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Cancers
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New Insights into Neurofibromatosis
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New Insights into Neurofibromatosis

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 August 2019) | Viewed by 52616

Special Issue Editors

Prof. Dr. Yasin Temel

E-Mail Website
Guest Editor
1. Department of Neurosurgery, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands
2. Academic Alliance for Skull Base Pathology, Maastricht and Radboud University Medical Centers, 6229 ER Maastricht, The Netherlands
Interests: chordoma; meningioma; vestibular schwannoma; deep brain stimulation for movement and psychiatric disorders
Special Issues, Collections and Topics in MDPI journals
Dr. Koos Hovinga

E-Mail Website
Guest Editor
Department of Neurosurgery, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands
Interests: neurosurgery and tumor biology; neuro-oncology

Special Issue Information

Dear Colleagues,

The neurofibromatosis family of hereditary tumor predisposition disorders significantly impair quality-of-life and lead to early mortality through the development of innumerable nervous system tumors. In the context of neurofibromatosis type 1 (NF-1), the management of neurofibromas, malignant peripheral nerve sheath tumors (MPNSTs), and gliomas is challenging due to the limited therapeutic options. Similarly, neurofibromatosis type 2 (NF-2) and schwannomatosis lead to the development of multiple schwannomas and meningiomas within the cranial vault, spinal canal, and extremities. Over the past decade, there has been significant progress in our understanding of the molecular drivers of these tumors and the identification of potential targeted therapies. Here, we welcome papers reviewing the current state of management of these disorders and the advances in characterization of the molecular landscape of the different subtypes afflicting this population.

Prof. Dr. Yasin Temel
Dr. Koos Hovinga
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurofibromatosis
  • peripheral nerve sheath tumors
  • glioblastomas
  • meningiomas

Published Papers (11 papers)

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Editorial

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3 pages, 144 KiB  
Editorial
Neurofibromatosis
by Koos E. Hovinga and Yasin Temel
Cancers 2020, 12(10), 2851; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102851 - 02 Oct 2020
Viewed by 2021
Abstract
In this Special Issue of Cancer, a series of 10 papers (seven papers, three reviews) on Neurofibromatosis is presented by international leaders in this field of research [...] Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)

Research

Jump to: Editorial, Review

18 pages, 29094 KiB  
Article
Contribution of mTOR and PTEN to Radioresistance in Sporadic and NF2-Associated Vestibular Schwannomas: A Microarray and Pathway Analysis
by Isabel Gugel, Florian H. Ebner, Florian Grimm, Stefan Czemmel, Frank Paulsen, Christian Hagel, Marcos Tatagiba, Sven Nahnsen and Ghazaleh Tabatabai
Cancers 2020, 12(1), 177; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010177 - 10 Jan 2020
Cited by 12 | Viewed by 3301
Abstract
The use of radiation treatment has increased for both sporadic and neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS). However, there are a subset of radioresistant tumors and systemic treatments that are seldom used in these patients. We investigated molecular alterations after radiation in [...] Read more.
The use of radiation treatment has increased for both sporadic and neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS). However, there are a subset of radioresistant tumors and systemic treatments that are seldom used in these patients. We investigated molecular alterations after radiation in three NF2-associated and five sporadically operated recurrent VS after primary irradiation. We compared these findings with 49 non-irradiated (36 sporadic and 13 NF2-associated) VS through gene-expression profiling and pathway analysis. Furthermore, we stained the key molecules of the distinct pathway by immunohistochemistry. A total of 195 differentially expressed genes in sporadic and NF2-related comparisons showed significant differences based on the criteria of p value < 0.05 and a two-fold change. These genes were involved in pathways that are known to be altered upon irradiation (e.g., mammalian target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN) and vascular endothelial growth factor (VEGF) signaling). We observed a combined downregulation of PTEN signaling and an upregulation of mTOR signaling in progressive NF2-associated VS after irradiation. Immunostainings with mTOR and PTEN antibodies confirmed the respective molecular alterations. Taken together, mTOR inhibition might be a promising therapeutic strategy in NF2-associated VS progress after irradiation. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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17 pages, 2320 KiB  
Article
Minimal Effect of Bevacizumab Treatment on Residual Vestibular Schwannomas after Partial Resection in Young Neurofibromatosis Type 2 Patients
by Isabel Gugel, Lan Kluwe, Julian Zipfel, Christian Teuber, Marcos Tatagiba, Victor-Felix Mautner, Martin Ulrich Schuhmann and Florian Grimm
Cancers 2019, 11(12), 1862; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121862 - 25 Nov 2019
Cited by 16 | Viewed by 2492
Abstract
Hearing-preserving partial resection of neurofibromatosis type 2 (NF2) associated vestibular schwannomas (VS) is a preferred treatment strategy, particularly for children and adolescents. However, the residual tumors do grow and lead at some point to continued hearing deterioration. An adjuvant bevacizumab treatment may provide [...] Read more.
Hearing-preserving partial resection of neurofibromatosis type 2 (NF2) associated vestibular schwannomas (VS) is a preferred treatment strategy, particularly for children and adolescents. However, the residual tumors do grow and lead at some point to continued hearing deterioration. An adjuvant bevacizumab treatment may provide an option for slowing down this process. In this retrospective study, we reviewed tumor volume and hearing data of 16 operated VS in nine patients younger than 30 years over a period of 63 to 142 months. All these patients had one or more bevacizumab treatment periods and most of them had a non-treatment period after surgery. Four different patterns of growth were observed for the residual tumors: (1) growth in the non-treatment periods, which slowed down in the treatment periods; (2) growth slowed down in one but not in another on-period; (3) unaffected growth; (4) no or minimal growth regardless of the treatment. Neither radiological regression of tumor volume nor hearing improvement were observed in the treatment periods. Accelerated hearing deterioration was observed in several non-treatment periods, but also in some treatment periods. No straightforward correlation can be drawn between tumor growth and hearing scores. Tumor growth and worsening of hearing between two measurement points were slightly less in the treatment periods; however, the differences were not significant, because variations were large. In conclusion, our comprehensive follow-up on 16 VS in nine NF2 patients did show heterogenous effects of bevacizumab on small residual vestibular schwannomas after surgery both regarding tumor size and hearing preservation. Thus, smaller and slower growing tumor residuals seem to behave differently to bevacizumab than reported for not-operated faster growing VS. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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25 pages, 1403 KiB  
Article
Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort
by Giulia Melloni, Marica Eoli, Claudia Cesaretti, Donatella Bianchessi, Maria Cristina Ibba, Silvia Esposito, Giulietta Scuvera, Guido Morcaldi, Roberto Micheli, Elena Piozzi, Sabrina Avignone, Luisa Chiapparini, Chiara Pantaleoni, Federica Natacci, Gaetano Finocchiaro and Veronica Saletti
Cancers 2019, 11(12), 1838; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121838 - 21 Nov 2019
Cited by 17 | Viewed by 4695
Abstract
The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the [...] Read more.
The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring NF1 mutations in the 5’ tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of NF1 mutation with the development of OPG was analysed using the χ2 test and Fisher’s exact probability test; odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni’s correction for multiple comparisons was applied; multiple logistic regression was also used to study genotype–phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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20 pages, 4690 KiB  
Article
Brain Tumors in NF1 Children: Influence on Neurocognitive and Behavioral Outcome
by Matilde Taddei, Alessandra Erbetta, Silvia Esposito, Veronica Saletti, Sara Bulgheroni and Daria Riva
Cancers 2019, 11(11), 1772; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111772 - 11 Nov 2019
Cited by 10 | Viewed by 3903
Abstract
Neurofibromatosis type-1 (NF1) is a monogenic tumor-predisposition syndrome creating a wide variety of cognitive and behavioral abnormalities, such as decrease in cognitive functioning, deficits in visuospatial processing, attention, and social functioning. NF1 patients are at risk to develop neurofibromas and other tumors, such [...] Read more.
Neurofibromatosis type-1 (NF1) is a monogenic tumor-predisposition syndrome creating a wide variety of cognitive and behavioral abnormalities, such as decrease in cognitive functioning, deficits in visuospatial processing, attention, and social functioning. NF1 patients are at risk to develop neurofibromas and other tumors, such as optic pathway gliomas and other tumors of the central nervous system. Few studies have investigated the impact of an additional diagnosis of brain tumor on the cognitive outcome of children with NF1, showing unclear results and without controlling by the effect of surgery, radio- or chemotherapy. In the present mono-institutional study, we compared the behavioral and cognitive outcomes of 26 children with neurofibromatosis alone (NF1) with two age-matched groups of 26 children diagnosed with NF1 and untreated optic pathway glioma (NF1 + OPG) and 19 children with NF1 and untreated other central nervous system tumors (NF1 + CT). NF1 + CT and NF1 + OPG showed significantly impaired cognitive abilities compared to NF1 group, with weaknesses in visuo-spatial abilities, visual scanning and verbal working memory, while general verbal abilities are preserved. Moreover, NF1 + OPG patients present more frequent internalizing problems and increased oppositional-deviant behaviors. These results suggest that the co-diagnosis of a brain tumor in NF1 children may partially worsen the cognitive and emotional outcome. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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12 pages, 861 KiB  
Article
Long-Term Outcomes of Stereotactic Radiosurgery for Vestibular Schwannoma Associated with Neurofibromatosis Type 2 in Comparison to Sporadic Schwannoma
by Yuki Shinya, Hirotaka Hasegawa, Masahiro Shin, Takehiro Sugiyama, Mariko Kawashima, Wataru Takahashi, Shinichi Iwasaki, Akinori Kashio, Hirofumi Nakatomi and Nobuhito Saito
Cancers 2019, 11(10), 1498; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101498 - 07 Oct 2019
Cited by 19 | Viewed by 3556
Abstract
The efficacy of radiosurgery for neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS) remains debatable. We retrospectively analyzed radiosurgical outcomes for NF2-associated VS compared to sporadic VS using our database of 422 consecutive VS patients. Twenty-five patients with 30 NF2-associated VSs with a mean [...] Read more.
The efficacy of radiosurgery for neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS) remains debatable. We retrospectively analyzed radiosurgical outcomes for NF2-associated VS compared to sporadic VS using our database of 422 consecutive VS patients. Twenty-five patients with 30 NF2-associated VSs with a mean follow-up of 121 months were identified. NF2-associated VSs exhibited excellent tumor control (10-year cumulative rate, 92% vs. 92% in sporadic VSs; p = 0.945) and worse overall survival (73% vs. 97%; p = 0.005), mainly due to tumor progression other than the treated VSs. The presence of NF2 was not associated with failed tumor control via multivariate Cox proportional hazard analyses. No difference in radiation-induced adverse events (RAEs) was confirmed between cohorts, and prescription dose (hazard ratio 8.30, 95% confidence interval 3.19–21.62, p < 0.001) was confirmed as a risk for cranial nerve injuries via multivariate analysis. Further analysis after propensity score matching using age, volume, and sex as covariates showed that NF2-associated VSs exhibited excellent local control (100% vs. 93%; p = 0.240) and worse overall survival (67% vs. 100%; p = 0.002) with no significant difference in RAEs. Excellent long-term tumor control and minimal invasiveness may make radiosurgery a favorable therapeutic option for NF2 patients with small to medium VS, preferably with non-functional hearing or deafness in combination with postoperative tumor growth or progressive non-operated tumors, or with functional hearing by patients’ wish. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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9 pages, 444 KiB  
Article
Impact of Surgery on Long-Term Results of Hearing in Neurofibromatosis Type-2 Associated Vestibular Schwannomas
by Isabel Gugel, Florian Grimm, Marina Liebsch, Julian Zipfel, Christian Teuber, Lan Kluwe, Victor-Felix Mautner, Marcos Tatagiba and Martin Ulrich Schuhmann
Cancers 2019, 11(9), 1376; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091376 - 16 Sep 2019
Cited by 16 | Viewed by 2782
Abstract
Hearing preservation is a major goal in the treatment of neurofibromatosis type 2 (NF2) associated vestibular schwannoma (VS), particularly in children and adolescents. In this study, we retrospectively reviewed hearing and volumetry data sets of 39 operated tumors (ears) in 23 patients under [...] Read more.
Hearing preservation is a major goal in the treatment of neurofibromatosis type 2 (NF2) associated vestibular schwannoma (VS), particularly in children and adolescents. In this study, we retrospectively reviewed hearing and volumetry data sets of 39 operated tumors (ears) in 23 patients under the age of 25 and in a follow-up period of 21 to 167 months. Hearing data over a compatible period on 20 other tumors, which did not receive surgery due to their less aggressive nature, were included for comparison. Surgery was carried out via a retrosigmoid approach with the brainstem auditory evoked potential (BAEP) guide. Immediately after surgery, functional hearing was maintained in 82% of ears. Average hearing scores were better in the non-surgery ears. However, the hearing scores in both groups worsened gradually with a similar dynamic during the 42-month postoperative follow-up period. No accelerated impairment of hearing was evident for the operated cases. Rather, the gap between the two hearing deterioration lines tended to close at the end of the follow-up period. Our result suggested that the BAEP-guided surgery did not cause additional hearing deterioration in the long-term and seemed to slow down hearing deterioration of those tumors that were initially more aggressive. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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12 pages, 417 KiB  
Article
NF1 Patients Receiving Breast Cancer Screening: Insights from The Ontario High Risk Breast Screening Program
by Nika Maani, Shelley Westergard, Joanna Yang, Anabel M. Scaranelo, Stephanie Telesca, Emily Thain, Nathan F. Schachter, Jeanna M. McCuaig and Raymond H. Kim
Cancers 2019, 11(5), 707; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050707 - 22 May 2019
Cited by 14 | Viewed by 4853
Abstract
Neurofibromatosis Type I (NF1) is caused by variants in neurofibromin (NF1). NF1 predisposes to a variety of benign and malignant tumor types, including breast cancer. Women with NF1 <50 years of age possess an up to five-fold increased risk of developing [...] Read more.
Neurofibromatosis Type I (NF1) is caused by variants in neurofibromin (NF1). NF1 predisposes to a variety of benign and malignant tumor types, including breast cancer. Women with NF1 <50 years of age possess an up to five-fold increased risk of developing breast cancer compared with the general population. Impaired emotional functioning is reported as a comorbidity that may influence the participation of NF1 patients in regular clinical surveillance despite their increased risk of breast and other cancers. Despite emphasis on breast cancer surveillance in women with NF1, the uptake and feasibility of high-risk screening programs in this population remains unclear. A retrospective chart review between 2014–2018 of female NF1 patients seen at the Elizabeth Raab Neurofibromatosis Clinic (ERNC) in Ontario was conducted to examine the uptake of high-risk breast cancer screening, radiologic findings, and breast cancer characteristics. 61 women with pathogenic variants in NF1 enrolled in the high-risk Ontario breast screening program (HR-OBSP); 95% completed at least one high-risk breast screening modality, and four were diagnosed with invasive breast cancer. Our findings support the integration of a formal breast screening programs in clinical management of NF1 patients. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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Review

Jump to: Editorial, Research

20 pages, 1607 KiB  
Review
Therapy of Sporadic and NF2-Related Vestibular Schwannoma
by Longping Yao, Mohammed Alahmari, Yasin Temel and Koos Hovinga
Cancers 2020, 12(4), 835; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040835 - 31 Mar 2020
Cited by 20 | Viewed by 4797
Abstract
Vestibular schwannoma (VS) is a benign primary brain tumor that occurs sporadic or as part of a genetic syndrome. The most common cause is the mutation of the NF2 tumor suppressor gene that is involved in the production of the protein merlin. Merlin [...] Read more.
Vestibular schwannoma (VS) is a benign primary brain tumor that occurs sporadic or as part of a genetic syndrome. The most common cause is the mutation of the NF2 tumor suppressor gene that is involved in the production of the protein merlin. Merlin plays a role in cell growth and cell adhesion. In patients with NF2, the VSs arise bilaterally and coincide with other brain tumors. In sporadic VS, the tumor is typically unilateral and does not coincide in combination with other tumors. MRI is the standard imaging technique and can be used to assess the size and aspect of the tumor as well as the progression of disease. The preferred management of large VS in both VS types is surgery with or without adjuvant radiation. The management for the medium- or small-sized VS includes wait and scan, radiotherapy and/or surgery. This choice depends on the preference of the patient and institutional protocols. The outcomes of surgical and radiotherapy treatments are improving due to progress in surgical equipment/approaches, advances in radiation delivery techniques and dose optimizations protocols. The main purpose of the management of VS is preserving function as long as possible in combination with tumor control. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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15 pages, 1395 KiB  
Review
An Update on Neurofibromatosis Type 1-Associated Gliomas
by Mina Lobbous, Joshua D. Bernstock, Elizabeth Coffee, Gregory K. Friedman, Laura K Metrock, Gustavo Chagoya, Galal Elsayed, Ichiro Nakano, James R. Hackney, Bruce R. Korf and Louis B. Nabors
Cancers 2020, 12(1), 114; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010114 - 01 Jan 2020
Cited by 44 | Viewed by 9918
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that affects children and adults. Individuals with NF1 are at high risk for central nervous system neoplasms including gliomas. The purpose of this review is to discuss the spectrum of intracranial gliomas [...] Read more.
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that affects children and adults. Individuals with NF1 are at high risk for central nervous system neoplasms including gliomas. The purpose of this review is to discuss the spectrum of intracranial gliomas arising in individuals with NF1 with a focus on recent preclinical and clinical data. In this review, possible mechanisms of gliomagenesis are discussed, including the contribution of different signaling pathways and tumor microenvironment. Furthermore, we discuss the recent notable advances in the developing therapeutic landscape for NF1-associated gliomas including clinical trials and collaborative efforts. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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14 pages, 824 KiB  
Review
The Role of Merlin/NF2 Loss in Meningioma Biology
by Sungho Lee, Patrick J. Karas, Caroline C. Hadley, James C. Bayley V, A. Basit Khan, Ali Jalali, Alex D. Sweeney, Tiemo J. Klisch and Akash J. Patel
Cancers 2019, 11(11), 1633; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111633 - 24 Oct 2019
Cited by 42 | Viewed by 9403
Abstract
Mutations in the neurofibromin 2 (NF2) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular schwannomas but later have a high incidence of meningiomas. The [...] Read more.
Mutations in the neurofibromin 2 (NF2) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular schwannomas but later have a high incidence of meningiomas. The NF2 gene product, merlin, is a tumor suppressor that is thought to link the actin cytoskeleton with plasma membrane proteins and mediate contact-dependent inhibition of proliferation. However, the early recognition of the crucial role of NF2 mutations in the pathogenesis of the majority of meningiomas has not yet translated into useful clinical insights, due to the complexity of merlin’s many interacting partners and signaling pathways. Next-generation sequencing studies and increasingly sophisticated NF2-deletion-based in vitro and in vivo models have helped elucidate the consequences of merlin loss in meningioma pathogenesis. In this review, we seek to summarize recent findings and provide future directions toward potential therapeutics for this tumor. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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