Secondary cutaneous involvement in peripheral T-cell lymphoma: Diagnostic frameworks,staging integration,and therapeutic implications

Abstract

The occurrence of secondary cutaneous manifestations in peripheral T-cell lymphoma (PTCL) is relatively infrequent and can resemble benign dermatoses, leading to diagnosis delays. We present the case of a 78-year-old female patient with a diagnosis of PTCL affecting the left parotid gland, who experienced a 2-day sudden and intensely pruritic skin eruption, which progressed from both forearms to the trunk, involving more than 50% of the total body surface area. Initially, the eruption was managed as a hypersensitivity reaction with antihistamines and corticosteroids, with temporary symptomatic relief; however, the rapid clinical progression in the context of an established diagnosis of PTCL raised suspicion of secondary cutaneous involvement. Previous pathological examinations indicated a mature T-cell phenotype (CD2⁺/CD3⁺/CD5⁺/TCRβF1⁺), partial expression of CD4, loss of CD7 in larger cells, minimal CD30 expression (10%), and a high proliferative index (Ki-67 70%). Imaging studies demonstrated persistent disease in the parotid gland and partially necrotic cervical lymph nodes, without evidence of distant metastasis. Considering significant cardiac comorbidities and CD30 expression, an anthracycline-sparing, CD30-targeted therapeutic approach was chosen. Treatment with brentuximab vedotin yielded early alleviation of pruritus and progressive resolution of lesions by the third cycle, with favorable tolerability. This case serves as a foundation for a narrative review that underscores the diagnostic challenges associated with “allergic-appearing” eruptions in patients with T-cell lymphoma, the importance of integrated staging utilizing TNMB (skin/blood) in conjunction with Lugano/Deauville positron emission tomography–computed tomography to assess systemic burden and therapeutic response, and biologically informed systemic therapy options aligned with comorbidities, including emerging targeted treatment strategies.

Keywords

peripheral T-cell lymphoma skin neoplasms cutaneous lymphoma CD30-directed therapy

Introduction

Primary cutaneous lymphomas (PCLs) are distinguished by their confinement to the cutaneous region at the time of diagnosis, whereas secondary cutaneous involvement indicates the spread from systemic or nodal lymphoma, typically requiring systemic therapeutic interventions rather than exclusive skin-targeted approaches. The WHO–EORTC 2018 update offers a widely accepted framework for the nomenclature of PCLs, while the WHO fifth edition (2022), in conjunction with the International Consensus Classification, further standardizes the classification of lymphoid neoplasms across the domains of dermatology, hematology, and pathology.^1,2

Cutaneous infiltration by peripheral T-cell lymphoma (PTCL) is relatively rare but has significant clinical relevance: it may manifest with features akin to hypersensitivity reactions and has been linked to poorer prognostic outcomes compared with primary cutaneous T-cell lymphoma (CTCL). These clinical manifestations underscore the imperative for prompt recognition, clinicopathologic correlation, and comprehensive staging to inform the selection of systemic treatment modalities.^3,4

This narrative review employs a succinct, case-specific vignette concerning the potential secondary cutaneous involvement by PTCL to formulate a clinically focused methodology for diagnosis, comprehensive staging (including TNMB evaluation of both cutaneous and hematologic involvement in conjunction with Lugano positron emission tomography–computed tomography (PET–CT) employing Deauville scoring for systemic pathology), and personalized therapeutic decision-making for patients presenting with significant comorbid conditions, with particular emphasis on CD30-targeted interventions and advancing treatment modalities.

Background

In 1806, Jean-Louis Alibert first described mycosis fungoides (MF), delineating a persistent scaly dermal eruption that progresses to neoplasms resembling mushrooms.³ In 1975, Lutzner et al. coined the term CTCL to categorize T-cell-derived lymphomas primarily afflicting the integumentary system, with a particular emphasis on MF and Sézary syndrome (SS).⁵

From an epidemiological perspective, MF exhibits a male predominance of ∼2:1, with a median age at the time of diagnosis occurring in the mid-50s; various cohorts indicate a heightened incidence and poorer prognostic outcomes among Black/African American patients in comparison to White or Asian counterparts. Human T-lymphotropic virus type 1 is associated with adult T-cell leukemia/lymphoma; however, its role in the pathogenesis of classic MF remains unproven.^6,7

A prominent pathogenic hypothesis posits that persistent antigenic stimulation of skin-resident CD4⁺ memory T cells plays a critical role. As the disease advances, immune dysregulation becomes evident, characterized by compromised antigen-specific responses and diminished cytotoxicity, which may facilitate tumor progression.^8,9 The early diagnosis of MF continues to pose significant challenges due to the fact that clinical and histopathological characteristics may resemble those of inflammatory dermatoses, frequently necessitating clinicopathologic correlation and serial biopsies over an extended duration.¹⁰

Clinical anchor

A 78-year-old woman with previously diagnosed PTCL involving the left parotid gland developed an abrupt, intensely pruritic eruption over 2 days, progressing from the forearms to involve more than 50% of the body surface area. Examination revealed widespread erythematous patches and plaques with sparing of the palms, soles, and mucous membranes, accompanied by left cervical lymphadenopathy (Figures 1 and 2). Initial treatment as a hypersensitivity reaction resulted in only transient improvement.

Figure 1.

Diffuse erythematous eruption involving the back and chest, with scattered papules and plaques consistent with widespread truncal cutaneous involvement by peripheral T-cell lymphoma.

Figure 2.

(Left) Erythematous, slightly scaly plaques on the forearm consistent with cutaneous involvement of PTCL. (Right) Visible left parotid mass reflecting nodal involvement by PTCL.

Her oncologic history was notable for biopsy-confirmed PTCL with a mature T-cell immunophenotype and low-level CD30 expression, persistent cervical and parotid nodal disease on imaging, and significant cardiovascular comorbidities limiting anthracycline use. In the setting of known systemic PTCL and rapid cutaneous progression, secondary cutaneous involvement was favored. The patient ultimately initiated palliative, CD30-directed therapy with brentuximab vedotin, achieving marked improvement in pruritus and skin lesions by the third cycle, with good tolerability under cardio-oncology guidance.⁴

Diagnostic pitfalls and differential diagnosis

Timely recognition of cutaneous involvement by T-cell lymphomas is often delayed due to substantial clinicopathologic overlap with benign inflammatory dermatoses. Acute, pruritic, “allergic-appearing” eruptions are frequently managed with antihistamines and corticosteroids; however, transient symptomatic improvement does not exclude malignant cutaneous disease, particularly in patients with known systemic T-cell lymphoma. Maintaining diagnostic vigilance and clinicopathologic correlation is essential to avoid missed or delayed diagnosis.¹¹

Secondary cutaneous involvement by PTCL should be suspected in patients with established nodal disease who develop rapidly progressive, extensive skin involvement accompanied by lymphadenopathy or supportive imaging findings. However, because nonspecific lymphoma-associated eruptions may also improve with systemic PTCL therapy, the clinical response to brentuximab vedotin should be interpreted as supportive but not diagnostic of secondary cutaneous PTCL involvement in the absence of skin biopsy.

Primary CTCLs, including MF and SS, are generally less likely in the setting of known systemic PTCL and abrupt disease tempo; SS additionally requires formal assessment of peripheral blood involvement, including B2 classification.^12,13

Common inflammatory mimics such as drug eruptions, hypersensitivity reactions, and psoriasis may present with overlapping morphologic features but are typically distinguished by medication exposure history, characteristic distribution or scaling patterns, and the absence of progressive nodal disease.¹⁴ Importantly, partial or transient response to corticosteroids does not reliably differentiate benign from malignant cutaneous processes.

Role of skin biopsy in suspected cases

Histopathologic confirmation via skin biopsy remains the gold standard for establishing secondary cutaneous involvement of PTCL. However, in real-world clinical settings, biopsy may not always be feasible due to patient-related factors, clinical instability, or therapeutic decision-making constraints. In such cases, clinicians may rely on a combination of clinical evolution, disease context, imaging findings, and response to systemic therapy to support a diagnosis of suspected secondary involvement. Nonetheless, the absence of histologic confirmation represents a limitation and should be acknowledged explicitly.^13,14

Distinguishing CTCL from secondary cutaneous involvement of PTCL

Primary CTCLs, particularly MF and SS, arise in the skin and typically follow a chronic, indolent course, especially in early-stage disease.^1,12,13 By contrast, systemic PTCLs may involve the skin secondarily as part of disseminated disease and should be evaluated as systemic lymphomas rather than PCLs.^2,3

These entities differ in staging, prognosis, and management. CTCL is staged using the TNMB classification system, which evaluates skin, nodal, visceral, and blood involvement.^12,13 By contrast, systemic PTCL is staged using the Lugano classification, and TNMB should not be applied in this context. Misclassification may lead to inappropriate staging and therapeutic decision-making.^2,3,12

Staging approach: Integrating TNMB with Lugano/Deauville

Precise classification and staging guide management are of paramount importance. For primary CTCL, particularly MF and SS, the TNMB classification system (skin T, nodes N, viscera M, blood B) remains as the definitive standard. A significant blood tumor burden (B2), as delineated by the International Society for Cutaneous Lymphomas criteria utilizing Sézary cell counts, flow cytometry anomalies, and/or T-cell clonality, escalates the disease to stage IV and affects the strategic approach to systemic therapies and eligibility for clinical trials.^12–15

By contrast, systemic PTCL with suspected secondary cutaneous involvement should be staged using the Lugano classification, which incorporates PET-CT assessments of overall disease extent and response evaluation employing Deauville criteria. Applying TNMB to systemic PTCL may result in misclassification and inappropriate management.^{11,12,16–19}

Treatment principles: CTCL versus PTCL with secondary skin involvement

Therapeutic interventions must be aligned with the specific stage of the disease and the extent of tumor burden. Skin-directed therapies (e.g. topical corticosteroids, topical mechlorethamine, and phototherapy) are considered suitable for localized CTCL, whereas more advanced cases of CTCL and systemic PTCL with cutaneous dissemination generally require systemic therapy.¹⁴

Randomized controlled trials substantiate the efficacy of targeted systemic therapies: brentuximab vedotin demonstrated higher response rates and prolonged progression-free survival compared with physician’s choice in patients with CD30-expressing CTCL (ALCANZA), while mogamulizumab showed improved progression-free survival compared with vorinostat in patients with relapsed MF/SS (MAVORIC). In the context of systemic PTCL, the frontline regimen A + CHP yielded superior progression-free and overall survival outcomes compared to CHOP in CD30-positive subtypes (ECHELON-2).^14,15,20,21

In advanced CTCL, additional systemic and adjunctive therapies play a critical role, including retinoids such as bexarotene, interferon-based therapies, extracorporeal photopheresis, localized radiotherapy, and hematopoietic stem cell transplantation in selected patients. These approaches highlight the importance of individualized treatment strategies based on disease subtype, stage, and patient comorbidities.^13,14,18

This clinical case reinforces the critical role of decision-making, that is, cognizant of comorbidities: given the patient’s reduced ejection fraction and ∼10% CD30 expression, a strategy that spares anthracyclines while targeting CD30 with brentuximab vedotin was chosen, resulting in early clinical amelioration of pruritus and skin lesions by the third treatment cycle. Continued management should encompass response-adapted reassessment and the incorporation of multidisciplinary perspectives (including input from cardio-oncology) to optimize the balance between therapeutic efficacy and safety.^{14,15,20–22}

Therapeutic targets and emerging strategies in CTCL/PTCL (Table 2)

CTCL and PTCL exhibit molecular heterogeneity characterized by recurrent alterations that converge upon T-cell receptor signaling, NF-κB, and JAK/signal transducer and activator of transcription (STAT) pathways. In addition to traditional chemotherapy, the utilization of precision therapies and immunotherapeutic strategies is progressively impacting clinical management, particularly pertinent for elderly patients, those with treatment-limiting comorbidities, or individuals with relapsed or refractory disease (Table 1).²³

Table 1.

Selected targeted and immunotherapeutic agents in CTCL/PTCL, highlighting molecular targets and the clinical or translational rationale supporting their use.

Target	Why
CD30 – brentuximab vedotin	Guideline-backed, case-relevant
CCR4 – mogamulizumab	Phase III data
KIR3DL2 – lacutamab	Late-phase, highly specific
miR-155 – cobomarsen	Translational but biomarker-relevant

CCR4: C–C motif chemokine receptor 4; CTCL: cutaneous T-cell lymphoma; PTCL: peripheral T-cell lymphoma.

Table 2.

Therapeutic targets and emerging strategies in CTCL/PTCL.^15,24–37

Target/pathway	Mechanism/rationale in CTCL/PTCL	Lead therapy (examples)	Key evidence (trial/phase)	Common/notable AEs	Practical notes (incl. patient fit)
miRNA (miR-155 and signature panels)	miR-155 overexpression links STAT signaling to malignant T-cell proliferation; multi-miR signatures (155/21/199/214/486) help discriminate malignant vs benign	Cobomarsen (MRG-106, anti-miR-155)	Positive phase 1; multicenter phase 2 ongoing	Local reactions; cytopenias (class effect, under investigation)	Biomarker-driven approach; commonly requires clinical trial access
CD30 (TNFR family)	Pro-survival signaling; variable expression in MF/SS, high in ALCL; defines an actionable subset	Brentuximab vedotin (anti-CD30 ADC)	ALCANZA (phase 3): BV superior to physician’s choice in CD30+ CTCL	Neuropathy; cytopenias; infusion reactions	Greater benefit when CD30 is present; monitor neuropathy; if combined with anthracycline (PTCL), consider cardiac comorbidity
CCR4 (skin homing)	CCL17/CCL22 recruit malignant T cells to the skin; overexpression is linked to worse prognosis	Mogamulizumab (anti-CCR4)	MAVORIC (phase 3): improved PFS vs vorinostat in MF/SS	Rash; infusion reactions; GVHD risk if subsequent transplant	Useful when CD30 is low; suitable for systemic disease; consider transplant planning
Immune checkpoints (PD-1/PD-L1; CTLA-4, TIM-3, LAG-3)	Exhaustion signatures in tumor/TME; heterogeneous checkpoint biology	Pembrolizumab; other ICIs	CITN-10 (phase 2, single arm) showed responses; rare hyperprogression was described	irAEs (dermatitis, colitis, endocrinopathies); possible flares/exacerbations	Consider genomic/immune profiling; counsel about hyperprogression risk
CD47–SIRPα (innate “do-not-eat-me”)	CD47 blocks macrophage phagocytosis via SIRPα	TTI-621 (SIRPα-Fc)	Phase 1: preliminary activity in lymphomas, including CTCL	Thrombocytopenia; infusion reactions	Promising combinations with antibodies that enhance ADCP
Cytokine axes (IL-15, IL-13; Th2 shift)	IL-15 supports survival; IL-13 autocrine growth; progression with Th2 bias (IL-4/5/10/13) contributing to pruritus and immune dysregulation	JAK/STAT inhibitors; IL antagonists (early stage)	Translational/early evidence (IL-15/IL-13 dependence)	Class AEs (cytopenias, transaminase elevations)	May improve pruritus and underlying biology; trial access commonly required
KIR3DL2 (CD158k)	Inhibitory receptor enriched in SS and present in MF; selective tumor marker	Lacutamab (IPH4102)	Positive phase 1; confirmation in TELLOMAK	Generally well tolerated; infusion reactions	Requires target expression (companion Dx); typically clinical-trial setting
Cellular engineering/innate engagers	Redirect cytotoxic effectors (CAR-T/NK) to antigens (CD30, CD70, CD4, TRBC1/2)	CAR-T; AFM13 (CD30 × CD16A) ± allogeneic NK	Early signals; AFM13 active in R/R PTCL and in combination with NK	Cytopenias; CRS/ICANS (CAR-T); infusion reactions	Consider in CD30+ disease and trial settings; logistics/eligibility important

STAT: signal transducer and activator of transcription; MRG: miRNA regulator gene; MF/SS: mycosis fungoides/Sézary syndrome; ALCL: anaplastic large cell lymphoma; ADC: antibody–drug conjugate; ADCP: antibody-dependent cellular phagocytosis; BV: brentuximab vedotin; CCL: C–C motif chemokine ligand; CCR4: C–C motif chemokine receptor 4; PFS: progression-free survival; GVHD: graft-versus-host disease; TME: tumor microenvironment; PD-1/PD-L1: programmed death-1/programmed death-ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; TIM-3: T-cell immunoglobulin and mucin-domain containing-3; LAG-3: lymphocyte activation gene-3; SIRPα: signal regulatory protein alpha; ICIs: immune checkpoint inhibitors; TTI-621: Trillium Therapeutics compound #621; CITN: Cancer Immunotherapy Trials Network; irAE: immune-related advserse event; IL: interleukin; AE: adverse effects; IPH4102: International Patent Holder 4102; CAR-T: chimeric antigen receptor T-cell therapy; NK: natural killer; TRBC1/2: T-cell receptor beta constant 1/2; AFM13: Affimed 13; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; miRNA: microRNA; CTCL: cutaneous T-cell lymphoma; PTCL: peripheral T-cell lymphoma.

MicroRNA pathways (miR-155 and others)

MicroRNAs (miRNAs) function as post-transcriptional regulators and possess considerable potential as both biomarkers and therapeutic targets. Dysregulation of miR-155 is observed across various subtypes of CTCL, establishing a connection between upstream STAT signaling and the proliferation of malignant T-cells. Cobomarsen (MRG-106), an antisense inhibitor targeting miR-155, has demonstrated on-target effects as well as preliminary clinical indications, thereby endorsing its continued assessment in a multicenter framework. The characterization of miRNA signatures (e.g. miR-155/21/199/214/486) may facilitate the differentiation between malignant conditions and benign inflammatory dermatoses, ultimately guiding therapeutic decision-making.^24,25

CD30 and antibody–drug conjugates

CD30 expression varies across MF/SS and is high in anaplastic large-cell lymphoma. The anti-CD30 antibody–drug conjugate brentuximab vedotin improved outcomes versus the physician’s choice in CD30-positive CTCL (ALCANZA) and is incorporated into frontline regimens for selected CD30-positive PTCL subtypes (ECHELON-2). Toxicities include peripheral neuropathy, cytopenias, and infusion reactions, with practical emphasis on neuropathy monitoring and comorbidity-driven avoidance of anthracyclines when indicated.^14,15,20,21

C–C motif chemokine receptor 4 and trafficking blockade

C–C motif chemokine receptor 4 (CCR4) supports skin homing via C–C motif chemokine ligand 17 (CCL17)/CCL22 and is associated with disease severity. Mogamulizumab (anti-CCR4) improved progression-free survival versus vorinostat in previously treated MF/SS (MAVORIC). Notable adverse events include rash and infusion reactions; graft-versus-host disease risk is relevant if an allogeneic transplant is later considered.²⁶

Immune checkpoints and T-cell exhaustion

Advanced CTCL often shows exhaustion signatures (programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4, T-cell immunoglobulin and mucin-domain containing-3, lymphocyte activation gene-3) within the tumor and microenvironment. Pembrolizumab has produced durable responses in a subset of relapsed/refractory MF/SS; however, hyperprogression after PD-1 blockade has been reported, emphasizing careful patient selection and informed consent.^27–29

Innate immune checkpoint: CD47–signal regulatory protein alpha axis

CD47 overexpression can enable immune evasion by inhibiting macrophage phagocytosis. The signal regulatory protein alpha-Fc decoy TTI-621 demonstrated acceptable safety and preliminary activity in early-phase trials that included T-cell and cutaneous lymphomas, supporting further evaluation alone or in combination regimens enhancing antibody-dependent cellular phagocytosis.³⁰

Cytokine circuits (interleukin-15, interleukin-13, Th1 → Th2 shift)

Cytokine networks contribute to disease persistence and symptoms. Interleukin-15 (IL-15) acts as a survival/growth factor and has been implicated in CTCL biology; IL-13 is overexpressed in lesional skin and can function as an autocrine growth factor. Disease progression often reflects a Th2-skewed milieu (IL-4/-5/-10/-13), potentially linking immune dysregulation with pruritus and offering rationale for cytokine- and JAK/STAT-focused strategies.^31–33

KIR3DL2 targeting

KIR3DL2 (CD158k) is upregulated in CTCL, particularly SS, providing a selective tumor marker. Lacutamab (International Patent Holder 4102) has demonstrated clinical activity and tolerability in phase-1 evaluation, with ongoing confirmation in TELLOMAK. Target expression assessment is essential.³⁴

Engineered cellular immunotherapies and bispecifics

Chimeric antigen receptor T-cell therapy strategies for T-cell malignancies face challenges, including antigen overlap with normal T cells, fratricide, and manufacturing contamination. Emerging designs targeting CD70, CD4, or T-cell receptor beta constant 1/2 with safety switches are entering early clinical evaluation. Bispecific innate cell engagers (e.g. CD30 × CD16A engager Affimed 13 (AFM13)/acimtamig) have shown activity in relapsed PTCL, and combinations with allogeneic natural killer (NK) cells show promising signals, supporting a growing role for NK-cell redirection strategies in CD30-expressing disease.^35–37

Epidemiology

CTCL are rare extranodal non-Hodgkin lymphomas with low, relatively stable incidence. Population registries estimate overall CTCL incidence around 0.3–1.0/100,000 person-years, with MF as the predominant subtype;Surveillance, Epidemiology, and End Results (SEER)-based analyses place MF near 0.5–0.6/100,000 and suggest rising case ascertainment, likely suggesting better recognition. Median age is mid-50s to early-60s, with male predominance (1.6–2:1).^7,38,39

Racial/ethnic disparities are consistently reported. Black/African American patients have a higher incidence, present younger with more advanced disease, and have worse survival even after adjustment for socioeconomic variables. Differences in phenotype (including large-cell transformation) may contribute to outcome gaps, supporting the need for tailored diagnostic vigilance in skin of color.^40–42

Stage at diagnosis remains the dominant prognostic anchor. Contemporary data show high 5-year overall survival in early stages but substantial decline with tumoral skin disease, erythroderma, nodal/visceral spread, and blood tumor burden. TNMB blood class B2 is independently associated with inferior outcomes and may reclassify patients to stage IV.^18,43,44 Additional geographic and socioeconomic variation has been documented, and prevalence is rising as survival improves. Pediatric-onset MF remains uncommon but increasingly recognized.^45–47

Practical approach

In patients with known PTCL who develop an abrupt, extensive, or intensely pruritic eruption:

Do not assume hypersensitivity alone; assess tempo, Body Surface Area (BSA), adenopathy, systemic symptoms.¹¹

Perform clinicopathologic correlation and maintain a low threshold for skin biopsy when in doubt persists.^4,10,11

Use integrated staging: TNMB for skin/blood (B2 awareness) plus Lugano/Deauville PET-CT for systemic burden and response.^{11,12–14,18,19}

Select therapy based on biology and comorbidity: consider CD30-directed strategies when CD30 is present, and anthracyclines are limited by cardiac risk; monitor neuropathy and cytopenias.^{14,15,20–22}

If refractory/progressive disease, evaluate phenotype-driven options and clinical trials (e.g. CCR4, KIR3DL2, miRNA, bispecific/NK strategies).^15,24–37

Incorporate goal-concordant care and palliative oncology early when appropriate.¹⁷

Conclusion

In individuals diagnosed with PTCL, a rapidly spreading rash should call for urgent concern for secondary cutaneous involvement rather than being attributed solely to drug hypersensitivity. Timely diagnosis depends on clinicopathologic correlation and a low threshold for biopsy when uncertainty persists. Optimal management begins with integrated staging: TNMB classification for cutaneous and blood compartments (with attention to B2) combined with the Lugano 2014 (PET-CT/Deauville) framework to define overall disease burden and standardize response assessment when systemic PTCL manifests with skin disease.

Management plans must correspond to tumor biology with comorbidity constraints. Evidence supports brentuximab vedotin for CD30-expressing CTCL and improved survival when brentuximab is incorporated as a frontline treatment for CD30-positive PTCL, while mogamulizumab remains effective in relapsed MF/SS. In the presented case, CD30 expression ∼10% and reduced ejection fraction supported an anthracycline-sparing, CD30-directed approach with brentuximab vedotin, resulting in early improvement by cycle three. Continued response-adapted reassessment and toxicity monitoring, particularly neuropathy, are essential. For persistent or progressive disease, biomarker-driven strategies and clinical trials (e.g. KIR3DL2 targeting with lacutamab) should be considered where appropriate, alongside early goal-concordant care to align treatment intensity with patient values.

Footnotes

Ethical considerations

Our institution does not require ethical approval for reporting individual cases.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article:

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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