==== Front PLoS One PLoS One plos PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0288077 PONE-D-23-02766 Research Article Medicine and Health Sciences Urology Genitourinary Cancers Bladder Cancer Medicine and Health Sciences Oncology Cancers and Neoplasms Genitourinary Tract Tumors Bladder Cancer Medicine and Health Sciences Oncology Cancers and Neoplasms Lung and Intrathoracic Tumors Medicine and Health Sciences Oncology Cancer Treatment Biology and Life Sciences Anatomy Musculoskeletal System Muscles Skeletal Muscles Medicine and Health Sciences Anatomy Musculoskeletal System Muscles Skeletal Muscles Medicine and Health Sciences Clinical Medicine Signs and Symptoms Sarcopenia Research and Analysis Methods Mathematical and Statistical Techniques Statistical Methods Metaanalysis Physical Sciences Mathematics Statistics Statistical Methods Metaanalysis Medicine and Health Sciences Oncology Cancer Treatment Surgical Oncology Medicine and Health Sciences Clinical Medicine Clinical Oncology Surgical Oncology Medicine and Health Sciences Oncology Clinical Oncology Surgical Oncology Medicine and Health Sciences Surgical and Invasive Medical Procedures Predictive role of pretreatment skeletal muscle mass index for long-term survival of bladder cancer patients: A meta-analysis SMI in bladder cancer Yuan Qian Data curation Formal analysis Investigation Methodology Writing – original draft 1 2 Hu Jianrong Data curation Methodology Software Validation Writing – review & editing 1 2 Yuan Feng Data curation Formal analysis Methodology Resources Software Writing – original draft 1 2 https://orcid.org/0000-0002-6085-1785 An Jingjing Conceptualization Supervision Writing – review & editing 1 2 * 1 Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China 2 West China School of Nursing, Sichuan University, Chengdu, Sichuan, China D’Aviero Andrea Editor Mater Olbia Hospital, ITALY Competing Interests: The authors have declared that no competing interests exist. * E-mail: anjingjing2022@163.com 30 6 2023 2023 18 6 e02880771 2 2023 19 6 2023 © 2023 Yuan et al 2023 Yuan et al https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Purpose To identify the predictive role of pretreatment skeletal muscle mass index (SMI) for long-term survival of bladder cancer patients. Methods Several databases were searched for studies investigating the relationship between pretreatment SMI and prognosis in bladder cancer. The overall survival (OS) and cancer-specific survival (CSS) were defined as primary and secondary outcomes, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were combined. Results Nine studies involving 1476 cases were included. The results demonstrated that a lower pretreatment SMI was significantly related to poorer OS (HR = 1.56, 95% CI: 1.33–1.82, P<0.001) and subgroup analysis based on thresholds of SMI revealed similar results. Besides, pretreatment SMI was also obviously related to CSS (HR = 1.75, 95% CI: 1.36–2.25, P<0.001). Conclusion Lower pretreatment SMI was associated with worse long-term survival of bladder cancer patients. The author(s) received no specific funding for this work. Data AvailabilityAll data used in this meta-analysis are presented in the paper. Data Availability All data used in this meta-analysis are presented in the paper. ==== Body pmcIntroduction Bladder cancer remains one of the most common urinary malignancies and mainly occurs in the elderly patients [1]. According to the latest cancer data, there was 570,000 new cases in 2020 all over the world, with the tenth morbidity [2]. For male patients, 440,000 bladder cancer cases occur with the sixth morbidity and 160,000 patients died with the ninth mortality among all cancers in 2020 [2]. Besides, the incidence tends to increase gradually, which causes a certain tumor burden to the society. Up to now, the prognosis of bladder cancer is still poor despite advances in surgical technologies and chemotherapy [3, 4]. Increasing evidence has demonstrated that tumor progression and prognosis depend not only on the biological aggressiveness of the tumor but also on the host’s response to the tumor. Host factors such as the nutritional status and local or systemic inflammation response are also important indicators of clinical treatment [5]. Systemic inflammation response index (SII) has been verified to be significantly associated with treatment response and survival of bladder cancer patients [6, 7]. Loss of weight and body mass index (BMI) are usually applied to evaluate the nutritional status and cachexia in cancer patients, but these indexes only reflect the total body composition and do not distinguish the proportion and change of fat and muscle mass. Actually, the muscle mass is significantly related to the overall body condition and nutritional status of cancer patients [8, 9]. Many studies have manifested that sarcopenia could reflect potential malnutrition and weakness caused by cancers and skeletal muscle mass index (SMI) is the most authoritative indicator to evaluate the presence or absence of sarcopenia in cancer patients [10, 11]. SMI is calculated by dividing the total area of all skeletal muscles, including the psoas major muscle, erector spinae muscle, quadratus lumborum muscle, transverse muscle of abdomen, obliquus externus abdominis and obliquus internus abdominis, in the third lumbar level of CT images by the square of height [12]. Up to now, the association of pretreatment SMI with long-term survival has been verified by meta-analyses in several types of cancers like the lung cancer [12, 13]. However, the prognostic value of pretreatment SMI in bladder cancer remains unclear now. Therefore, the aim of this meta-analysis was to identify predictive role of pretreatment SMI for long-term survival of bladder cancer patients. Materials and methods This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA 2020) checklist [14]. The detailed checklist information was presented in the S1 File. Literature search The PubMed, EMBASE, WOS and CNKI database were searched up to September 21, 2022. Terms used during the literature search are as follows: skeletal muscle mass index, SMI, bladder, tumor, cancer, neoplasm, carcinoma, survival, prognostic and prognosis. Search strategy was as follows: (skeletal muscle mass index OR SMI) AND bladder AND (tumor OR cancer OR neoplasm OR carcinoma) AND (survival OR prognostic OR prognosis). Besides, the free texts and MeSH terms were used. Inclusion criteria The inclusion criteria included: 1) patients were diagnosed with primary bladder cancer; 2) SMI was calculated according to the CT images of the third lumbar vertebra as previously reported [15]; 3) the SMI values were obtained before anti-tumor therapy such as the surgery and chemoradiotherapy; 4) patients were divided into two groups according to values of SMI and long-term survival representing as the overall survival (OS) and cancer-specific survival (CSS) were compared; 5) hazard ratios (HRs) and 95% confidence intervals (CIs) were provided in the articles. Exclusion criteria The exclusion criteria included: 1) letters, editorials, case reports, reviews or animal trials; 2) duplicated or overlapped data; 3) insufficient information for methodological quality assessment. Data extraction Data were collected from included studies: the name of first author, publication year, country, sample size, tumor-node-metastasis (TNM) stage, treatment (surgery or non-surgery), cutoff value of SMI, endpoint, HR and 95% CI. Methodological quality assessment Methodological quality was evaluated according to Newcastle-Ottawa Scale (NOS) score due to the retrospective nature of study design [16]. Studies with a NOS score ≥6 were regarded as high-quality studies. Statistical analysis Statistical analysis was conducted by STATA 15.0 software. HRs with 95% CIs were combined to assess the relationship between pretreatment SMI and prognosis of bladder cancer patients. The heterogeneity among included studies was evaluated by I2 statistics and Q test. When significant heterogeneity was observed representing as I2 > 50% and (or) P < 0.1, the random-effects model was applied; otherwise, the fix-effects model was applied. The sensitivity analysis was performed to evaluate stability of results. Furthermore, Begg’s funnel plot and Egger’s test were conducted to detect publication bias [17, 18]. Results Literature search A total of 126 records were identified from databases and 27 duplicated records were removed. Eventually, nine studies were included [19–27]. The detailed selection process was shown in the Fig 1. 10.1371/journal.pone.0288077.g001 Fig 1 Prisma flow diagram of this meta-analysis. Basic characteristics of included studies Among nine retrospective included studies, 1476 patients were enrolled and the sample size ranged from 80 to 500 [19–27]. Among four of included studies the cutoff values of SMI, 55cm2/m2 for male and 39cm2/m2 for female, were applied [19, 21, 24, 27]. In the other five studies, the cutoff values of SMI, 43/53cm2/m2 for male and 39cm2/m2 for female, were applied and the cutoff value of SMI for male patients was adjusted by the body mass index (BMI), SMI <43cm2/m2 for patients with BMI<25kg/m2 and <53cm2/m2 for patients with BMI≥25 kg/m2 [20, 22, 23, 25, 26]. All included studies were with high-quality with a NOS score ≥6. Specific information was displayed in Table 1. 10.1371/journal.pone.0288077.t001 Table 1 Basic characteristics of included studies. Author Year Country Sample size TNM stage Treatment Cutoff value Endpoint NOS Psutka [19] 2014 USA 205 Mixed Surgery male: 55cm2/m2, female: 39cm2/m2 OS, CSS 7 Miyake [20] 2017 Japan 89 NR Surgery male: 43/53cm2/m2, female: 41cm2/m2 OS, CSS 7 Abe [21] 2018 Japan 87 NR Chemotherapy/ chemotherapy plus surgery male: 55cm2/m2, female: 39cm2/m2 OS 6 Mayr [22] 2018 Netherlands 500 Mixed Surgery male: 43/53cm2/m2, female: 41cm2/m2 OS, CSS 7 Ha [23] 2019 Republic of Korea 80 Mixed Surgery male: 43/53cm2/m2, female: 41cm2/m2 OS 7 Lyon [24] 2019 USA 183 Mixed Surgery male: 55cm2/m2, female: 39cm2/m2 OS, CSS 7 Stangl [25] 2019 Austria 94 Mixed Radiotherapy male: 43/53cm2/m2, female: 41cm2/m2 OS, CSS 6 Yuan [26] 2021 China 97 cT1-2 Surgery male: 43/53cm2/m2, female: 41cm2/m2 OS 8 Almarzouq [27] 2022 Canada 141 Mixed Radiotherapy plus chemotherapy male: 55cm2/m2, female: 39cm2/m2 OS 6 NR: not reported; OS: overall survival; CSS: cancer-specific survival; NOS: Newcastle-Ottawa Scale. The predictive role of pretreatment SMI for OS in bladder cancer All included studies explored predictive role of pretreatment SMI for OS [19–27]. Pooled results indicated that a lower pretreatment SMI was significantly associated with poor OS in bladder cancer (HR = 1.56, 95% CI: 1.33–1.82, P<0.001; I2 = 6.4%, P = 0.382) (Fig 2). Subgroup analysis stratified by thresholds of SMI showed similar results (non-adjusted SMI: HR = 1.63, 95% CI: 1.22–2.17, P = 0.001; BMI-adjusted: HR = 1.52, 95% CI: 1.26–1.84, P<0.001) (Table 2). 10.1371/journal.pone.0288077.g002 Fig 2 The association between pretreatment skeletal muscle mass index and overall survival of bladder cancer patients. 10.1371/journal.pone.0288077.t002 Table 2 Results of meta-analysis. No. of studies HR 95% CI P value I2 (%) P value Overall survival 9 [19–27] 1.56 1.33–1.82 <0.001 6.4 0.382 Cutoff value of SMI Non-adjusted 4 [19, 21, 24, 27] 1.63 1.22–2.17 0.001 20.7 0.286 BMI-adjusted 5 [20, 22, 23, 25, 26] 1.52 1.26–1.84 <0.001 13.4 0.329 Cancer-specific survival 5 [19, 20, 22, 24, 25] 1.75 1.36–2.25 <0.001 15.5 0.316 HR: hazard ratio; CI: confidence interval; SMI: skeletal muscle mass index. The predictive role of pretreatment SMI for CSS in bladder cancer Five studies investigated predictive role of SMI for CSS of bladder cancer patients [19, 20, 22, 24, 25]. Pooled results revealed that lower pretreatment SMI was related to worse CSS (HR = 1.75, 95% CI: 1.36–2.25, P<0.001; I2 = 15.5%, P = 0.316) (Fig 3). 10.1371/journal.pone.0288077.g003 Fig 3 The association between pretreatment skeletal muscle mass index and cancer-specific survival of bladder cancer patients. Sensitivity analysis and publication bias Sensitivity analysis for OS demonstrated that our results were stable and reliable (Fig 4). Besides, symmetrical Begg’s funnel plot (Fig 5) and P = 0.096 of Egger’s test both indicated non-significant publication bias. 10.1371/journal.pone.0288077.g004 Fig 4 Sensitivity analysis about the association between pretreatment skeletal muscle mass index and overall survival of bladder cancer patients. 10.1371/journal.pone.0288077.g005 Fig 5 Begg’s funnel plot. Discussion The current meta-analysis demonstrated that pretreatment SMI was associated with long-term survival in bladder cancer and lower pretreatment SMI predicted poorer OS and CSS. Therefore, pretreatment SMI might serve as a reliable prognostic indicator in bladder cancer. However, due the limitations existed in this meta-analysis like to the retrospective nature of included studies more prospective high-quality studies are still needed to verify our results. Actually, the predictive role of SMI for survival in cancers has been verified. Pan et al. included 12 studies involving 3002 cases and demonstrated that a lower SMI was obviously related to poorer OS (HR = 1.23, P<0.001) [12]. The subgroup analysis based on treatment, stage and tumor type further manifested prognostic role of SMI in lung cancer and showed similar results [12]. Yao et al. enrolled 2441 patients from 17 studies and demonstrated that lower pretreatment SMI was associated with poorer OS (HR = 1.18, P<0.001) and disease-free survival (DFS) (HR = 1.78, P = 0.019) [13]. Subgroup analysis stratified by the treatment, tumor type and thresholds of SMI revealed similar findings [13]. Our meta-analysis was the first to determine predictive role of pretreatment SMI in bladder cancer and strongly verified that lower pretreatment SMI was related to worse prognosis. SMI is the most common indicator assessing the presence or absence of sarcopenia. Initially, sarcopenia is regarded as a disease of old age characterized by degeneration of muscle tissue. However, increasing evidence indicated that a number of factors could cause sarcopenia such as the disuse, cachexia, malabsorption and also tumors [28]. Meanwhile, the occurrence and development of sarcopenia are closely related to the prognosis of cancer patients [13]. Sarcopenia includes physiological and pathological sarcopenia and the latter is caused by malignant or benign diseases. Tumor-associated sarcopenia is usually closely related to cachexia, representing as marked muscle mass loss and systemic chronic inflammation [29, 30]. The incidence rate of tumor-associated sarcopenia is about 50%-90% in untreated cancer patients [31]. Among patients with bladder cancer, the occurrence rate of sarcopenia is more than 50% [32]. Bladder cancer patients may experience malnutrition due to the impact of the tumor on the body’s metabolism and absorption, or due to adverse reactions during treatment, such as loss of appetite, nausea, and vomiting. Besides, bladder cancer patients with sarcopenia may have reduced tolerance to surgical and chemotherapeutic treatments, and the disruption of the body’s immune and metabolic functions may interfere with the normal response to these treatments [33]. In the past years, the association between sarcopenia and prognosis in cancers has been widely reported and revealed. For now, the predictive role of sarcopenia has been confirmed in several types of tumors including esophageal cancer, rectal cancer and hepatocellular carcinoma [34–37]. Therefore, our meta-analysis indirectly proved that the sarcopenia assessed by SMI before any anti-tumor treatment was a novel and reliable prognostic factor in bladder cancer. In the current meta-analysis, we failed to conduct more analysis about clinical role of SMI in bladder cancer because of lack of original data and limited current evidence. There are still many fields worthy of further investigations. For example, our meta-analysis only identified the association between pretreatment SMI and long-term survival. However, whether the change of SMI during the anti-tumor treatment could predict survival and contribute to the therapy strategy remains unclear. Besides, the cutoff values of SMI are gender-specific and BMI is sometimes considered. It is not clear whether more parameters should be considered such as the age and tumor stage. Furthermore, skeletal muscle plays an essential role in the systemic inflammation response and a large number of evidences have shown that the status of systemic inflammation response is closely related to prognosis of cancer patients [38–40]. Thus, a combination of SMI and some inflammation indexes like the SII might be better in predicting the long-term survival of bladder cancer patients. Limitation of this study Several limitations exist in this meta-analysis. First, all included studies are retrospective with relatively small sample sizes, which might cause some bias. Second, some clinicopathological parameters are unobtainable such as the TNM stage and age and we were unable to conduct more subgroup analysis based on these important indicators due to the lack of original data. Conclusion Lower pretreatment SMI was associated with worse long-term survival of bladder cancer patients. However, more prospective high-quality studies are still needed to verify our results. Supporting information S1 File PRISMA 2020 checklist for this meta-analysis. (DOCX) Click here for additional data file. 10.1371/journal.pone.0288077.r001 Decision Letter 0 D’Aviero Andrea Academic Editor © 2023 Andrea D’Aviero 2023 Andrea D’Aviero https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version0 16 Apr 2023 PONE-D-23-02766Predictive role of pretreatment skeletal muscle mass index for long-term survival of bladder cancer patients: a meta-analysisPLOS ONE Dear Dr. an, 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. 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The topic is absolutely interesting but there are a few points that I would like the authors to address more in detail as follows: 1) Please explain the rationale to focus on pretreatment skeletal muscle mass index as indicator of long-term survival: is it just for sarcopenia? is there a specific link with bladder cancer? is it related to the treatment burden (chemotherapy? surgery? radiotherapy?) 2) Is the value of pretreatment skeletal muscle mass index prognostic or predictive? 3) Please add further information about the "non-surgery" and "mixed" treatment to table 1 Reviewer #2: The paper reports an interesting systematic review with pooled analysis on the role of the pretreatment skeletal muscle mass index in predicting survival outcomes. The introduction well circumscribes the study in the scientific landscape, the rigorous and appropriate methodologies are clearly stated, the results are comprehensively presented and the discussion offers perspectives and limitations of the work. The language is clear and needs no further revision. Translated with www.DeepL.com/Translator (free version) ********** 6. 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. 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Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0288077.r002 Author response to Decision Letter 0 Submission Version1 18 Apr 2023 Response to 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 https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Answer 1: We have thoroughly and carefully checked and modified this manuscript according to PLOS ONE’s style requirements. 2. Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap between your submission and previous work in the abstract, methods, results and discussion. We would like to make you aware that copying extracts from previous publications, especially outside the methods section, word-for-word is unacceptable. In addition, the reproduction of text from published reports has implications for the copyright that may apply to the publications. Please revise the manuscript to rephrase the duplicated text, cite your sources, and provide details as to how the current manuscript advances on previous work. Please note that further consideration is dependent on the submission of a manuscript that addresses these concerns about the overlap in text with published work. We will carefully review your manuscript upon resubmission and further consideration of the manuscript is dependent on the text overlap being addressed in full. Please ensure that your revision is thorough as failure to address the concerns to our satisfaction may result in your submission not being considered further. Answer 2: Dear editor, thanks for your comment. We have completely revised our manuscript to reduce the repetition rate, from 40% to 30%. However, the duplication is mainly in the methodological section. The similarity detection was performed by Turnitin system. If necessary, we would be happy to further reduce the repetition rate. 3. 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. Answer 3: We have added the caption for the Supporting Information file at the end of this manuscript (page 24. line 1) and also cited this file in the text (page 4, line 7-8) Response to reviewer 1: Reviewer #1: The authors present a paper about "Predictive role of pretreatment skeletal muscle mass index for long-term survival of bladder cancer patients: a meta-analysis". The topic is absolutely interesting but there are a few points that I would like the authors to address more in detail as follows: Question 1: Please explain the rationale to focus on pretreatment skeletal muscle mass index as indicator of long-term survival: is it just for sarcopenia? is there a specific link with bladder cancer? is it related to the treatment burden (chemotherapy? surgery? radiotherapy?) Answer 1: Dear reviewer, thanks for your valuable comment. We have carefully explained the rationale to focus on pretreatment SMI as indicator of long-term survival in the discussion part. “SMI is the most common indicator assessing the presence or absence of sarcopenia. Initially, sarcopenia is regarded as a disease of old age characterized by degeneration of muscle tissue. However, increasing evidence indicated that a number of factors could cause sarcopenia such as the disuse, cachexia, malabsorption and also tumors [28]. Meanwhile, the occurrence and development of sarcopenia are closely related to the prognosis of cancer patients [13]. Sarcopenia includes physiological and pathological sarcopenia and the latter is caused by malignant or benign diseases. Tumor-associated sarcopenia is usually closely related to cachexia, representing as marked muscle mass loss and systemic chronic inflammation [29, 30]. The incidence rate of tumor-associated sarcopenia is about 50%-90% in untreated cancer patients [31]. Among patients with bladder cancer, the occurrence rate of sarcopenia is more than 50% [32]. Bladder cancer patients may experience malnutrition due to the impact of the tumor on the body's metabolism and absorption, or due to adverse reactions during treatment, such as loss of appetite, nausea, and vomiting. Besides, bladder cancer patients with sarcopenia may have reduced tolerance to surgical and chemotherapeutic treatments, and the disruption of the body's immune and metabolic functions may interfere with the normal response to these treatments [33]. In the past years, the association between sarcopenia and prognosis of cancer patients has been widely reported and revealed. For now, the predictive role of sarcopenia has been verified in several types of cancers such as the esophageal cancer, rectal cancer and hepatocellular carcinoma [34-37]. Therefore, our meta-analysis indirectly proved that the sarcopenia assessed by SMI before any anti-tumor treatment was a novel and reliable prognostic factor in bladder cancer.” (page 12, line 17-22; page 13, line 1-17) Question 2: Is the value of pretreatment skeletal muscle mass index prognostic or predictive? Answer 2: Dear reviewer, we deem that these two phrases, “predictive role of SMI for survival” and “prognostic role of SMI”, may mean the same thing. After carefully reviewing previous similar articles, we found that both of these expressions were quite common although the latter is more common. If necessary, we would like to unify to the latter type of expression, “prognostic”. Question 3: Please add further information about the "non-surgery" and "mixed" treatment to table 1 Answer 3: We have added further information about the “non-surgery” and “mixed” treatment in table 1. (page 7-8) Response to reviewer 2 The paper reports an interesting systematic review with pooled analysis on the role of the pretreatment skeletal muscle mass index in predicting survival outcomes. The introduction well circumscribes the study in the scientific landscape, the rigorous and appropriate methodologies are clearly stated, the results are comprehensively presented and the discussion offers perspectives and limitations of the work. The language is clear and needs no further revision. Answer: Thank you very much for your recognition of the quality of this article Attachment Submitted filename: answer to comments.docx Click here for additional data file. 10.1371/journal.pone.0288077.r003 Decision Letter 1 D’Aviero Andrea Academic Editor © 2023 Andrea D’Aviero 2023 Andrea D’Aviero https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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. Andrea D’Aviero Academic Editor PLOS ONE ==== Refs References 1 Ferlay J , Colombet M , Soerjomataram I , Mathers C , Parkin DM , Piñeros M , et al . Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. 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