Abstract
According to the latest WHO classification of hematopoietic malignancies, myeloid and lymphoid neoplasms with eosinophilia and gene rearrangements include three specific rare diseases and one provisional entity. Myeloid/lymphoid neoplasms with platelet-derived growth factor receptor alpha (PDGFRA) rearrangements are the most frequent of these disorders and are usually present in adult males with a median age of the late 40s. Patients usually have chronic eosinophilic leukemia but can occasionally manifest as acute myeloid leukemia or extramedullary T- or B-lineage lymphoblastic lymphoma. We report a case of a previously healthy 2-year-old girl who presented with a right supraorbital swelling with no associated lymphadenopathy. Peripheral blood smear evaluation at initial presentation revealed microcytic hypochromic red blood cells and leukocytosis with marked eosinophilia, occasional myelocytes, and occasional blasts. Whole-body CT scans and PET scans revealed hypermetabolic potentially lymphomatous mass in the superior medial aspect of the right orbit in addition to splenomegaly but no evidence of hypermetabolic mediastinal, hilar, abdominal, or pelvic lymph nodes. Bone marrow aspirate and biopsy revealed hypercellular bone marrow with quantitatively decreased erythroid precursors and increased granulocytic precursors with 60% of the cells being eosinophilic cells in different stages of maturation. The diagnosis of myeloid neoplasm with eosinophilia and rearrangement of PDGFRA was made following confirmation by fluorescence in situ hybridization (FISH) test for FIP1L1-PDGFRA gene fusion. An incisional biopsy of the supraorbital mass revealed B-cell lymphoblastic lymphoma (B-LBL). FISH test for FIP1L1-PDGFRA gene fusion was positive in 70% of the cells studied. Thus, the final diagnosis was B-cell lymphoblastic lymphoma arising in the setting of myeloid/lymphoid neoplasm with eosinophilia and PDGFRA rearrangement. The patient was started on imatinib with concomitant therapy for B-LBL per the Children Oncology Group (COG) standard therapy for localized B-LBL and demonstrated a favorable outcome in the 2.5-year follow-up period. To our knowledge, this is the first pediatric case of myeloid/lymphoid neoplasm with PDGFRA rearrangement presenting with synchronous myeloproliferative disease and B-LBL. We present our diagnostic and management approach of this patient and review prior relevant pediatric cases of myeloid/lymphoid neoplasms with PDGFRA rearrangement.
Introduction
Myeloid/lymphoid neoplasms with eosinophilia (M/LN-Eo) and rearrangements of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2 genetic variants constitute a rare but well-defined category of hematologic malignancies recognized by the WHO revised classification (1). Despite having myeloproliferative neoplasm (MPN) and eosinophilia as common manifestations in most reported cases, individual patients may display remarkable heterogeneity at initial presentation and clinical course (2). Myeloid/lymphoid neoplasms with PDGFRA rearrangements are the most frequently encountered of these disorders and are usually present in adult males with a median age of the late 40s (1–3). Patients usually have chronic eosinophilic leukemia (CEL) but can also manifest as acute myeloid leukemia (AML), systemic mastocytosis (SM) with hypereosinophilia, or extramedullary T- or B-lineage lymphoblastic lymphoma (T-LBL/B-LBL) (2). Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangements are extremely rare in the pediatric population with only few cases reported in the literature.
Given its exceptional therapeutic benefit demonstrated in previous reports, the tyrosine kinase inhibitor imatinib is currently considered first-line therapy for patients with M/LN-Eo harboring rearrangements of PDGFRA (2). However, due to the rarity of these diseases in the pediatric population, and the lack of reports describing imatinib monotherapy in cases presenting with T-LBL/B-LBL, treating physicians are often left with challenging decisions when formulating their management plans. In this report, we present the first pediatric case of myeloid/lymphoid neoplasm with PDGFRA rearrangement presenting with synchronous myeloproliferative disease and B-cell lymphoblastic lymphoma (B-LBL). We present our diagnostic and management approach of this patient and review prior relevant pediatric cases of myeloid/lymphoid neoplasms with PDGFRA rearrangements.
Case report
A previously healthy 2-year-old girl presented with right supraorbital swelling that developed over 1.5 months with no other symptoms at the time of initial presentation. Notable on examination was a right firm supraorbital swelling causing ptosis, with no overlying skin changes (Figure 1A). Examination was also notable for hepatosplenomegaly but not lymphadenopathy. Initial laboratory data were significant for anemia (Hb 8.2 g/dl) and leukocytosis (WBC 19.5 × 109/L) with eosinophilia of 32% and an absolute eosinophilic count of 6.3 × 109/L. Blood smear showed microcytic, hypochromic red blood cells (RBCs) in addition to leukocytosis with marked eosinophilia (32%), occasional myelocytes (2%), and occasional myeloblasts (less than 1%). Some of the eosinophils had three to four nuclear segments and polarized distribution of the cytoplasmic granules.
Figure 1
Whole-body PET/CT scan revealed hypermetabolic potentially lymphomatous mass in the superior medial aspect of the right orbit in addition to splenomegaly, but no evidence of hypermetabolic mediastinal, hilar, abdominal or pelvic lymph nodes. MRI of the orbits revealed a lobulated well-defined nonhomogenous enhancing mass in the superior medial aspect of the right orbit measuring 2.2 cm × 0.6 cm × 2.8 cm. The lesion was mostly involving the anterior aspect of the medial rectus muscle, causing destruction of the medial aspect of the right orbital roof with mild extra-axial intracranial extension but no compression of the brain parenchyma. There was a mild extension of the subcutaneous tissue in the supraorbital space, with compression of the right eye globe but no evidence of invasion of the sclera or retro-ocular extension (Figure 2A).
Figure 2
Bone marrow (BM) aspirate and biopsy revealed hypercellular BM with quantitatively decreased erythroid precursors and quantitatively increased granulocytic precursors with 60% of the cells being eosinophilic cells in different stages of maturation. Megakaryocytes were quantitatively normal (Figure 3A). Flow cytometry showed less than 1% myeloblasts. No B-cell lymphoblasts were detected. The diagnosis of myeloid neoplasm with eosinophilia and rearrangement of PDGFRA was made following confirmation by fluorescence in situ hybridization (FISH) test for FIP1L1-PDGFRA gene fusion. Cerebrospinal fluid (CSF) examination showed an acellular specimen with no blast or atypical cells. An incisional biopsy of the supraorbital mass revealed B-cell lymphoblastic lymphoma (B-LBL) (Figure 3B–D). FISH test for FIP1L1-PDGFRA gene fusion was positive in 70% of the cells studied (Figure 3E). Thus, the final diagnosis was B-cell lymphoblastic lymphoma arising in the setting of myeloid/lymphoid neoplasm with eosinophilia and PDGFRA rearrangement.
Figure 3
Cardiac evaluation was normal. Gastrointestinal evaluation that included upper endoscopy and colonoscopy showed chronic gastric, duodenal, and rectal inflammation but no evidence of eosinophilic infiltration or B-cell lymphoma.
The patient was started on imatinib 340 mg/m2/day with concomitant therapy for B-LBL per the Children Oncology Group (COG) standard therapy for localized B-LBL. WBC count and absolute eosinophilic count normalized after 4 days of imatinib. One month after the initiation of therapy, which corresponded to the end of chemotherapy induction phase, the supraorbital swelling decreased grossly to 50% of its original size. The BM evaluation was morphologically normal and the FIP1L1-PDGFRA gene fusion by FISH analysis was decreased to 2.5%. Five months following treatment, the supraorbital swelling had completely resolved (Figure 1B). Whole-body PET CT showed almost complete metabolic response, and the brain and orbital MRI showed almost complete resolution of the right orbital mass (Figure 2B). The BM evaluation was also in morphologic remission with negative FISH for PDFGRA rearrangement. After 2.5 years of treatment, the multiagent chemotherapy for B-LBL was completed and the patient is now on imatinib monotherapy with close follow-up.
Discussion
Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangements are extremely rare in the pediatric population with only few cases reported in the literature. To the best of our knowledge, only a few pediatric cases were reported describing myeloid/lymphoid neoplasms harboring PDGFRA rearrangements (4–14) (Table 1).
Table 1
| Reference | Age (years) | Gender | Clinical features at presentation | Initial WBC count (× 109/l) | Initial eosinophilic count (× 109/l) | Disease type | Imatinib dose | Other treatment lines used | Time until achieving hematologic and molecular remission | Follow-up/Long-term outcome | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| CHR | CMR | ||||||||||
| Rives et al. 2005 (4) | 7 | Male | Incidental eosinophilia detected on a preoperative blood followed by generalized pruritus and malaise | 13.5 | 6.1 | Chronic MPN with eosinophilia/CEL | – | Prednisone | 1 month | Not reported | Relapsed after corticosteroids discontinuation but responded to resuming treatment with prednisone, which was maintained for 6 months. Authors intend to treat with imatinib in case of relapse. |
| Rathe et al. 2010 and 2014 (5, 6) | 2 | Female | Malaise, fatigue, loss of appetite, and pain | 125.0 | 22.5 | Chronic MPN with eosinophilia/CEL | 300 mg/m2 daily | — | 2 weeks | 3 months | Continued imatinib for 5 years. Five months after discontinuing therapy, the patient relapsed and imatinib was restarted. CHR and CMR were reached at 4 weeks. |
| Rapanotti et al, 2010 (7) | 16 | Male | Lymphadenopathy, splenomegaly, restrictive cardiomyopathy | 13.5 | 5.3 | Chronic MPN with eosinophilia/CEL | 400 mg daily | — | Achieved with imatinib, timeline not specified | Remained in remission for 36 months | |
| Farruggia et al. 2014 (8) | 14 | Male | Pallor, weight loss (3 kg in 2 months), and left shoulder pain, lymphadenopathy, hepatosplenomegaly | 131.1 | 49.0 | Chronic MPN with eosinophilia/CEL | 200 mg daily | Hydroxycarbamide treatment—initiated prior to identifying gene rearrangement—did not control the disease | 40 days | 8 months | Remained in remission for 12 months |
| Zeng et al. 2015 (9) | 9 | Female | Malnutrition, fever, cough, diarrhea, lymphadenopathy, hepatosplenomegaly, progressive skin rash starting at 1 month of age, bilateral keratomalacia with corneal erosions at 3 years, stroke at 7 years, cardiac dysfunction, pneumatosis effusion along within the intestine tract | 39.7 | 28.9 | Chronic MPN with eosinophilia/CEL | 100 mg daily | Corticosteroid treatment—initiated prior to identifying gene rearrangement—did not control the disease. It was gradually tapered and withdrawn | 6 weeks | Not reported | Improved end organs functions at 6 weeks |
| Oberley et al. 2017 (10) | 13 | Male | Enlarged right supraclavicular lymph node | 1.4 | 0.0 | T-cell lymphoblastic leukemia/lymphoma | 400 mg daily (added on relapse) | Received standard chemotherapy for T-LBL but had a refractory disease. Imatinib was added after PDGFRA rearrangement was detected. The patient did not respond and died of disease progression at day +217 from diagnosis | |||
| Srinivasan et al. 2019 (11) | 15 | Male | Migrating joint pain, and leukocytosis, splenomegaly | 49.2 | 16.7 | Chronic MPN with eosinophilia/CEL | 100 mg daily switched to maintenance dose of 200 mg weekly at around 18 months | Initially started on hydroxyurea prior to identifying gene rearrangement | 1 month | 3 months | Remained in remission for 42 months since diagnosis and doing well on maintenance imatinib |
| Bota et al. 2019 (12) | 5 | Female | Constitutional symptoms, multifocal bone pain, headache, gastrointestinal complaints, hepatosplenomegaly, lymphadenopathy cardiomyopathy | 59.7 | 29.4 | Chronic MPN with eosinophilia/CEL | 100 mg daily (∼133 mg/m2/day) Switched to 100 mg every other day (∼54 mg/m2/day) at 9 months | Concomitant methylprednisolone (1 mg/kg/day for 14 days) | 3 days | 9 months | Remained in remission for 16 months. Cardiomyopathy completely resolved |
| Jain et al. 2020 (13) | 6 | Male | Fever, fatigue, massive splenomegaly | 18.5 | 6.1 | Chronic MPN, blast phase (23% BM blasts) | 100 mg daily (∼100 mg/m2/day) | — | 6 weeks | 19 weeks | Remained in remission for 2 years since diagnosis |
| Voeller et al. 2020 (14) | 13 | Female | Iron deficiency, anorexia, anxiety, frequent panic attacks and exertional shortness of breath, severe restrictive cardiomyopathy with pulmonary hypertension | Not reported— | 4–6 | Chronic MPN with eosinophilia/CEL | 100 mg daily | Steroids | 1 month | 3 months | Remained in remission after nearly a year on continued monotherapy with imatinib. Remained asymptomatic from a cardiovascular standpoint, but continued to have pulmonary hypertension and severe diastolic dysfunction |
| Current case | 2 | Female | Right supraorbital swelling, hepatosplenomegaly | 19.5 6.3 | 6.3 | B-cell lymphoblastic lymphoma | ∼340 mg/m2/day | Concomitant therapy for B-LBL per the COG standard therapy protocol | 4 days | 5 months | Remained in remission for 2.5 years since diagnosis |
Summary of reported pediatric cases of myeloid/lymphoid neoplasms with FIP1L1-PDGFRA rearrangement.
WBC, white blood cell; CHR, complete hematologic remission; CMR, complete molecular remission; MPN, myeloproliferative neoplasm; CEL, chronic eosinophilic leukemia; COG, children oncology group; PDGFRA, platelet-derived growth factor receptor alpha.
Despite the well-known and very strong male predominance in adult cases of hypereosinophilic syndromes (HES), in general, and myeloid/lymphoid neoplasms with PDGFRA rearrangements, in particular, pediatric cases demonstrate a less pronounced male predominance (13, 15). In adults, patients with M/LN-Eo with PDGFRA rearrangements usually present as CEL, but can rarely manifest as AML, SM with hypereosinophilia, or extramedullary T-LBL/B-LBL (2). All previously reported pediatric cases manifested as chronic MPN with eosinophilia/CEL with only one case presenting as T-lymphoblastic lymphoma (T-LBL) without eosinophilia (10). To the best of our knowledge, we report the first pediatric case of myeloid/lymphoid neoplasm with PDGFRA rearrangement presenting with synchronous myeloproliferative disease and B-lymphoblastic lymphoma (B-LBL).
The product of the FIP1L1-PDGFRA fusion gene is a constitutively activated tyrosine kinase, thus, making the tyrosine kinase inhibitor imatinib a well-known agent for targeting conditions with this specific genetic abnormality (16). Imatinib is currently considered the first-line therapy for patients with M/LN-Eo harboring rearrangements of PDGFRA (2). In 2005, Rives et al. reported the first child with HES/CEL harboring FIP1L1-PDGFRA rearrangement. However, this genetic abnormality was not identified at initial presentation. The patient had received corticosteroids for the diagnosis of primary hypereosinophilic syndrome and achieved complete hematologic response in 1 month. The patient relapsed after discontinuation of the corticosteroids but responded to resuming same treatment. After the FIP1L1-PDGFRA fusion gene was identified, the diagnosis was modified to FIP1L1-PDGFRA-positive CEL and the authors declared the intent of initiation of imatinib if their patient exhibits a second relapse (4). All subsequent reported pediatric cases included imatinib in their treatment plan (5, 7–14). Favorable outcomes were reported in all cases except the case presenting as T-LBL that was reported by Oberley et al. in 2017 (10). Their 13-year-old male patient had chemotherapy-resistant T-LBL, and once the FIP1L1-PDGFRA rearrangement was detected, imatinib was added. However, the patient did not respond and eventually died of his disease (10). Our patient was treated with both imatinib and standard chemotherapy for the B-LBL due to the lack of reports describing imatinib monotherapy in cases presenting with T-LBL/B-LBL in all age groups, in addition to the serious initial presentation of B-LBL that posed an imminent threat to the patient's vision and central nervous system as evident by the aforementioned imaging findings. Five months following treatment, our patient achieved complete clinical, hematologic, and molecular remission. After 2.5 years of treatment, multiagent chemotherapy for B-LBL was completed and the patient is now on imatinib monotherapy and close follow-up.
Discontinuation of imatinib has been associated with relapse in FIP1L1/PDGFRA-positive chronic eosinophilic leukemia in both adult and pediatric cases (6, 17, 18). Although few authors reported maintained remission after decreasing imatinib maintenance dose, there is a lack of consensus regarding the optimal maintenance duration (11, 12). It is advised that patients remain on regular follow-up by molecular monitoring to dictate optimal duration of continuation therapy. Moreover, it is generally presumed that patients may require lifelong therapy (6, 13).
Conclusion
Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangements are extremely rare in the pediatric population with only few cases reported in the literature. In this report, we presented the first pediatric case of myeloid/lymphoid neoplasm with PDGFRA rearrangement presenting with synchronous myeloproliferative disease and B-LBL. Our patient demonstrated a favorable outcome after initiating combined chemotherapy with imatinib.
Statements
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.
Ethics statement
Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1.
SwerdlowSHCampoEHarrisNLJaffeESPileriSASteinHet al editors. WHO classification of tumours of haematopoietic and lymphoid tissues (revised 4th edition). Lyon: IARC (2017).
2.
PozdnyakovaOOraziAKelemenKKingRReichardKKCraigFEet alMyeloid/lymphoid neoplasms associated with eosinophilia and rearrangements of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. Am J Clin Pathol. (2021) 155(2):160–78. 10.1093/ajcp/aqaa208
3.
VegaFMedeirosLJBueso-RamosCEArboledaPMirandaRN. Hematolymphoid neoplasms associated with rearrangements of PDGFRA, PDGFRB, and FGFR1. Am J Clin Pathol. (2015) 144(3):377–92. 10.1309/AJCPMORR5Z2IKCEM
4.
RivesSAlcortaITollTTusetEEstellaJCrossNC. Idiopathic hypereosinophilic syndrome in children: report of a 7-year-old boy with FIP1L1-PDGFRA rearrangement. J Pediatr Hematol Oncol. (2005) 27(12):663–5. 10.1097/01.mph.0000193467.06938.77
5.
RatheMKristensenTKMollerMBCarlsenNL. Myeloid neoplasm with prominent eosinophilia and PDGFRA rearrangement treated with imatinib mesylate. Pediatr Blood Cancer. (2010) 55(4):730–2. 10.1002/pbc.22655
6.
RatheMSchomerusEWehnerPSKristensenTKMollerMB. Relapse of myeloid neoplasm with eosinophilia and PDGFRA rearrangement after imatinib discontinuation in a pediatric patient. Pediatr Blood Cancer. (2014) 61(12):2328. 10.1002/pbc.25199
7.
RapanottiMCCarusoRAmmatunaEZazaSTrottaLDivonaMet alMolecular characterization of paediatric idiopathic hypereosinophilia. Br J Haematol. (2010) 151(5):440–6. 10.1111/j.1365-2141.2010.08394.x
8.
FarruggiaPGiuglianoERussoDTrizzinoALorenzattiRSantoroAet alFIP1L1-PDGFRalpha-positive Hypereosinophilic syndrome in childhood: a case report and review of literature. J Pediatr Hematol Oncol. (2014) 36(1):e28–30. 10.1097/MPH.0b013e31827e6386
9.
ZengKLiLHuangLLiangYH. Newly identified phenotypes in a FIP1L1/PDGFRA-associated paediatric HES patient: thrombocytosis, mHPA, young stroke and blindness. J Eur Acad Dermatol Venereol. (2015) 29(3):614–6. 10.1111/jdv.12416
10.
OberleyMJDentonCJiJHiemenzMBhojwaniDOstrowDet alA neoplasm with FIP1L1-PDGFRA fusion presenting as pediatric T-cell lymphoblastic leukemia/lymphoma without eosinophilia. Cancer Genet. (2017) 216–217:91–9. 10.1016/j.cancergen.2017.07.007
11.
SrinivasanAScordinoTBakerA. Myeloid neoplasm with eosinophilia and FIP1L1-PDGFRA rearrangement treated with imatinib mesylate: a pediatric case with long-term follow-up. J Pediatr Hematol Oncol. (2019) 41(4):334–5. 10.1097/MPH.0000000000001446
12.
BotaSAlvesPConstantinoCMaiaR. Hypereosinophilia and severe bone disease in an African child: an unexpected diagnosis. BMJ Case Rep. (2019) 12(4):e227653. 10.1136/bcr-2018-227653
13.
JainJWeinzierlEPSaxeDBergsagelJGotlibJReiterAet alSustained complete molecular remission with imatinib monotherapy in a child presenting with blast phase FIP1L1-PDGFRA-associated myeloid neoplasm with eosinophilia. Hemasphere. (2020) 4(6):e486. 10.1097/HS9.0000000000000486
14.
VoellerJDeNapoliTGriffinTC. Two pediatric oncologic cases of hypereosinophilic syndrome and review of the literature. Cancer Rep. (2022) 5:e1710. 10.1002/cnr2.1710
15.
KatzHTHaqueSJHsiehFH. Pediatric hypereosinophilic syndrome (HES) differs from adult HES. J Pediatr. (2005) 146(1):134–6. 10.1016/j.jpeds.2004.09.014
16.
CoolsJDeAngeloDJGotlibJStoverEHLegareRDCortesJet alA tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. (2003) 348(13):1201–14. 10.1056/NEJMoa025217
17.
BrecciaMCilloniDCannellaLStefanizziCTafuriAFamaAet alIsolated molecular relapse in FIP1L1-PDGFRalpha hypereosinophilic syndrome after discontinuation and single weekly dose of imatinib: need of quantitative molecular procedures to modulate imatinib dose. Cancer Chemother Pharmacol. (2009) 63(6):1161–3. 10.1007/s00280-008-0858-8
18.
KlionADRobynJMaricIFuWSchmidLLemerySet alRelapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing. Blood. (2007) 110(10):3552–6. 10.1182/blood-2007-07-100164
Summary
Keywords
myeloid/lymphoid neoplasms, eosinophilia, PDGFRA, B-cell lymphoblastic lymphoma (B-LBL), imatinib
Citation
Akiely R, Almasri F, Almasri N and Abu-Ghosh A (2022) Case Report: Pediatric myeloid/lymphoid neoplasm with eosinophilia and PDGFRA rearrangement: The first case presenting as B-lymphoblastic lymphoma. Front. Pediatr. 10:1059527. doi: 10.3389/fped.2022.1059527
Received
01 October 2022
Accepted
22 November 2022
Published
14 December 2022
Volume
10 - 2022
Edited by
Daniele Zama, Sant'Orsola-Malpighi Polyclinic, Italy
Reviewed by
Barbara Buldini, Università degli Studi di Padova, Italy Yana Pikman, Dana-Farber Cancer Institute, United States
Updates
Copyright
© 2022 Akiely, Almasri, Almasri and Abu-Ghosh.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Amal Abu-Ghosh mousa1991@msn.com
This author shares first authorship
Specialty Section: This article was submitted to Pediatric Hematology and Hematological Malignancies, a section of the journal Frontiers in Pediatrics
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.