappa tests present similar results, with a substantial agreement for females (K = 0.729) and males (K = 0.673).

Table 3

Accuracy test for sensitivity and specificity between different methods for low muscle mass assessment, using EWGSOP2 sarcopenia criteria in cancer patients.

	Total (n = 108)	Male (n = 51)	Female (n = 57)
Kappa (p-value)	0.704 (p < 0.001)	0.673 (p < 0.001)	0.729 (p < 0.001)
Accuracy (%)	88.9	88.2	89.5
Prevalence (%)	25.9	23.5	28.1
Sensitivity (%)	80.8	75.0	85.7
Specificity (%)	91.5	92.3	90.7
Positive predictive value (%)	75.0	75.0	75.0
Negative predictive value (%)	93.8	92.3	95.1

Discussion

The main finding of the present study points out that CC can be used, with good accuracy, as a MM marker to diagnose sarcopenia in elderly patients with cancer. CC is a relatively quick, cost-effective, and easy measurement that can help to identify sarcopenia without the need for sophisticated and expensive techniques. To the best of our knowledge, this is a pioneer study evaluating the accuracy of sarcopenia-based CC, compared to CT images, in this population. Previously, Velazquez-Alva et al. conducted a cross-sectional study to compare the prevalence of sarcopenia according to EWGSOP using SMI and CC in 137 Mexican elderly women [14, 28]. However, the population was composed only of women without cancer, and the diagnostic algorithm used in the study was that of the previous version published in 2010, not yet reviewed [14].

Low skeletal MM is highly prevalent in older patients with cancer and affects 5% to 89% of them depending on the type and stage of cancer [29]. The prevalence of sarcopenia in the present study is quite similar to other previous recent ones, reporting 21.2% to 48.2%, but it is important to note that the criteria to define sarcopenia used by the studies are different, being the majority only by CT images [30-34]. A recent study found a similar prevalence of sarcopenia (27.1%) in 439 older patients with cancer (60–95 years; 43.5% women), using the same diagnostic criteria of the present study (EWGSOP2) [35]. Another important issue is that most patients of the present study had advanced cancer and had already undergone some type of treatment that can accelerate declines in MM. Williams et al., evaluating older adults before and after cancer diagnosis, observed that after cancer diagnosis, there was a decline in MM, but not in HGS or gait speed, and these declines were more striking in patients with metastases [36].

To our knowledge, few studies available in the literature have used CC as an indicator of MM in cancer patients. Our research group recently showed that low CC can predict the risk of mortality in a cohort of 250 patients with cancer [37]. Patients with low CC have a risk of death three times higher than patients with normal CC, even after adjustment for confounders; low SMI was significantly associated with mortality in crude analysis, but not after adjustment for age, sex, and stage of disease [37]. These findings reinforce the use of CC as a simple, easy, cost-effective anthropometric measurement for assessing MM and screening patients with cancer.

Other studies have compared different MM indicators, including CC, for the diagnosis of sarcopenia and malnutrition in cancer patients. SARC-F is a simple and easy tool for screening sarcopenia, based on a 5-item questionnaire that measures strength, assistance in walking, rising from a chair, climbing stairs, and falls [38]. However, a major problem of SARC-F is its low sensitivity. Researches from Brazil developed an enhanced version of SARC-F (SARC-CalF) by incorporating CC into the SARC-F, which could significantly increase its sensitivity and overall diagnostic accuracy in community-dwelling older populations [39]. Because of the grown interest in this tool, other researchers also verified that SARC-CalF have better diagnostic performance as compared to the original questionnaire in the same population [40-42]. Similar results also were observed in cancer patients, when it was compared SARC-F wit SARC-CalF for screening sarcopenia in 309 advanced cancer patients [43].

Recently, the Global Leadership Initiative on Malnutrition (GLIM) criteria was proposed to identify malnutrition in adults in a clinical setting [44]. With the aim to evaluate malnutrition according to the GLIM criteria using different MM indices in lung cancer patients, Yin et al. [45] performed a multicenter, observational cohort study, and found that CC was effective for determining the nutritional status of patients, having the best performance in comparing with other anthropometric methods. In fact, other studies also showed the fair performance of CC for identifying low MM in cancer patients, and its good performance to predict mortality [37, 46, 47]. In non-cancer patients, CC was also positively correlated with skeletal MM, and it could be used as a surrogate marker of MM for diagnosing sarcopenia [20, 48].

Nowadays, there is an increase in the number of reports on body composition assessment in patients with cancer for the diagnostic of sarcopenia. The definition of sarcopenia as a state of severe depletion of skeletal MM (SMI), known as secondary sarcopenia, has been largely established for cancer patients using CT measures and defined based on the risk of mortality [49-51]. Other measures of body composition have been used in cancer patients, including dual-energy X-ray absorptiometry (DEXA) and bioelectrical impedance (BIA) [52]. Although the use of the algorithm EWGSOP2 for the diagnosis of sarcopenia in the elderly is well established for this population, researchers are not yet unanimous about the use of this reference to define sarcopenia in patients with cancer. The use of different sarcopenia criteria for cancer patients makes it difficult to compare studies, and it is suggested that this criterion should be standardized to better understand this phenomenon.

The cutoffs of low MM and low SMD varied significantly across studies, and it can represent a limitation for the present study. As we do not have any reference values developed for the Brazilian population, we used those proposed by Caan et al. [25] from a sample of American patients with stage I–III invasive colorectal cancer, and it is possible that it may not have been adequate for our population (Latin-American patients with cancer). For low CC, the cutoffs used in this study came from a regional reference, validated against DXA in a sample representative for the local population [20]. Despite the limitations, the results are relevant demonstrating the practical applicability of CC measures for the diagnostic of sarcopenia in cancer patients.

In conclusion, the agreement of sarcopenia defined by EWGSOP2 using MM assessed by CC or CT images (SMI) was moderate, with high specificity and negative predictive value, suggesting that CC can be used as a MM indicator in cancer patients. Although the application of the EWGSOP2 in the definition of sarcopenia in older cancer patients is still not a consensus, it may indeed be advantageous in clinical settings, because the measurements used in the algorithm (low HGS associated with low CC) are easier to obtain than the analysis of MM by CT images.

15 Feb 2021

PONE-D-20-33755

Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass

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Reviewer #1: ‘Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass’ is a research article that is a pioneer study evaluating the accuracy of sarcopenia-based CC, compared to CT images.

This study is very valuable because it highlights the fact that calf circumference measurement can be used to muscle mass assessment for sarcopenia diagnosis in cancer patients, instead of computed tomography (CT). Calf circumference measurement is a simple, easy and cheap procedure, in opposite to CT, which is costly method and requiring specialized staff to operate it. The paper reads well.

I would only recommend to widen the description of the use of the SARC-CalF questionnaire in research on sarcopenia around the world, because interest in this tool has grown significantly in recent years (lines 256-258).

Please refer to the following articles:

1) Yang M, Hu X, Xie L, et al. Screening sarcopenia in community-dwelling older adults: SARC-F vs SARC-F combined with calf circumference (SARC-CalF). J Am Med Dir Assoc. 2018;19(3):277.e1-277.e8. doi:10.1016/j.jamda.2017.12.016

2) Krzymińska-Siemaszko R, Deskur-Śmielecka E, Kaluźniak-Szymanowska A, Lewandowicz M, Wieczorowska-Tobis K. Comparison of Diagnostic Performance of SARC-F and Its Two Modified Versions (SARC-CalF and SARC-F+EBM) in Community-Dwelling Older Adults from Poland. Clin Interv Aging. 2020; 15: 583–594.

3) Mo Y, Dong X, Wang XH. Screening accuracy of SARC-F combined with calf circumference for sarcopenia in older adults: a diagnostic meta-analysis. J Am Med Dir Assoc. 2020;21(2):288–289. doi:10.1016/j.jamda.2019.09.002

Reviewer #2: This manuscript reports the comparison of sarcopenia in cancer patients using computed tomography and calf circumference. Overall the study is important and it will certainly add to the current evidence on the potential of using a simpler method to measure muscle mass in cancer patients. However, I have some minor comments on the manuscript, which are outlined below,

Abstract

• Please write L3 in full when it's first mentioned in the text, i.e. "third lumbar vertebra".

• Mean ± “standard deviation” age of 70.6 ± 7.4 years?

Materials and Methods

• Was this trial registered in clinical trials registration? If so, please include this information in the Methods section.

Design and subjects

• Lines 83-84: Please include the institution of the ethics board.

Anthropometric evaluation

• Lines 96-99: How many measurements were taken for the calf circumference, e.g. once or twice?

Muscle strength assessment

• Lines 104-105: Is there any reason why the handgrip strength of the non-dominant hand was captured as well?

Results

• Table 1: Please include the definition for each of the BMI categories.

• Line 161: Should this read "Chi-square test"?

• Line 180: Please write the abbreviations in full when first mentioned.

• Table 2: It will be good to include the prevalence of low handgrip strength, low MM, and low CC in this table. Thank you.

• Line 183: Please change “according” to "according to".

• Table 2 header: Please include the denominator for all the "No" and "Yes" categories, e.g. Sarcopenia by low MM, Yes: "26 of 108 patients = 24.1%".

• Line 194: Should this read "moderate"?

• Table 3: Are all the kappa p-values referring to "p<0.001"?

Discussion

• Lines 250-251: Suggest using another term for 'patients at risk of death'.

• Line 256: Should this read 'researchers"?

**********

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Reviewer #1: No

Reviewer #2: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

15 Mar 2021

February 17th, 2021.

RESPONSE LETTER

Manuscript PONE-D-20-33755

Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass

Dear Stephen E Alway, Ph.D.

Academic Editor:

Thank you for your email enclosing the reviewers’ comments. We have carefully reviewed the comments and have revised the manuscript accordingly. Our responses are given point-by-point below. Changes to the manuscript are tracked.

Sincerely,

Ana Paula Trussardi Fayh, PhD

Editor comments:

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

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: The manuscript meets the style and templates provided by the journal.

2. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"This study was financed in part by the Coordenação de Aperfeiçoamento de

306 Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

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

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Response: Thank you for the comment. The statement was included in the submission form and removed from the manuscript. The cover letter was also changed accordingly.

Reviewers' comments:

Reviewer #1:

‘Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass’ is a research article that is a pioneer study evaluating the accuracy of sarcopenia-based CC, compared to CT images.

This study is very valuable because it highlights the fact that calf circumference measurement can be used to muscle mass assessment for sarcopenia diagnosis in cancer patients, instead of computed tomography (CT). Calf circumference measurement is a simple, easy and cheap procedure, in opposite to CT, which is costly method and requiring specialized staff to operate it. The paper reads well.

I would only recommend to widen the description of the use of the SARC-CalF questionnaire in research on sarcopenia around the world, because interest in this tool has grown significantly in recent years (lines 256-258).

Please refer to the following articles:

1) Yang M, Hu X, Xie L, et al. Screening sarcopenia in community-dwelling older adults: SARC-F vs SARC-F combined with calf circumference (SARC-CalF). J Am Med Dir Assoc. 2018;19(3):277.e1-277.e8. doi:10.1016/j.jamda.2017.12.016

2) Krzymińska-Siemaszko R, Deskur-Śmielecka E, Kaluźniak-Szymanowska A, Lewandowicz M, Wieczorowska-Tobis K. Comparison of Diagnostic Performance of SARC-F and Its Two Modified Versions (SARC-CalF and SARC-F+EBM) in Community-Dwelling Older Adults from Poland. Clin Interv Aging. 2020; 15: 583–594.

3) Mo Y, Dong X, Wang XH. Screening accuracy of SARC-F combined with calf circumference for sarcopenia in older adults: a diagnostic meta-analysis. J Am Med Dir Assoc. 2020;21(2):288–289. doi:10.1016/j.jamda.2019.09.002

Response: Thank you for the recommendation. Additional informations were included in the manuscript to refer to these studies.

Reviewer #2: Reviewer #2: This manuscript reports the comparison of sarcopenia in cancer patients using computed tomography and calf circumference. Overall the study is important and it will certainly add to the current evidence on the potential of using a simpler method to measure muscle mass in cancer patients. However, I have some minor comments on the manuscript, which are outlined below,

Abstract

• Please write L3 in full when it's first mentioned in the text, i.e. "third lumbar vertebra".

Response: Thank you for observation.

• Mean ± “standard deviation” age of 70.6 ± 7.4 years?

Response: Thank you for your observation, it was corrected according to the suggestion.

Materials and Methods

• Was this trial registered in clinical trials registration? If so, please include this information in the Methods section.

Response: Thank you for your observation. Considering the fact that the design of the study is cross-sectional (observational), no clinical trial registration was performed.

Design and subjects

• Lines 83-84: Please include the institution of the ethics board.

Response: Thank you for your observation. The institution was included according to the suggestion.

Anthropometric evaluation

• Lines 96-99: How many measurements were taken for the calf circumference, e.g. once or twice?

Response: Thank you for your observation. The information about the measurements was corrected and included in the manuscript (not in the dominant leg; both leg calf muscle circumferences were measured).

Muscle strength assessment

• Lines 104-105: Is there any reason why the handgrip strength of the non-dominant hand was captured as well?

Response: Thank you for your valuable observation. There is a mistake in this information, because handgrip strength was measured in both arms.

Results

• Table 1: Please include the definition for each of the BMI categories.

Response: Thank you for your observation. The definition was included in the footnote Table.

• Line 161: Should this read "Chi-square test"?

Response: Thank you for your observation, the term was modified.

• Line 180: Please write the abbreviations in full when first mentioned.

Response: Thank you for your observation. The abbreviations were defined in following sentences: BMI (line 97), CC (line 68), SMA (line 119), SMI (line 121), SMD (line 127) and HGS (line 107)

• Table 2: It will be good to include the prevalence of low handgrip strength, low MM, and low CC in this table. Thank you.

Response: Thank you for the recommendation to include these prevalences. However, we decided to present this information in the text (line 181-182).

• Line 183: Please change “according” to "according to".

Response: Thank you for your observation, the term was changed.

• Table 2 header: Please include the denominator for all the "No" and "Yes" categories, e.g. Sarcopenia by low MM, Yes: "26 of 108 patients = 24.1%".

Response: Thank you for your observation, the number of subjects was added on the title of Table.

• Line 194: Should this read "moderate"?

Response: Thank you for your observation, we corrected the word in the sentence.

• Table 3: Are all the kappa p-values referring to "p<0.001"?

Response: Thank you for your observation. Yes, all kappa p-values are p < 0.001. We changed the manuscript accordingly.

Discussion

• Lines 250-251: Suggest using another term for 'patients at risk of death'.

Response: Thank you for your observation, we changed the term in the sentence limiting to the studied population.

• Line 256: Should this read 'researchers"?

Response: Thank you for your observation, we corrected the word in the sentence.

Submitted filename: responsetoreviewers.docx

Click here for additional data file.

21 Jun 2021

PONE-D-20-33755R1

Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass

PLOS ONE

Dear Dr. Trussardi Fayh,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

This paper has only a few minor things to address. All of the major issues have been resolved so i am confident that the next revision can be done quickly.

Please submit your revised manuscript by Aug 05 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Stephen E Alway, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

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 #1: All comments have been addressed

Reviewer #3: 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 #1: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: I Don't Know

**********

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 #1: Yes

Reviewer #3: No

**********

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 #1: Yes

Reviewer #3: 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 #1: Thank you for considering my comments. I recommend publishing this revised version of manuscript titled Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass.

Reviewer #3: Overall, I think the authors have done a good job at addressing the previous round of revisions. Below are a few thoughts and minor suggestions for improvement.

General Comments:

Double check all abbreviations are used consistently in paper. E.g. “Muscle mass” has frequently been abbreviated to MM. However, in some cases it still remains written in full.

Abstract:

Please introduce European 56 Work Group on Sarcopenia in Older People (EWGSOP) in abstract before referring to abbreviation.

Line with “prevalence of sarcopenia by the EWGSOP2” – suggest revising to “according to the EWGSOP2 criteria.”

Line with “evaluate the accuracy of sarcopenia using low CC considering MM assessment by computed tomography (CT)…” – suggest revising to “evaluate the accuracy of sarcopenia using low CC relative to MM assessment…”

Line “Data included sociodemographic, clinical and anthropometric variables.” – suggest deleting from abstract if you need to reduce word count. I don’t think this is necessary.

Suggest adding one additional statement at the end of the abstract or slightly revise the current last statement of the abstract. What is the key takeaway message from this study, i.e. what is the primary reason people will cite this paper? E.g. Measuring CC and HGS may serve as a useful alternative to identify sarcopenia in people with cancer relative to relying on CT imaging to diagnose low MM.

Introduction:

Line 60: remove capitalisation of sarcopenia.

Methods:

Line 90: This needs further clarification. How were patients approached for the study? Was there a set time period for recruitment, e.g. mm-yy to mm-yy?

Line 101: Was the calf measurement performed by the same researcher?

Line 103: After three measures of CC were taken, was the average then calculated across both legs or was it the maximum value that was used? This needs to be clearly articulated to allow for study replication or translation into practice.

Results:

Line 152: Was there a primary reason patients were unable to have their calf assessed? A little further detail might be helpful here.

Line 160: I would not refer to this as a nutritional evaluation, as that would require a more comprehensive assessment beyond BMI alone. Suggest revising this to: According to BMI categories, 47.2% of patients were classified as having a normal body weight and 30.6% were considered overweight.”

Line 202-207: This is a very long sentence. Suggest condensing or breaking into two or more statements for clarity. Please also double check use of brackets. One seems to be missing before “all p-value <0.001.”

Discussion:

Line 228: This sentence is a bit difficult to follow. Try to be very clear here. E.g. “The main finding of the present study is that CC can be used to diagnose sarcopenia in elderly patients with cancer and has similar accuracy to assessing MM using CT imaging.”

Line 230: Remove “In fact”

The utility of measuring CC versus relying on sophisticated and costly imaging techniques to identify low MM should be highlighted. One of the most important findings of this study is that a relatively quick, cost-effective and easy measurement can help identify sarcopenia. I suggest highlighting this more in the discussion.

**********

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 #1: Yes: Roma Krzymińska-Siemaszko

Reviewer #3: 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.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

22 Jun 2021

June 22nd, 2021.

RESPONSE LETTER

Manuscript PONE-D-20-33755R1

Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass

Dear Stephen E Alway, Ph.D.

Academic Editor:

Thank you for your email enclosing the reviewers’ comments. We have carefully reviewed the comments and have revised the manuscript accordingly. Our responses are given point-by-point below. Changes to the manuscript are tracked.

Sincerely,

Ana Paula Trussardi Fayh, PhD

Reviewers' comments:

Reviewer #1

Thank you for considering my comments. I recommend publishing this revised version of manuscript titled Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass.

Response: Thank you for your comments; we appreciate your contributions to our manuscript.

Reviewer #3

Double check all abbreviations are used consistently in paper. E.g. “Muscle mass” has frequently been abbreviated to MM. However, in some cases it still remains written in full.

Response: Thank you for your observation; we have double-checked the main document and now all mentions of muscle mass after the abbreviation are abbreviated in the manuscript.

Abstract:

- Please introduce European Work Group on Sarcopenia in Older People (EWGSOP) in abstract before referring to abbreviation.

Response: Thank you for point this out. We have included the meaning of the abbreviation in the first mention.

- Line with “prevalence of sarcopenia by the EWGSOP2” – suggest revising to “according to the EWGSOP2 criteria.”

Response: Thank you for your comment, we have adjusted the sentence accordingly.

- Line with “evaluate the accuracy of sarcopenia using low CC considering MM assessment by computed tomography (CT)…” – suggest revising to “evaluate the accuracy of sarcopenia using low CC relative to MM assessment…”

Response: Thank you for your observation. We have changed the main document.

- Line “Data included sociodemographic, clinical and anthropometric variables.” – suggest deleting from abstract if you need to reduce word count. I don’t think this is necessary.

Response: Thank you for your observation. However, there was no need to reduce the word count after the changes in the abstract, the word count remains according to the journal guidelines (not exceed 300 words).

- Suggest adding one additional statement at the end of the abstract or slightly revise the current last statement of the abstract. What is the key takeaway message from this study, i.e. what is the primary reason people will cite this paper? E.g. Measuring CC and HGS may serve as a useful alternative to identify sarcopenia in people with cancer relative to relying on CT imaging to diagnose low MM.

Response: Thank you for your suggestion. We included additional information in the conclusion of the abstract to support the takeaway message of our study.

Introduction:

-Line 60: remove capitalisation of sarcopenia.

Response: Thank you for your observation. The capitalization was removed.

Methods:

- Line 90: This needs further clarification. How were patients approached for the study? Was there a set time period for recruitment, e.g. mm-yy to mm-yy?

Response: Thank you for your comments. We have included this information in the manuscript (lines 94 to 96).

- Line 101: Was the calf measurement performed by the same researcher?

Response: Thank you for your observation. Three trained researchers performed the calf measurement. This information was added in the revised manuscript (line 102).

- Line 103: After three measures of CC were taken, was the average then calculated across both legs or was it the maximum value that was used? This needs to be clearly articulated to allow for study replication or translation into practice.

Response: Thank you for your comments. After the three measures, it was used the maximum value. The additional information was included in the manuscript (line 110).

Results:

- Line 152: Was there a primary reason patients were unable to have their calf assessed? A little further detail might be helpful here.

Response: Thank you for your observation. The patients were unable to have their calf assessed because of the presence of leg edema or amputation. Additional information is provided in the revised version of the manuscript (Methods section, line 89 and Results section, line 159).

- Line 160: I would not refer to this as a nutritional evaluation, as that would require a more comprehensive assessment beyond BMI alone. Suggest revising this to: According to BMI categories, 47.2% of patients were classified as having a normal body weight and 30.6% were considered overweight.”

Response: Thank you for your suggestion. We have agreed with your comment and changed the manuscript according to your recommendation.

- Line 202-207: This is a very long sentence. Suggest condensing or breaking into two or more statements for clarity. Please also double check use of brackets. One seems to be missing before “all p-value <0.001.”

Response: Thank you for your observation. We have revised the sentence in the manuscript.

Discussion:

- Line 228: This sentence is a bit difficult to follow. Try to be very clear here. E.g. “The main finding of the present study is that CC can be used to diagnose sarcopenia in elderly patients with cancer and has similar accuracy to assessing MM using CT imaging.”

Response: Thank you for your comment. However, the sentence in the document is “The main finding of the present study points out that CC can be used, with good accuracy, as a MM marker to diagnose sarcopenia in elderly patients with cancer.”

-Line 230: Remove “In fact”

Response: Thank you for your observation. We have removed the sentence in the revised manuscript.

- The utility of measuring CC versus relying on sophisticated and costly imaging techniques to identify low MM should be highlighted. One of the most important findings of this study is that a relatively quick, cost-effective and easy measurement can help identify sarcopenia. I suggest highlighting this more in the discussion.

Response: Thank you for your suggestion. We agreed and included a sentence in the discussion section to highlight the importance of the use of CC (lines 237 to 238).

Submitted filename: responsetoreviewers.docx

Click here for additional data file.

2 Sep 2021

Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass

PONE-D-20-33755R2

Dear Dr. Trussardi Fayh,

The expert Reviewers who reviewed your manuscript are satisfied that the concerns have been addressed in this revision and I agree. Therefore 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 meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- 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.

Congratulations on a great paper, and kind regards,

Stephen E Alway, Ph.D.

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 #3: 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 #3: Yes

**********

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

Reviewer #3: 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 #3: 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 #3: 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 #3: The authors have carefully gone through the suggested comments and revised the manuscript accordingly. I feel the manuscript is improved and have no further comments.

**********

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 #3: No

6 Sep 2021

PONE-D-20-33755R2

Comparison of revised EWGSOP2 criteria of sarcopenia in patients with cancer using different parameters of muscle mass

Dear Dr. Trussardi Fayh:

I'm 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 let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, 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.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Stephen E Alway

Academic Editor

PLOS ONE