Intratumoral para-toluenesulfonamide as a tumor-ablative therapy for equine cutaneous tumors: a case series of three horses

Highlights

• •Intratumoral para-toluenesulfonamide induced complete responses in fibroblastic sarcoid and penile squamous cell carcinoma, while the perianal melanoma achieved a partial response at the protocol-defined evaluation and complete clinical resolution during follow-up.
• •Treatment induced consistent tumor necrosis and sloughing in all cases.
• •Progressive wound healing resulted in complete re-epithelialization of treated lesions.
• •Treatment was well tolerated under field clinical conditions.
• •These findings support further investigation of intratumoral para-toluenesulfonamide as a minimally invasive treatment for equine cutaneous tumors.

Abstract

Equine neoplasia, including sarcoids, melanomas, and squamous cell carcinomas, presents therapeutic challenges due to recurrence and limitations of conventional treatments. Para-toluenesulfonamide (p-TLS) is a tumor-ablating agent that is associated with localized tumor necrosis and subsequent lesion resolution. It has been evaluated in human clinical settings as an intratumoral treatment of malignant airway obstruction caused by non-small cell lung cancer. This study aimed to describe the clinical outcomes and tolerability of intratumoral p-TLS in equine neoplasia. Three equine cases, including a fibroblastic sarcoid, perianal melanoma, and penile squamous cell carcinoma, were treated. The fibroblastic sarcoid and penile squamous cell carcinoma achieved complete response. The melanoma fulfilled the criteria for partial response at the protocol-defined clinical evaluation timepoint and subsequently demonstrated complete clinical resolution during follow-up. All cases demonstrated a consistent pattern of response characterized by tumor necrosis, sloughing, and subsequent wound healing with complete re-epithelialization. Local adverse effects were limited to transient inflammation and mild discomfort, which were effectively managed with supportive care. No severe adverse events or tumor recurrence were observed during the follow-up period ranging from 120 days to 15 months. These findings suggest that p-TLS may represent a feasible, highly minimally invasive intratumoral therapeutic approach for equine neoplasia and support further evaluation.

Introduction

Para-toluenesulfonamide (p-TLS) is a novel tumor-ablating small molecule that has demonstrated antitumor activity in human clinical studies and is currently under clinical evaluation as an intratumoral treatment for various types of cancers in both humans and companion animals (Li et al., 2016; Lin et al., 2022). p-TLS exerts its antitumor effects primarily through localized tumor ablation following intratumoral administration, characterized by disruption of tumor cell membrane integrity and subsequent tumor necrosis, resulting in reduction of tumor burden (Gao et al., 2013). In addition to its necrotic effects, p-TLS has been shown to induce apoptosis through mitochondrial dysfunction involving the pro-apoptotic proteins Bak and PUMA and inhibits both Akt-dependent and Akt-independent mTOR/p70S6K signaling pathways associated with cancer cell survival and proliferation (Hsu et al., 2018). It has also been shown to disrupt lipid raft integrity and alter cholesterol homeostasis, further contributing to its antitumor activity (Hsu et al., 2018). Studies in canine melanoma xenograft models have demonstrated increased apoptotic activity, including enhanced TUNEL staining, elevated cleaved caspase-3 expression, and decreased Bcl-2 expression, following p-TLS treatment (Lin et al., 2022). More recently, p-TLS has been reported to modulate hypoxia-associated pathways by downregulating carbonic anhydrase IX (CAIX), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) under hypoxic conditions, potentially contributing to its selective antitumor activity within the tumor microenvironment (Chen et al., 2023).

Equine neoplasia represents a significant clinical concern in equine practice, with cutaneous tumors accounting for a large proportion of diagnosed cases. Among these, sarcoids, squamous cell carcinomas (SCC), and melanomas are the most commonly reported tumor types in horses (Knottenbelt, 2005). Equine sarcoids are the most prevalent and are characterized by locally invasive growth and high recurrence rates, with surgical excision alone often resulting in recurrence rates ranging from approximately 20–80% depending on treatment modality (Ogłuszka et al., 2021). Similarly, SCC is a locally aggressive tumor in which achieving complete local control can be challenging, and local recurrence has been reported following treatment (O'Brien et al., 2026). Equine melanoma, particularly common in grey horses, may initially exhibit slow growth but can progress to locally invasive and metastatic disease (MacGillivray et al., 2002). Despite the availability of multiple treatment modalities, management of equine cutaneous tumors remains challenging, particularly when lesions are large, located in anatomically sensitive regions, or situated in areas where complete surgical excision may compromise function or cosmetic outcome. In these situations, alternative local treatment strategies that minimise tissue disruption while maintaining therapeutic efficacy may offer clinical advantages (Knottenbelt, 2005; Ogłuszka et al., 2021).

In this context, locally acting tumor-ablating agents such as p-TLS may offer a promising approach for the management of equine cutaneous tumors. By inducing localized tumor necrosis while minimizing damage to surrounding tissues, intratumoral therapies may address limitations associated with conventional treatments, particularly in cases where complete surgical excision is not feasible or recurrence is likely. However, the application of p-TLS in equine species has not been well characterized, and species-specific responses to treatment remain largely unknown.

Given the unique physiological and inflammatory responses observed in horses, careful consideration of treatment administration and post-procedural management is required. Therefore, an equine-specific treatment protocol was implemented, incorporating controlled intratumoral administration and supportive measures to optimize safety and tolerability. As an initial step in evaluating the potential of p-TLS for the treatment of equine cutaneous tumors, the present study aimed to describe clinical outcomes and tolerability of intratumoral p-TLS in equine neoplasia. Here, we report three equine cases treated with intratumoral p-TLS, including a fibroblastic sarcoid, a perianal melanoma at the tail base, and a squamous cell carcinoma, in order to evaluate tumor response, local tolerability and treatment-associated outcomes.

Methods

Ethical approval

This study was conducted under an exploratory, open-label clinical protocol approved by the Institutional Animal Care and Use Committee (IACUC) of National Pingtung University of Science and Technology (NPUST) (Approval No. IACUC-23009). Written informed consent was obtained from all horse owners prior to enrolment and treatment initiation. The study was performed in accordance with institutional guidelines for the ethical use of animals in research.

Case selection

This report describes a case series of three client-owned horses enrolled in an exploratory, open-label clinical study of intratumoral para-toluenesulfonamide (p-TLS). Horses presenting with superficial cutaneous tumors were prospectively screened for eligibility. Inclusion criteria were adapted from the study protocol and included histopathological confirmation of neoplasia, the presence of at least one lesion accessible for intratumoral administration, an estimated survival time exceeding three months, and suitability for sedation and local treatment as determined by the attending veterinarian. Histopathological diagnosis was established prior to treatment initiation using 14-gauge Tru-Cut core biopsy specimens obtained from representative lesions. Horses with severe systemic illness, uncontrolled comorbidities, pregnancy, concurrent cancer therapy, or conditions considered incompatible with study participation were excluded.

Consecutive horses meeting the eligibility criteria and whose owners consented to participation were considered for enrolment during the study period. No predefined upper limit for tumor size was specified in the exploratory protocol; treatment feasibility was determined according to lesion accessibility, anticipated safety, and the attending veterinarian's clinical judgement.

Tumors considered for treatment included equine sarcoids, melanomas and squamous cell carcinomas. Selection for treatment was based on tumor accessibility, anticipated limitations of conventional therapeutic approaches, owner preference following discussion of available treatment options, and the clinical judgement of the attending veterinarian.

Treatment protocol

All treatments were performed under field clinical conditions by attending veterinarians. Sedation, analgesia, and local or regional anesthesia were administered as required according to tumor location and patient temperament (Table 1).

Table 1.

Overview of p-TLS protocol under development for equine sarcoid, melanoma and squamous cell carcinoma.

Protocol component	Descriptions/comments
1. Patient restraint	•Sedation was performed at the discretion of the attending veterinarian using standard equine sedation protocols.
2. Analgesia	•Administered as required to minimize patient discomfort and movement during intratumoral injection
3. Tumor assessment	•Tumor volume was estimated using caliper measurements. Tumor volume (cm³) = length × width × height × 0.5
4. Dose determination	•p-TLS (330 mg/mL) was administered using an ITVR-guided approach. Tumor volume was estimated using caliper measurements, and the recommended injection volume corresponded to an ITVR of approximately 50%, while ensuring that the total administered dose did not exceed 30 mg/kg per treatment.
5. Dose administration	•The drug was delivered using standard intratumoral injection techniques to achieve adequate distribution within the lesion.
6. Treatment schedule	•Treatments were administered at approximately weekly intervals, with a maximum of 10 treatment sessions per horse. The total number of sessions was adjusted according to clinical response and the attending veterinarian's clinical judgement.
7. Concomitant medications	•Supportive medications, including anti-inflammatory agents (NSAIDs) and antibiotics, were administered as clinically indicated. NSAIDs were used in horses with clinically significant inflammatory responses, whereas antibiotics were reserved for suspected or confirmed secondary wound infection. Horses with uncomplicated dry tumor necrosis and no evidence of infection were managed with local wound care alone.

Prior to each treatment, tumor dimensions (length, width, and height) were measured using digital calipers to estimate tumor volume according to the modified ellipsoid formula:

$$\mathbf{Tumor}\mathbf{volume}\left(\mathbf{c}{\mathbf{m}}^{\mathbf{3}}\right)=\mathbf{length}\times \mathbf{width}\times \mathbf{height}\times \mathbf{0}.\mathbf{5}.$$

An injection-to-tumor volume ratio (ITVR) approach was used to guide intratumoral administration of para-toluenesulfonamide (p-TLS; investigational veterinary formulation, 330 mg/mL). ITVR was defined as the injected volume divided by tumor volume and expressed as a percentage. An ITVR target of approximately 50% was used to guide treatment planning, such that the intended injection volume corresponded to approximately 50% of the calculated tumor volume:

$$Targetinjectionvolume\left(mL\right)=tumorvolume\left(c{m}^3\right)\times 0.5$$

The calculated target volume served as a guide for treatment planning and could be modified at the discretion of the attending veterinarian according to tumor morphology, local tissue characteristics, and the practicality of achieving adequate intratumoral distribution. The total administered dose did not exceed the protocol-defined safety limit of 30 mg/kg per treatment established through interspecies dose conversion. Actual injected volumes administered to each case are summarized in Supplementary Table S2.

Para-toluenesulfonamide was delivered using standard multipoint intratumoral injection techniques to achieve adequate distribution throughout the lesion. Treatments were performed at approximately weekly intervals, and the total number of treatment sessions was determined according to tumor response and clinical judgement. Supportive care, including anti-inflammatory medications, wound management, and debridement of necrotic tissue when indicated, was provided throughout the treatment period. Patients were monitored for local and systemic treatment-related adverse effects during follow-up. Detailed treatment parameters are summarized in Table 2.

Table 2.

Clinical characteristics, treatment parameters, and outcomes of three equine cases treated with intratumoral para-toluenesulfonamide (p-TLS).

Case	Tumor type	Tumor location	Tumor volume (cm3)	Dose (mL per lesion)	Sessions	Necrosis onset	Treatment interval (days)	Outcome
1	Fibroblastic sarcoid	Right iliac	12.57	4	3	Day 7	7	CR
2	Perianal & tail base melanoma	(A)Perianal (B) Perianal (C) Tail Base	(A) 1.15 (B) 19.15 (C) 0.94	1 5 1	4	Day 5	6–8	CR PR CR
3	Penile Squamous Cell Carcinoma	Glans penis	6.78	5	6	Day 10	7–8	CR

CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

* Necrosis onset was defined as the first clinical observation of tumor discoloration, softening, or tissue breakdown following treatment.

*Complete response (CR) was defined as complete disappearance of all measurable or evaluable target lesions at the protocol-defined clinical evaluation timepoint (CV day).

Partial response (PR) was defined as a ≥ 30% decrease in the tumor volume of target lesions compared with baseline measurements.

Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Progressive disease (PD) was defined as a ≥ 20% increase in the tumor volume of target lesions or the appearance of new lesions.

Tumor response assessment

Treatment response was assessed according to modified VCOG-RECIST v1.0 criteria at the protocol-defined clinical evaluation timepoint (CV day), supplemented by serial clinical evaluations performed by the attending veterinarians throughout the treatment and follow-up periods. Assessments included gross lesion appearance, tumor measurements, photographic documentation, and evaluation of lesion characteristics.

Tumor responses were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Complete response was defined as the complete disappearance of all measurable or evaluable target lesions. Partial response was defined as at least a 30% reduction in the tumor volume of target lesions without meeting the criteria for CR or PD. Stable disease was defined as neither sufficient tumor shrinkage to qualify for PR nor sufficient increase to qualify for PD, corresponding to less than a 30% reduction and less than a 20% increase in the tumor volume of target lesion diameters. Progressive disease was defined as at least a 20% increase in the sum of tumor volume of target lesions or the appearance of new lesions indicative of tumor progression.

The durability of treatment responses was evaluated through follow-up examinations conducted at approximately 3-month intervals, incorporating serial photographic documentation and owner-reported outcomes when available.

Detailed case-specific information is provided in Supplementary Table S1 and S2.

Results

All three cases demonstrated tumor regression, with two achieving complete response and one partial response. Following treatment with p-TLS, tumors in all three equine patients demonstrated a consistent pattern of clinical response. This was characterized by early localized inflammatory changes at the treatment site, followed by tumor necrosis and sloughing, and subsequent wound healing with re-epithelialization.

The observed changes at th treatment site progressed in a predictable sequence, with initial swelling and erythema, followed by tissue breakdown and detachment of devitalized tumor mass, and eventual restoration of tissue integrity.

Fibroblastic sarcoid

A 10-year-old bay KWPN-cross mare presented in August 2024 with a raised, non-healing lesion on the right iliac region. The lesion was first noticed by the owner approximately four months prior to presentation and progressively enlarged, forming additional nodules with intermittent bleeding and discharge. Over time, the lesions coalesced into a single mass with continued enlargement and exudation. Fourteen-gauge Tru-Cut core biopsy samples were obtained from the lesion and submitted for histopathological examination, confirming the diagnosis of fibroblastic sarcoid.

The clinical progression of the fibroblastic sarcoid following p-TLS treatment is illustrated in Fig. 1. On Day 7, early post-treatment changes included surface necrosis and initial tissue discoloration (Fig. 1B). This was followed by progressive tumor breakdown, with evident necrosis and detachment of devitalized tissue, exposing the underlying dermis (Fig. 1C,D). By the third treatment (Day 15), marked wound contraction with reduction in lesion size and re-epithelialization at the margins was observed (Fig. 1F). At the latest follow-up (65 weeks later) the lesion had completely healed, with full epithelialization and hair regrowth (Fig. 1G). No evidence of local recurrence or development of new lesions was observed during the follow-up period (65 weeks), and no changes in behavior or general health status were reported by the attending veterinarian or owner.

Fig. 1.

(A) tumor before treatment; (B,C) Early post-treatment changes with tumor necrosis and sloughing; (D) Partial lesion detachment with exposure of underlying tissue; (E, F) Granulation tissue formation and progressive wound contraction; (G) Healed lesion at 15 months post-treatment, showing complete epithelialization; (H) histopathology confirming the diagnosis as a sarcoid.

Tail base & perianal melanoma

A 20-year-old gray Belgian pony gelding with no prior medical history presented in December 2024 with multiple raised, black, nodular masses around the tail base and perianal region. The lesions were first noticed approximately six months prior to presentation. Fourteen-gauge Tru-Cut core biopsy samples were obtained from representative lesions and submitted for histopathological examination, confirming the diagnosis of melanoma. Clinically, the distribution of multiple perianal and tail-base lesions in an older grey horse was consistent with dermal melanomatosis. Because the diagnosis was based on Tru-Cut biopsy specimens rather than complete excision, further histopathological classification as benign or malignant could not be determined.

The clinical progression of tail base and perianal melanoma following p-TLS treatment is shown in Fig. 2, 3. Prior to treatment, multiple nodular, pigmented masses were observed in the perianal region and tail base, with variable sizes and well-defined margins (Fig. 3A, B). After the first few treatments, early changes included localized swelling, discoloration, and surface necrosis within the first few days (Fig. 2, Fig. 3, Days 1 and 5). These changes progressed to evident tumor necrosis and crust formation, with gradual softening and breakdown of the lesion structure (Fig. 2, Fig. 3, Days 9 and 15).

Fig. 2.

Temporal progression of perianal melanoma following intratumoral p-TLS treatment. Sequential images demonstrate progressive tumor necrosis, sloughing, and wound healing from Day 1 to Day 120. Early stages show swelling and discoloration, followed by necrosis and tissue breakdown (Days 5–23). Continued sloughing and wound contraction are evident through intermediate time points (Days 30–80), culminating in complete healing with re-epithelialization and no visible recurrence was observed during the follow-up period, Day 120.

Fig. 3.

Temporal progression of tail base melanoma following intratumoral p-TLS treatment. Sequential images demonstrate the evolution of the lesion from Day 1 to Day 120. Early treatment stages showed localized swelling and discoloration (Days 1–5), followed by progressive necrosis and crust formation (Days 9–23). Continued tissue sloughing and wound contraction are evident at intermediate time points (Days 30–80), with subsequent re-epithelialization and restoration of normal skin appearance by Day 120.

Between Days 15 and 30, progressive sloughing of devitalized tumor tissue was observed, accompanied by exposure of the underlying tissue and reduction in lesion volume (Fig. 2, Fig. 3, Days 23 and 30). In some areas, partial detachment of necrotic tissue resulted in open wound beds, which subsequently demonstrated healthy granulation tissue formation. Continued wound contraction was evident during intermediate time points (Fig. 2, Fig. 3, Days 30–80), with progressive reduction in lesion size and improvement in surrounding tissue condition (Fig. 2, Fig. 3, Days 30 and 80).

At later stages, both perianal and tail base lesions showed marked healing, with re-epithelialization and restoration of normal skin architecture (Fig. 2E and 3, Day 120). The treated areas exhibited smooth skin surfaces with no visible residual tumor mass. Hair regrowth was observed in previously affected regions, indicating restoration of normal integumentary structure.

At the protocol-defined clinical evaluation timepoint (CV day), lesion A and C achieved complete response (CR), whereas lesion B fulfilled the criteria for partial response (PR) according to modified VCOG-RECIST v1.0. Continued regression and re-epithelialization were subsequently observed during extended follow-up, with no visible local recurrence detected up to Day 120. Throughout the follow-up period, no evidence of local recurrence or development of new lesions was detected. Additionally, no adverse systemic effects or changes in behavior, appetite, or general health status were reported by the attending veterinarian or owner.

Penile squamous cell carcinoma

A 10-year-old white pony stallion presented in May 2025 with multiple proliferative nodular lesions affecting the penile shaft. The lesions were first noticed by the trainer approximately one month prior to presentation, particularly during urination, and were reported to have progressively increased in number and size over time. Based on their appearance and location, squamous cell carcinoma (SCC) was suspected and subsequently confirmed by histopathological examination.

The clinical progression of the penile squamous cell carcinoma following intratumoral p-TLS treatment is illustrated in Fig. 4.

Fig. 4.

Temporal progression of penile squamous cell carcinoma following intratumoral p-TLS treatment. The lesion appeared as a proliferative, nodular mass with surface disruption and localized inflammatory changes (Day 1 and 8). Marked tumor necrosis and tissue sloughing were observed, accompanied by a visible reduction in tumor volume (Day 15 and 22). Continued regression was evident, with substantial loss of tumor mass and improvement in local tissue contour (Day 29 and 37). Near-complete resolution of the lesion was observed, with restoration of tissue architecture and only mild residual surface irregularities at the treatment site (Day 173 and 294).

The lesion presented as a large, irregular, exophytic mass involving the distal penile tissue, with several smaller surrounding nodules. The lesion had a proliferative surface and was associated with marked distortion of normal tissue architecture (Fig. 4, Day 1). Following the first treatment, localized swelling and erythema were observed at the treatment site (Fig. 4, Day 5 and 9).

Extensive tumor necrosis and tissue sloughing were observed, with exposure of underlying tissue and a clear reduction in tumor volume. (Fig. 4, Day 15 and 22)

Continued tumor regression was evident with subsequent treatments. There was substantial loss of tumor mass with improvement in local tissue contour (Fig. 4, Day 29 and 37). The lesion was reduced to small residual nodular areas, with evidence of re-epithelialization and tissue contraction.

Near-complete resolution of the lesion was observed. The treated area demonstrated restoration of a more normalized tissue architecture, with smooth surface contour and no visible proliferative tumor mass. Residual changes were limited to mild surface irregularities and localized tissue remodeling at the previous tumor site (Fig. 4, Day 173 and 294).

Discussion

In this preliminary study, application of intratumoral p-TLS protocol was associated with resolution of three equine cutaneous tumors, including a fibroblastic sarcoid, a tail base and perianal melanoma, and a penile squamous cell carcinoma. The fibroblastic sarcoid and penile squamous cell carcinoma achieved complete response at the protocol-defined clinical evaluation timepoint, whereas the melanoma fulfilled the criteria for partial response before demonstrating continued regression and complete clinical resolution during follow-up. All cases exhibited progressive tumor regression followed by wound healing, with favorable cosmetic and functional results at the treatment sites.

In all cases, tumor response followed a broadly consistent clinical course. Early localized swelling and erythema were typically observed at the treatment site, followed by progressive tumor necrosis and sloughing, and ultimately wound healing with re-epithelialization. A similar sequence of changes has been described for p-TLS in other tumor types and species, including human and experimental models (Li et al., 2016; Lin et al., 2022). These findings support the potential of intratumoral p-TLS as a minimally invasive local ablative therapy, particularly in cases where surgical intervention is not feasible or associated with high recurrence risk. Supportive care was individualized according to clinical findings rather than administered routinely. NSAIDs were prescribed only for horses exhibiting clinically significant inflammatory responses, whereas antibiotics were reserved for cases with suspected or confirmed secondary wound infection, such as purulent discharge or abscess formation. Horses with uncomplicated tumor necrosis, characterized by dry necrotic tissue without clinical or laboratory evidence of infection, were managed with local wound care alone. This individualized approach reflects routine equine clinical practice and may have contributed to effective wound healing while avoiding unnecessary systemic medication.

The pattern of tumor regression observed here is consistent with the proposed mode of action of p-TLS, which involves induction of tumor cell death and subsequent necrosis (Gao et al., 2013). In addition, effects on tumor-associated hypoxia pathways may contribute to its localized activity within the tumor microenvironment (Chen et al., 2023).

No severe adverse events were observed in any of the cases, and all treatment sites healed without the need for intensive intervention. Although the follow-up period was limited, no evidence of tumor recurrence was identified. Notably, the melanoma case fulfilled PR criteria at the predefined evaluation timepoint despite continued regression thereafter, ultimately resulting in complete clinical resolution during follow-up. This finding illustrates the potential limitations of fixed response assessments in exploratory studies involving intratumoral therapies associated with delayed tissue necrosis, sloughing, and wound remodeling. Consequently, protocol-defined evaluation schedules may underestimate the final therapeutic outcome in some cases, highlighting the importance of incorporating longer-term follow-up assessments when interpreting treatment response. This study has several limitations. The small sample size and heterogeneity of tumor types limit the generalizability of the findings. Additionally, the absence of a control group precludes definitive conclusions regarding treatment efficacy. Histopathological confirmation of complete tumor resolution was not performed following treatment, and therefore microscopic residual disease cannot be excluded. Further studies involving a larger and more diverse equine population are needed to better define optimal dosing and administration strategies, and to more robustly assess the safety and clinical efficacy of p-TLS. Such investigations will be important in clarifying the potential role of p-TLS as a minimally invasive treatment option for equine cutaneous tumors.

Ethics statement

The study was conducted in accordance with applicable animal welfare regulations and under an approved clinical protocol. Owners provided informed consent for inclusion of their animals and for publication of case data.

Informed consent

Owners gave explicit consent for inclusion of their animal in the report

Publisher’s note

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Funding information

This study was supported by Gongwin Biopharm Co., Ltd. Clinical case management and veterinary services were conducted in collaboration with the National Pingtung University of Science and Technology (NPUST), Taiwan, and 20 Cents Equine Practice, Kaohsiung, Taiwan.

CRediT authorship contribution statement

Hsiao-Chien Lo: Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Data curation. Hsuuw Yan-Der: Visualization, Project administration, Investigation, Data curation. Pei-Ling Chang: Data curation. Mao-Yuan Lin: Writing – review & editing, Visualization, Funding acquisition, Formal analysis, Data curation. So Kee: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Funding acquisition, Formal analysis, Data curation.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for this journal and was not involved in the editorial review or the decision to publish this article.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.