Abstract
Background
Sarcopenia has been associated with negative clinical outcomes in cancer patients, particularly response to treatment and survival. The exponential growth in the use of immune checkpoint inhibitors (ICIs) has led to an increase in the reporting of both adverse events in general (AEs) and immune-related adverse events (irAEs), which are unintended immune-related phenomenon that take place as a result of checkpoint blockade. However, there are no systematic reviews evaluating the relationship between sarcopenia and the risk of developing AEs and irAEs in cancer patients on ICI therapies.
Methods
PubMed, MEDLINE, Embase, Cochrane and grey literature, repositories, websites Open Grey, Google Scholar, and abstracts of major international congresses were searched up to April 2020 for observational studies on sarcopenia and both AEs and irAEs in patients treated with ICIs. Study quality was assessed with The Newcastle–Ottawa quality assessment scale. PROSPERO registration number: CRD42020197178.
Results
One hundred and thirteen discrete articles were identified. Seven studies were included after evaluation of the eligibility criteria. Important sources of heterogeneity including the specific cut-points defining sarcopenia, sample size, inclusion and exclusion criteria, treatment regimen, and baseline demographics were evaluated and accounted for accordingly.
Conclusion
Most of the included studies showed an increased risk of AEs with use of ICIs in cancer patients with sarcopenia, and in the majority of these, the increase was statistically significant. Due to the small number of available studies and the expanding use of ICIs, additional research is warranted.
Supplementary Information
The online version of this article (10.1007/s00262-021-02888-6) contains supplementary material, which is available to authorized users.
Keywords: Adverse events, Cancer immunotherapy, Immune checkpoint inhibitors, Immune-related adverse events, Sarcopenia
Introduction
Over the last decade, sarcopenia has been linked with poor clinical outcomes in cancer patients [1–4]. Recently, studies have demonstrated that in cancer patients treated with immune checkpoints inhibitors (ICI), there is an association between sarcopenia and the risk of both adverse events (AEs), defined by the Common Terminology Criteria for Adverse Events (CTCAE) [5] as any abnormal clinical finding temporally associated with the use of a therapy for cancer, and with immune-related adverse events (irAEs), which are organ-specific inflammatory phenomena that take place as a result of removing some of the barriers that regulate the immune response to targeted stimuli [1, 6]. This link has been demonstrated in numerous different types of cancer, particularly melanoma, non-small cell lung carcinoma (NSCLC), and renal cell carcinoma (RCC), among others [1, 7–9].
A number of studies have explored the role of body composition on the immune response to ICIs [10–12]. Some papers have stressed the association between obesity, which is considered a persistently low-grade systemic inflammatory state, and the risk of developing AEs and irAEs in patients treated with ICIs. This effect has been attributed to the increased secretion of adipokines including leptin, as well as cytokines and other inflammatory markers, especially TNF-α, IL-6, and C-reactive protein in obese individuals. Other investigators have illustrated that sarcopenia is linked with a decline in immunity and inflammatory response as a result of reduced skeletal muscle-derived cytokines, myokines, including Nampt, TNF-α, and IL-6. In addition, healthy skeletal muscle tissue produces IL-15, which stimulates CD8 memory T cells, NKT cells, and intraepithelial T cell subsets. The wasting of muscle likely results in lower levels of circulating IL-15 levels, dampening the responses of these T-cell subclasses, with the most prominent effect seen among the understimulated NK cell population [10].
The increasing use of ICIs in clinical practice has led to a dramatic rise in the survival of cancer patients of diverse primary origins [1, 2]. However, their utilization has also led to a rise in the reporting of AEs. It has been reported that severe adverse events (grade 3 and 4) occurred in up to 55% of patients treated with ipilimumab, in 9 to 43% with nivolumab, in 11 to 14% with pembrolizumab, and in 54 to 86% of patients treated with both ipilimumab and nivolumab [13].
Research has linked several factors with the development of AEs with the use of ICIs, particularly irAEs [1]. These risk factors include higher body mass index, male sex, history of autoimmune disease, impaired renal function, tumor location and infiltration, number of treatment cycles, absence of prophylactic corticosteroid use, and simultaneous use of medications with known autoimmune toxicities [12, 14–16]. However, it remains unclear which patients will develop AEs and what factors may best predict the severity of these events.
To our knowledge, the relationship between sarcopenia and the risk of developing AEs and specifically irAEs has not yet been reviewed systematically. The aim of this study is to review the existing studies on the relationship between sarcopenia and both AEs and irAEs in patients treated with ICI therapies.
Methods
Search strategy
A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) Statement [17]. The protocol of this study was registered on the website of PROSPERO International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/prospero/) under the number CRD42020197178. PubMed, MEDLINE, Embase, Cochrane Library, OpenGrey and GetNet International were searched from inception until April 2020. The search was conducted using the following PICOS format (Patients, Interventions, Comparators, Outcomes and Studies): P: Adult participants (age ≥ 18 years) with sarcopenia; I: on immune checkpoint inhibitor treatment; C: control or comparator group no-sarcopenic patients; O: adverse events; S: observational studies.
Additionally, manual searches of reference citations in the reviewed literature sources were performed. A detailed description of the search strategy is provided in Supplementary Table S1. Two authors independently reviewed the titles and abstracts for eligible studies (YGP and OS). Disagreements were resolved by consensus.
Eligibility criteria
Eligibility was limited to: (1) studies involving humans; (2) ≥ 18-year-old participants were enrolled; (3) studies with more than 30 participants; (4) at least one dose of immune checkpoint inhibitors (anti CTLA-4 or anti PD-1/PD-L1) administered. Studies were excluded if: (1) they were case-reports, editorials, comments, letters, reviews, meta-analyses, or interventional studies; (2) they were duplicate; or (3) they were written in languages other than English or the English translated versions were not available.
Study selection
Two researchers (YGP and OS) independently performed the screening of the studies and identified relevant papers by titles and abstracts. If the articles were potentially eligible, full texts were retrieved and screened. Disagreements were resolved by consensus among all authors.
Data extraction and synthesis
The selected studies were reviewed and the data was independently extracted by two researchers (YGP and OS). Conflicting data was resolved by consensus among all authors. Information on author, publication year, country/region, study type, sample size, age, and outcomes were inserted into a bibliographic database using Microsoft® Office Excel® version 14.0 software (Microsoft, Redmond, WA, USA). Corresponding authors were contacted by email to provide additional data where possible. In papers reporting on the same cohort of patients, only the study with the largest sample was included.
Study quality assessment
The risk of bias of the observational studies was assessed using the Newcastle–Ottawa quality assessment scale, evaluating three items: patient selection, comparability of study groups and assessment of outcomes [18]. Each study was assessed as being of high quality (7–9 points), moderate quality (4–6 points) and low quality (≤ 3). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment was used to rate the overall quality of the evidence [19]. Two reviewers (YGP and OS) independently evaluated the risk of bias. Disagreements were resolved by consensus among all authors.
Data synthesis and analysis
A narrative synthesis from the included studies was conducted around the sample size, study design, cut-points used to define sarcopenia [4, 20, 21], type of ICIs, length of the treatment, type and severity of AEs and irAEs, OR, and 95% CI measurements.
Results
A total of 113 studies were identified. Eighty-seven articles remained after the duplicates were removed. After reviewing titles and abstracts, 14 studies met the PICOS criteria and were eligible for full‐text screening. Seven full text publications met the selection criteria and were included in the review (n = 793). The PRISMA flow diagram is shown in Fig. 1.
Fig. 1.
PRISMA Flowchart
Characteristics of included studies
Characteristics of the included studies are shown in Table 1. Five studies had a retrospective design [1, 2, 8, 22, 23] and two were prospective [7, 24]. Among them, three were published in abstract form [8, 23, 24]. The study population included 793 adult participants from four countries (Italy, Ireland, France, and Israel). Two articles reported patients with NSCLC [2, 8], three with melanoma [2, 7, 22], among three with RCC [2, 7, 24], among other malignancies described. Four articles reported use of single agent anti-PD-1 [7, 8, 22, 24] and three articles depicted use of anti-PD-1, anti-PD-L1, or anti-CTLA-4 (single or combination) [1, 2, 23]. The follow-up time was reported in two articles [22, 24] ranging from two to three months. Adverse events were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 in all of the included studies [5]. Three studies reported irAEs [1, 2, 7]. In the study led by Daly et al. [1] effect estimates for AEs and irAEs were distinguished. In all of the included studies, sarcopenia was evaluated using CT imaging to measure lumbar skeletal muscle area at the third lumbar vertebra (L3). Finally, different cut-offs were used to define sarcopenia within the included studies as follows: three studies [1, 7, 8] reported the cut-points described by Martin et al. [4] and Martin, Senesse et al. [20] which defines cut-offs of skeletal muscle index (SMI) according to the following subgroups: in individuals with body mass index (BMI) < 25 kg/m2, the cut-off of SMI is 43 cm2/m2 for men and 41 cm2/m2 for women; and for individuals with BMI > 25 kg/m2 the cut-off of SMI is 53 cm2/m2 for men and 41 cm2/m2 for women. Two other studies [22, 23] used the definition by Prado et al. [21] who demarcated a cut-off of SMI of 52.4 cm2/m2 for men and 38.5 cm2/m2 for women. Finally, two studies [2, 24] reported unique cut-points as outlined by the authors of those studies. Cortellini et al. [2] defined cutoffs of skeletal muscle index (SMI) according to the following subgroups: in individuals with BMI < 25 kg/m2 the cutoff of SMI was 48.4 cm2/m2 for men and 36.9 cm2/m2 for women; and for individuals with BMI > 25 kg/m2 the cut-off of SMI was 50.2 cm2/m2 for men and 59.6 cm2/m2 for women. Revel et al. [24] described a cut-point of SMI of 41 cm2/m2 though specifications for sex or BMI were not provided.
Table 1.
Characteristics of included studies
| Author, year | Country | Design | Number participants with sarcopenia | Number participants without sarcopenia | median age (years) | male/female (%) | Tumors | ICIs | Doses | median follow-up time | SMI (cm2/m2) | type adverse events | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Daly, et al. 2017 [1] | Ireland | ObR | 20 (23.8) | 64 (76.2%) | 54 (43–66) | 52 (62%) / 32 (38%) | 79% patients had stage M1c metastatic disease, with the most common metastatic sites being lung (70%) and liver (41%) | ipilimumab | 3 mg kg body weight over a 90-min period every 3 weeks for four doses | – | 51.4 (10.4) | Dermatologic/skin: pruritus, rash; gastrointestinal: diarrhoea, colitis; endocrine: hypothyroidism, hypopituitarism, hypophysitis; adrenal insufficiency; abnormal hepatic function; musculoskeletal: arthritis; other | BC and OS |
| Cortellini, et al. 2020 [2] | Italy | ObR | 50 (50%) | 50 (50%) | 66 (25–88) | 67 (67%) /33 (33%) | NSCLC (46%), melanoma (27%), RCC (46%) and others (12%) | anti-PD-1 (91%) anti-PD-L1 (9%) | – | – | 48.2 (28.2–95.2) | – | ORR, irAEs, PFS and OS |
| Hirsch, et al. 2020 [7] | France | ObP | 45 (51.7%) | 42 (48.3%) | 64.6 (56.3–69.8) | 58 (63%) /34 (37%) | Lung cancer, RCC, melanoma, others | nivolumab | 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity | – | 43.8 (39.3–50.4) | Respiratory: pneumonitis; gastrointestinal: colitis; musculoskeletal: arthralgia and myositis; acute renal failure; endocrine disorders: hypophysitis and diabetic ketoacidosis; other | SRT and BC |
| Strulov Shachar, et al. 2018 [8] | Israel | ObR | 52 (67%) | 26 (33%) | 67 (24–88) | – | Metastatic NSCLC | nivolumab | – | – | – | – | BC, PFS, OS |
| Heidelberger, et al. 2017 [22] | France | ObR | 34 (50%) | 34 (50%) | 65 (22–91) | 36 (53%) / 32 (47%) | Melanoma | nivolumab, pembrolizumab | 3 mg/kg-dose of nivolumab every 2 weeks or a 2 mg/kg-dose of pembrolizumab every 3 weeks intravenously | 3 months | – | interstitial pneumonitis, interstitial nephritis, polymyositi, hepatitis, uveitis, cytopenia and polyarthritis | ORR, ALT |
| Haik, et al., 2019 [23] | France | ObR | 167 (64%) | 94 (36%) | 61 | 198 (76%) /63 (24%) | metastatic solid tumors |
anti PD1, anti PD-L1, anti CTLA-4 and ICI combination |
– | – | – | – | PS, ORR, PFS, ST |
| Revel et al., 2018 [24] | France | ObP | 70 (61%) | 45 (39%) | 65 (19–87) | 60% / 40% | Lung, and renal cancer | anti-PD-1 | – | 2 months | – | – | PS and SRT |
*Of note, in the study by Eun [21], BMI was categorized based on the classification of weight by WHO in adult Asians: Underweight, BMI < 18.5 kg/m2; normal, 18.5 ≤ BMI < 23; overweight, 23 ≤ BMI < 25; obese, BMI ≥ 25
ALT, Acute limiting toxicity; BC, Body composition and risk of toxicity; BMI, Body mass index; HCC, Hepatocellular carcinoma; ICIs, Immune checkpoint inhibitors; irAEs, Immune-related adverse effects; N, Normal; NSCLC, Non-small cell lung carcinoma; O, Obesity; ObP, Observational prospective; ObR, Observational retrospective; ORR, Objective response rate; Ov, Overweight; PFS, Progression-free survival; PS, Performance status; OS, Overall survival; RCC, renal cell carcinoma; RF, Risk factors associated to irAEs; SRT, Sarcopenia and risk of toxicity; ST, Severe toxicities; TTF, Time to treatment failure; U, underweight
Study quality
Three studies were scored 7–9 (high quality) [1, 7, 22] and four studies [2, 8, 23, 24] were scored 6 (moderate quality) (Supplementary Table S2). The quality across all included studies was summarized in Supplementary Table S3. There was moderate quality of evidence in the included studies according to the GRADE quality of evidence (Supplementary Table S4).
Description of excluded studies
Seven studies were excluded from the review [9, 11, 25–29] (Supplementary Table S5). Among them: three studies had 30 or less participants, two studies did not link sarcopenia with adverse events, and two studies had insufficient data and the authors were not able to be reached by e-mail.
Sarcopenia and AEs
In a retrospective review of medical records, Daly et al. [1] described 84 patients with metastatic melanoma. Twenty-nine (34.5%) of the 84 patients were treated with ipilimumab as first-line treatment. The dosing regimen was 3 mg/kg of body weight administered intravenously over a 90-min period every 3 weeks for a total of four doses. Out of a total of 84 patients, twenty were considered sarcopenic (24%) according to the Martin et al. cut-points [4]. Even though there were no differences in the prevalence of grade 1 and 2 AEs between sarcopenic and non-sarcopenic patients, there was a statistically significant difference in the prevalence of high grade (grade 3 and 4) AEs in sarcopenic patients compared with those without (adjusted OR 5.34; 95% CI 1.15–24.88: p = 0.033). On the other hand, no significant difference was detected in the high grade (grade 3 and 4) irAEs that developed in the 2 groups.
Strulov et al. [8] investigated the association between body composition, outcomes and toxicity in 78 patients with metastatic NSCLC treated with nivolumab (regimen not specified). Among them, sixty seven percent of the patients were sarcopenic according to the cut-points established by Martin, Senesse et al. [20]. High grade AEs (grades 3 and 4) were reported in 15% of sarcopenic patients, and the difference in the risk of developing AEs between sarcopenic and non-sarcopenic groups was found to be statistically significant. Of note, while the adjusted OR was not shown, the authors reported the p value of the adjusted OR (p = < 0.0001).
In another retrospective study, Heidelberg et al. [22] described 68 patients with melanoma treated with either nivolumab (3 mg/kg-dose every 2 weeks) or pembrolizumab (2 mg/kg-dose every 3 weeks) as monotherapy. Thirty-four of 68 patients had sarcopenia according to the cut-points set by Prado et al. [21]. Eleven of the 68 patients developed AEs, among whom 6 (54%) were sarcopenic. The difference between groups of sarcopenic patients with and without AEs, however, was not found to be statistically significant.
Similarly, Haik et al. [23] defined sarcopenia in accordance with the cut-offs described by Prado et al. [21]. The authors retrospectively reviewed 261 patients with metastatic solid tumors, most of them (69%) with metastatic lung cancer, treated with anti-PD1, anti-PD-L1, anti-CTLA-4 agents or combination ICI therapy (regimen not described). In this study, the prevalence of sarcopenia was 64%. Thirty-six patients (14%) reported AEs, among which 23 patients (64%) had sarcopenia (adjusted OR 1.16; p = 0.71).
Revel et al. [24] published results from the French nationwide SCAN study, assessing the presence of an association between sarcopenia and AEs. They reported the results of a subgroup of 115 patients treated with anti-PD-1 agents (regimen not described). The study included 77 patients with lung cancer and 38 with renal cancer. Seventy percent of the patients had sarcopenia defined as SMI ≤ 41 cm2/m2. Notably, neither the criteria to used to establish the cut-off for sarcopenia nor different cut-points by sex were spelled out. Nonetheless, the authors reported that 5 (12.5%) patients with sarcopenia developed AEs in comparison with only 1 patient (1.5%) in the non-sarcopenic group (p = 0.05) and an increased risk in patients with a total muscle area < 144 cm2 (OR 7.74; 95% CI 1.01–92.79; p = 0.024). Table 2 summarizes the main findings reported in the included studies.
Table 2.
Findings reported in the included studies
| Author, year | SMI cut-points used | Relationship between Sarcopenia and AEs/irAEs | |
|---|---|---|---|
| AEs | irAEs | ||
| Daly, et al. [1] | cut-points described by Martin et al. [4] | Adjusted OR 5.34; 95% CI 1.15–24.88; p = 0.033 | Adjusted OR 2.17; 95% CI 0.58- 8.11; p = 0.248 |
| Cortellini, et al. [2] |
BMI < 25 kg/m2: 48.4 cm2/m2 for men and 36.9 cm2/m2 for women; BMI > 25 kg/m2: 50.2 cm2/m2 for men and 59.6 cm2/m2 for women |
– | 11 (22%) patients with sarcopenia and 14 (28%) patients without sarcopenia reported irAEs of any grade (p = 0.4906)*** |
| Hirsch, et al. [7] | cut-points described by Martin et al. [4] | – | Adjusted OR 3.84; 95% CI 1.02- 14.46; p = 0.047 |
| Strulov Shachar, et al. 2018 [8] | cut-points described by Martin, Senesse et al. [20] | Adjusted OR p = < 0.0001 | – |
| Heidelberger, et al. 2017 [22]* | cut-points described by Prado et al. [21] | 11 (16%) patients developed AEs, among whom 6 (54%) were sarcopenic (p = 1)*** | – |
| Haik, et al. [23] | cut-points described by Prado et al. [21] | OR = 1.16, p = 0.71 | – |
| Revel et al. [24]** | 41 cm2/m2 | 5 (12.5%) patients with sarcopenia developed AEs in comparison with only 1 patient (1.5%) without sarcopenia (p = 0.05)*** | – |
*There were differences in the occurrence of early acute limiting toxicity among groups of female patients with or without overweight sarcopenic (p = 0.01)
**There was a risk of developing acute limiting toxicity in patients with a total muscle area < 144 cm2 (OR 7.74; 95% CI 1.01–92.79; p = 0.024)
***OR was not reported
AEs, Adverse events; irAEs, Immune-related adverse effects. SMI, Skeletal muscle index
Sarcopenia and irAEs
Three studies [1, 2, 7] described the relationship between sarcopenia and irAEs in cancer patients treated with ICIs. In addition to looking at this relationship, Daly et al. [1] also evaluated the link between sarcopenia and AEs, identifying a significant association. The authors, nevertheless, did not find a statistically significant difference in the prevalence of high grade (grade 3 and 4) irAEs in patients with sarcopenia and in those without (adjusted OR 2.17; 95% CI 0.58–8.11: p = 0.248).
In addition, Cortellini et al. [2] conducted a retrospective study assessing 100 patients treated with anti-PD-1 and anti-PD-L1 agents. The median time of treatment duration was 3.4 months (dosing regimen not specified). Fifty patients (50%) had sarcopenia, defined as low SMI according with a newly computed SMI cut-point established by the authors in those with BMI > 25 kg/m2: SMI male > 50.2, SMI female > 59.6; and in BMI < 25 kg/m2: SMI male > 48.4, SMI female > 36.9. Twenty-five patients (25%) experienced irAEs of any grade. Among the 50 patients with sarcopenia, eleven patients (22%) developed irAEs. However, the difference between groups of sarcopenic and non-sarcopenic patients who had irAEs was not statistically significant.
Moreover, Hirsch et al. [7] prospectively reviewed the medical records of 87 patients who were treated with nivolumab for metastatic solid tumors of various origin. This study which outlined the dosing regimen as 3 mg/kg intravenously every 2 weeks, followed each case until disease progression or drug toxicity. The majority of patients (71.7%) had lung cancer. Forty-five patients (51.7%) were classified as sarcopenic according to the cut-points defined by Martin et al. [4]. Most of the patients who developed irAEs had sarcopenia compared with those without (adjusted OR 3.84; 95% CI 1.02–14.46, p = 0.047).
Discussion
To our knowledge, this is the first study to review the relationship between sarcopenia and both AEs and irAEs in cancer patients on ICI therapies. Our findings highlight the importance of considering the presence of sarcopenia as a potential risk factor for the development of both AEs and irAEs when initiating treatment with ICIs in cancer patients [3, 29–33].
The correlation between sarcopenia and irAEs in cancer patients on ICI therapies has been reported in several recent studies [1, 2, 7, 9, 29]. In this review, three studies [1, 2, 7] explore the association between sarcopenia and irAEs with the results showing a non-statistically significant association in two studies [1, 2]. Five studies described the relationship between sarcopenia and AEs in general, with no association identified in three of them [22–24] (Table 2). However, because of the small number of studies, further research is needed to validate the presence of relationship between sarcopenia and the risk of AEs and irAEs.
To date, little is known about the mechanisms by which sarcopenia influences the development of AEs. Studies estimate that close to half of patients with advanced cancers develop sarcopenia [29]. It has been linked with both inflammation and inadequate nutritional state, among other conditions, which may partially explain the increased treatment-related toxicities and the overall poorer survival [29]. Because skeletal muscle cells express major histocompatibility complexes which stimulate T cells, loss of skeletal muscle may disrupt the homeostatic balance [29, 34]. Moreover, the drop in myokines, especially IL-15, disturbs the tight balance of different T-cell subsets, most prominently NK cells. This effect is magnified by the replacement of muscle mass with adipose tissue, resulting in the secretion of adipokines, and a complex interplay of signaling that ultimately promotes a dysregulated inflammatory response. [35–37].
The limitations of this review include the small number of eligible studies, three of them reported in abstract form only [8, 23, 24]. Moreover, there were a number of single-center retrospective design studies [22, 23] and four of the included studies were deemed of moderate quality [2, 8, 23, 24]. Finally, the small number of studies and the differences in the specific cut-points used to define sarcopenia did not allow us to pool the data to support a valid meta-analysis. Despite these drawbacks, this is the first systematic review assessing the relationship between sarcopenia and AEs in patients receiving ICI therapies and incorporates studies which included patient populations of diverse ethnicities (Ireland, France, Italy, and Israel).
In conclusion, this systematic review identified the presence of a relationship between sarcopenia and AEs in those cancer patients treated with ICIs. In the studies that performed a multivariate analysis, the association was statistically significant [1, 8]. On the other hand, the differences between groups of sarcopenic and non-sarcopenic patients who developed irAEs were not statistically significant in two [1, 2] of the three included studies [1, 2, 7]. The small number of studies with different SMI cut-points defining sarcopenia and the lack of robust statistical evidence prevent us from making a conclusive statement about the relationship between sarcopenia and both AEs and irAEs. Nevertheless, the implications of this study are clinically relevant in suggesting a potential role for routine nutritional assessment at baseline and during the follow-up of patients treated with ICIs in order to minimize the elevated treatment risks associated with co-existent sarcopenia. Additional studies using large datasets and a common classification are needed to strengthen the association between AEs and sarcopenia and to help define targeted strategies to reduce the incidence of AEs and irAEs in patients with sarcopenia whose clinical picture warrants treatment with ICI therapies.
Supplementary Information
Below is the link to the electronic supplementary material.
Author contribution
All authors contributed to the study conception and design. Material preparation, data collection, analysis and validation were performed by Yuli Guzman-Prado, Jennifer Ben Shimol and Ondrej Samson. The first draft of the manuscript was written by Yuli Guzman-Prado and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Compliance with ethical standards
Conflict of interest
Yuli Guzman-Prado declares that she has no conflict of interest. Jennifer Ben Shimol declares that she has no conflict of interest. Ondrej Samson declares that he has no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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