Interdisciplinary Rhinology, Sinus/Skull Base Surgery and Head & Neck Cancer Programme

Group Leader: Matt Lechner
MD PhD FRCS (ORL-HNS) FHEA, Associate Professor of Surgery

This interdisciplinary programme aims to face the most significant challenges and unmet clinical needs in Rhinology, Sinus/Skull Base Surgery, Head and Neck Cancer and beyond, and to have the greatest impact on patients’ health and wellbeing.

The programme utilises its close collaborations with the NHS and with partners from around the world via large networks, e.g. INSICA-Brain, EUSICA and the ongoing collaboration with the Cole-Reagins Registry for Sinonasal Cancer (CORSICA) in the US, aiming to embrace the new age of engineering and computation to advance the detection, diagnosis, treatment and management of cancer, as well as identify and address the barriers that exist for many people around the world in accessing the care they need, e.g. via collaborative global health work with the foundation AGA-ENT.

We are kindly supported by multiple funding bodies and would like to acknowledge their invaluable help and support.

Selected publications

1. HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. M. Lechner, et al. Nature Reviews of Clinical Oncology. 2022; 19(5):306-327; doi: 10.1038/s41571-022-00603-7.

2. DNA methylation-based classification of sinonasal tumors. P. Jurmeister, … , M. Lechner, ... , D. Capper. Nature Communications. 2022; 13(1):7148. doi: 10.1038/s41467-022-34815-3..

3. Signatures of copy number alterations in human cancer. C.D. Steele, … , M. Lechner, … , N. Pillay; Nature. 2022; doi: 10.1038/s41586-022-04738-6.

4. A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution. T. Zhu, ... , M. Lechner, ... , A.E. Teschendorff. Nature Methods. 2022;19(3):296-306; doi: 10.1038/s41592-022-01412-7.

5. Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy. M. Lechner, et al.; Nature Communications. 2021; 12(1):117. doi: 10.1038/s41467-020-20308-8.

6. The COVANOS trial – insight into post-COVID olfactory dysfunction and the role of smell training. M. Lechner, et al. Rhinology. 2022; doi: 10.4193/Rhin21.470.

7. Clinical Outcomes, Kadish-INSICA Staging and Therapeutic Targeting of SSTR2 in Olfactory Neuroblastoma. M. Lechner, et al.; European Journal of Cancer. 2022; 162:221-236; doi: 10.1016/j.ejca.2021.09.046.

8. Anosmia and hyposmia in health-care workers with undiagnosed SARS-CoV-2 infection. M.Lechner et al.; The Lancet Microbe. 2020, 1(4): e150.

9. Olfactory Loss of Function as a Possible Symptom of COVID-19. M. Lechner, Z.M. Patel, C. Philpott, V.J. Lund; JAMA Otolaryngology - Head and Neck Surgery. 2020,10.1001/jamaoto.2020.1589. doi:10.1001/jamaoto.2020.1589

10. Early detection of HPV-associated oropharyngeal cancer. M. Lechner et al.; The Lancet. 2019; 393(10186):2123.

11. Betel nut chewing in high income countries—lack of awareness and regulation. M. Lechner et al.; The Lancet Oncology. 2019;20(2):181-183.

12. Gender-neutral HPV vaccination in the UK, rising male oropharyngeal cancer rates, and lack of HPV awareness. M. Lechner et al.; The Lancet Infectious Diseases. 2019; 19(2):131-132.

13. Pan-cancer deconvolution of tumour composition using DNA methylation. A. Chakravarthy, … , M. Lechner, …, T.R. Fenton. Nature Communications. 2018; 13;9(1): 3220.

14. DNA methylation-based reclassification of olfactory neuroblastoma. D. Capper, … , M. Lechner, … , U. Schüller. Acta Neuropatholica. 2018. doi: 10.1007/s00401-018-1854-7.

15. DNA methylation-based classification of central nervous system tumours. D. Capper, … , M. Lechner, … , Pfister SM; Nature. 2018; 555(7697):469-474.

16. Until eradication, awareness. O.S. Jones, C. Vassie, R. Gilson, M. Lechner; The Lancet Infectious Diseases. 2017, 17(4): 368-369

17. Expanding the benefits of HPV vaccination to boys and men. L. Masterson, J. O'Mahony, M. Lechner; The Lancet. 2017, 388(10063):2992

18. Human papillomavirus drives tumor development throughout the head and neck: Improved prognosis is associated with an immune response largely restricted to the oropharynx. A. Chakravarthy, … , M. Lechner, … , T. Fenton; Journal of Clinical Oncology. 2016, 34(34):4132-4141

19. Health policy: HPV vaccination in boys - will the UK join the fight? L. Masterson and M. Lechner; Nature Reviews of Clinical Oncology. 2016, 13(12):721-722

20. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing; G.M. Frampton, … , M. Lechner, …, R. Yelensky; Nature Biotechnology. 2013, 10.1038/nbt.2696.

21. Targeted Next-generation Sequencing of Head and Neck Squamous Cell Carcinoma identifies novel genetic alterations in HPV+ and HPV- tumours. M. Lechner, et al.; Genome Medicine. 2013, 5(5): 49.

Research

Smell dysfunction/COVID-19 associated Anosmia and Parosmia - COVANOS trial

Common conditions such as rhinitis, sinusitis or nasal polyps can cause a temporary loss of sense of smell and these can be treated. Smell can also be affected by a head injury, certain medications and medical conditions. Very rarely a tumour of the nerve for smell (olfactory nerve) can affect the sense of smell. A weakened, lost or distorted sense of smell can also be caused by degeneration of the sensitive cells for the reception of smell in the nose after a severe ‘cold’, influenza or COVID-19.

COVANOS and COPANOS trials

Since the onset of the current pandemic, our research team have worked hard to contribute to our knowledge of this phenomenon. We published the first case series on healthcare workers in the UK and demonstrated a high incidence of self-reported anosmia amongst healthcare workers across different healthcare systems in the UK, which highlighted the need to address the long-term effects of these symptoms. Crucially, this work identified that females, particularly those above forty years of age, and those with concurrent distorted perception of smell (parosmia), were more likely to experience persistent smell loss. Based on the above, we have run one of the largest prospective multi-institutional clinical studies on Covid-19 associated anosmia in the UK, investigating the course of symptoms over one-year (COVANOS UK study).

In brief, this study demonstrated that 70% of those, who experience smell problems due to Covid-19 infection, spontaneously recover within the first month. However, the remaining 30% of participants continue to experience some degree of olfactory loss even after this time-point. Importantly, 60% of our participants who had objective smell loss at enrolment saw no improvement in their sense of smell at the one-year follow-up, implying that spontaneous recovery is more unlikely to occur if olfactory dysfunction persists beyond one month at the outset. Ultimately, we confirm that, even though many will spontaneously recover their sense of smell shortly after onset, there is a significant proportion of individuals who will suffer long-term olfactory dysfunction, as seen at our one-year follow-up, with a high prevalence of continued objective olfactory loss and symptoms of a distorted sense of smell. More recently, we have conducted two prevalence surveys in a representative sample (gender-matched and age-matched) of the US (n=4,369) and the UK (n=1,160) population. In the US survey, the rates of persistent anosmia (beyond 6 months) and parosmia were reported as 2.7% and 0.9%, respectively, which extrapolates to 9.0 million (95% CI: 7.6 million to 10.8 million) and 3.1 million (95% CI: 2.3 million to 4.2 million) affected individuals in the US, alone. In the UK, the observed rates of persistent anosmia (beyond 12 months) and parosmia were 1.0% and 0.9%, respectively, which is equivalent to 695,331 (95% CI: 398,416 – 1.2 million) and 637,386 (95% CI: 356,454 – 1.1 million) affected individuals, demonstrating the immense burden of long-term smell dysfunction due to COVID-19 (studies completed and manuscript submitted). The similarity in the rates observed between the two countries demonstrates the robustness of these findings and is in line with other studies which altogether demonstrate the significant burden of Covid-19-associated smell loss.

We have now received funding by the Rosetrees Trust to run two more major trials on Covid-19-associated smell loss/anosmia and distorted sense of smell/parosmia (COVANOS-2 and COPANOS trials; Chief Investigator: Matt Lechner)

We are closely working with the charity Fifth Sense. Matt serves as Research Hub Co-Lead for Clinical Trials and Epidemiology and has facilitated the development of a questionnaire to evaluate Smell and Taste Dysfunction (SmellQx)

Matt serves as a Co-I of the I-smell project. The I-smell Project has received funding from the Engineering and Physical Sciences Research Council (EPSRC) as part of UKRI and the National Institute of Health Research (NIHR). EPSRC Reference: EP/W031574/1.

We are also collaborating with Prof. Eleni Nastouli on the ‘SARS-CoV-2 Acquisition in Frontline Healthcare Workers - Evaluation to inform Response – PLUS‘ Study (SAFER PLUS Study) with a specific focus on smell dysfunction.

Publications

1. High prevalence of persistent smell loss and qualitative smell dysfunction during the Covid-19 pandemic in the United States: urgent need for clinical trials. M. Lechner, et al. International Forum of Allergy & Rhinology. 2022; doi: 10.1002/alr.23100.

2. The burden of olfactory dysfunction during the COVID-19 pandemic in the United Kingdom. M. Lechner, et al. Rhinology. 2022; doi: 10.4193/Rhin22.232.

3. The COVANOS trial – insight into post-COVID olfactory dysfunction and the role of smell training. M. Lechner, et al. Rhinology. 2022; doi: 10.4193/Rhin21.470.

4. International consensus statement on allergy and rhinology: Olfaction. Z.M. Patel, E.H. Holbrook, J.H. Turner, … , M. Lechner, … , C.H. Yan. International Forum of Allergy & Rhinology. 2022; 12(4):327-680; doi: 10.1002/alr.22929.

5. Risk factors and characteristics associated with persistent smell loss in coronavirus disease 2019 (COVID-19) patients. B. Shahrvini, D.P. Prajapati, M. Said, J. Liu, S. Srinivas, S. Jayaraj, V.J. Lund, A.S. DeConde, M. Lechner, C.H. Yan; Int Forum Allergy Rhinol. 2021; 11(8):1280-1282. doi: 10.1002/alr.22802

6. Distorted chemosensory perception and female sex associate with persistent smell and/or taste loss in people with SARS-CoV-2 antibodies: a community based cohort study investigating clinical course and resolution of acute smell and/or taste loss in people with and without SARS-CoV-2 antibodies in London, UK. J. Makaronidis, C. Firman, C.G. Magee, J. Mok, N. Balogun, M. Lechner, A. Carnemolla, R.L. Batterham; BMC Infect Dis. 2021; 21(1):221. doi: 10.1186/s12879-021-05927-w.

7. Course of symptoms for loss of sense of smell and taste over time in one thousand forty-one healthcare workers during the Covid-19 pandemic. M. Lechner, et al.; Clinical Otolaryngology. 2020, doi: 10.1111/coa.13683.

8. Anosmia and hyposmia in health-care workers with undiagnosed SARS-CoV-2 infection. M. Lechner et al.; The Lancet Microbe. 2020, 1(4): e150.

9. Association of subjective olfactory dysfunction and 12‐item odor identification testing in ambulatory COVID‐19 patients. D.P. Prajapati, B. Shahrvini, B. Macdonald, Kavya L. Crawford, M. Lechner, A.S. DeConde, C.H. Yan; International Forum of Allergy & Rhinology. 2020; DOI: 10.1002/alr.22688

10. Loss of smell and taste: a new marker of COVID-19? Tracking reduced sense of smell during the coronavirus pandemic using search trends. G. Cherry, J. Rocke, M. Chu, J. Liu, M. Lechner, V.J. Lund, B.N. KumarLiu, M. Lechner, V.J. Lund, B.N. Kumar. Expert Rev Anti Infect Ther. 2020;1-6. doi:10.1080/14787210.2020.1792289

11. Olfactory Loss of Function as a Possible Symptom of COVID-19. M. Lechner, Z.M. Patel, C. Philpott, V.J. Lund; JAMA Otolaryngology - Head and Neck Surgery. 2020,10.1001/jamaoto.2020.1589. doi:10.1001/jamaoto.2020.1589

12. Anosmia as a presenting symptom of SARS-CoV-2 infection in healthcare workers – A systematic review of the literature, case series, and recommendations for clinical assessment and management. M. Lechner, et al. Rhinology. 2020; doi:10.4193/Rhin20.189.

SSTR2 and epi-NET Programme

This is one of the flagship projects of the newly established UCL/UCLH Cancer Biomarker Centre. The planned work is based on our discoveries in Nasopharyngeal cancer and Olfactory Neuroblastoma

SSTR2 and epi-NET Programme

a) SSTR2 Cancer Programme (companion diagnostic, prognostic biomarker, imaging and therapy)

We recently completed studies assessing the role of the somatostatin receptor 2 (SSTR2) in sinonasal cancers, with a particular focus on nasopharyngeal cancer (n=404 patients) and olfactory neuroblastoma (n=402 patients). With the promising efficacy of SSTR2 as a biomarker and therapeutic target in neuroendocrine tumours, we aim to apply the following to all SSTR2-positive cancers, incl. SCLC, GI tract neuroendocrine tumours, olfactory neuroblastoma, pituitary adenoma, brain cancers, nasopharyngeal Cancer and some forms of prostate cancer.

Milestone 1: Optimisation of companion diagnostic biomarker

Optimization and automatization of protocol for use as companion diagnostic and prognostic biomarker and automated image analysis (AI scoring algorithm of stained images) – framework for further pipeline development
Cancer landscape analysis of SSTR2 with a focus on head and neck cancers and brain cancers and correlation with clinical outcomes

Milestone 2: Identification of the mechanism of SSTR2 overexpression and targetable vulnerabilities

Multi-dimensional data analysis
Functional validations in vitro

Milestone 3: In vitro and in vivo testing of SSTR2-targeting agents and targeting related pathways in preparation for Clinical Phase I trials of most promising compounds (in collaboration with industry partner)

Project Leads

Jacklyn Liu: Sinonasal cancers, nasopharyngeal cancer, SCLC, NETs, neuroendocrine prostate cancers, virally induced NETs
Yvonne Power: Pituitary adenoma and brain cancers

Collaborators: EUSICA, ADC-T

b) epi-NET Programme

Funding application submitted.

Publications

1. Clinical Outcomes, Kadish-INSICA Staging and Therapeutic Targeting of SSTR2 in Olfactory Neuroblastoma. M. Lechner, et al.; European Journal of Cancer. 2022; 162:221-236; doi: 10.1016/j.ejca.2021.09.046.

2. SSTR2 in Nasopharyngeal Carcinoma: Relationship with Latent EBV Infection and Potential as a Therapeutic Target. O. Emanuel, J. Liu, V.H. Schartinger, W.L. Nei, Y.Y. Chan, C.M. Tsang,
H. Riechelmann, L. Masterson, J. Haybaeck, U. Oppermann, S.M. Willems, M.L. Ooft, G. Wollmann, D. Howard, B. Vanhaesebroeck, V.J. Lund, G. Royle, M.L.K. Chua, K.W. Lo, P. Busson, and M. Lechner; Cancers. 2021; 13(19), 4944; https://doi.org/10.3390/cancers13194944

3. Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy. M. Lechner, et al.; Nature Communications. 2021; 12(1):117. doi: 10.1038/s41467-020-20308-8.

4. PSMA PET Imaging and Therapy in Adenoid Cystic Carcinoma and Other Salivary Gland Cancers: A Systematic Review. B.F. Tan, W.C.C. Tan, F.Q. Wang, M. Lechner, V.H. Schartinger, D.S.W. Tan, K.S.H. Loke, W.L. Nei; Cancers (Basel). 2022; 14(15):3585. doi: 10.3390/cancers14153585.

5. A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution. T. Zhu, J. Liu, S. Beck, S. Pan, D. Capper, M. Lechner, C. Thirlwell, C.E. Breeze, A.E. Teschendorff. Nature Methods. 2022;19(3):296-306; doi: 10.1038/s41592-022-01412-7.

6. The genomics and epigenetics of olfactory neuroblastoma: A systematic review. R.P. Kaur, E. Izumchenko, D.M. Blakaj, N. Mladkova, M. Lechner, T.L. Beaumont; Laryngoscope Investigative Otolaryngology. 2021; doi.org/10.1002/lio2.597

7. Ultra-fast scalable estimation of single-cell differentiation potency from scRNA-Seq data; A. Teschendorff, A.K. Maity, X. Hu, C. Weiyan, M. Lechner; Bioinformatics. 2021, 12; 37(11): 1528-1534. doi: 10.1093/bioinformatics/btaa987.

8. Signatures of copy number alterations in human cancer. C.D. Steele, A. Abbasi, S.M.A. Islam, A.L. Bowes, A. Khandekar, K. Haase, S. Hames-Fathi, D. Ajayi, A. Verfaillie, P. Dhami, A. McLatchie, M. Lechner, N. Light, A. Shlien, D. Malkin, A. Feber, P. Proszek, T. Lesluyes, F. Mertens, A.M. Flanagan, M. Tarabichi,, P. Van Loo, L.B. Alexandrov, N. Pillay; Nature. 2022; doi: 10.1038/s41586-022-04738-6.

9. Novel Biomarkers in Sinonasal Cancers: From Bench to Bedside. M. Lechner et al.; Current Oncology Reports. 2020; 22(10):106.

10. Precision medicine in rare tumors and the need for multicenter trials and international collaboratives: Sinonasal cancer as paradigm. P. Bossi, M. Hermsen, M. Lechner, A. Franchi. Oral Oncology. 2020;104737. doi:10.1016/j.oraloncology.2020.104737

11. Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation? L. Masterson, J. Howard, J. Gonzalez-Cruz, C. Jackson, C. Barnett, L Overton, H. Liu, R. Ladwa, F. Simpson, M. McGrath, B. Wallwork, T.M. Jones, C. Ottensmeier, M.L.K. Chua, C. Perry, R. Khanna, B. Panizza, S. Porceddu & M. Lechner; International Journal of Cancer. 2020;146(8):2305-2314.

12. Pan-cancer deconvolution of tumour composition using DNA methylation. A. Chakravarthy, A. Furness, K. Joshi, E. Ghorani, K. Ford, M.J. Ward, E.V. King, M. Lechner, T. Marafioti, S.A. Quezada, G.J. Thomas, A. Feber, T.R. Fenton. Nature Communications. 2018; 13;9(1): 3220.

INSICA-Brain Network

The INSICA-Brain Network (we recently extended this network to include brain cancers – International Network for Research on Sinonasal Cancer, Nasopharyngeal Cancer, Skull Base Tumors and Brain Cancers) is a non-hierarchical, multi-disciplinary, multi-national collaboration of physicians, surgeons, scientists and centers of excellence around the world. We value equality, diversity and inclusion and focus on scientific output with the highest possible impact for our patients and the field.

INSICA-brain

We offer a platform for international collaboration under the umbrella of an IRB approval for multi- center data analysis from the University College London IRB/Research Ethics Committee with further local approval from all institutions. This allows us to publish the largest datasets on sinonasal cancers, nasopharyngeal cancer, skull base tumors and brain cancers in order to inform on clinical outcomes, improved staging systems and novel biomarkers.

Our aim is that the network’s collaborative research output (below publications) guide national and international organizations when establishing updated guidelines on the diagnosis and management of these malignancies. Moreover, INSICA-Brain has also been advocating the harmonisation of prospective data collection between various large collaborations with the aim to create even larger, global datasets on many orphan diseases.

Resulting guidelines may differ between high-income countries and low and middle-income countries (LMICs) based on local resources and differences in the way healthcare is provided. We make every effort to include data from LMICs and work closely with friends and colleagues, health care providers and charitable organizations (foundations), such as the Association for the Global Advancement of ENT Surgery and Head and Neck Cancer Research (AGA-ENT) in order to provide the relevant data on companion diagnostic and prognostic biomarkers locally.

As the INSICA-Brain Network, we have already published key publications, e.g. on the largest datasets on olfactory neuroblastoma, sinonasal melanoma, etc. published, to date.

Publications

1. Molecular Basis and Rationale for the Use of Targeted Agents and Immunotherapy in Sinonasal Cancers. A. Esposito, … , M. Lechner & P. Bossi. Journal of Clinical Medicine. 2022;11(22):6787. doi: 10.3390/jcm11226787.

2. Biphenotypic sinonasal sarcoma: European multicentre case-series and systematic literature review. M. Turri-Zanoni, G. Dalfino, M. Lechner, I. Dallan, P. Battaglia, C. Facco, F. Franzi, G. Gravante, M. Ferrari, D. Terzakis, A. Jay, M.D. Forster, A.L. Ambrosoli, M. Bignami, C. Georgalas, P. Herman, P. Nicolai, V.J. Lund, P. Castelnuovo. Acta Otorhinolaryngol Ital. 2022; 42(6):545-553. doi: 10.14639/0392-100X-N2087.

3. Clinical Outcomes, Kadish-INSICA Staging and Therapeutic Targeting of SSTR2 in Olfactory Neuroblastoma. M. Lechner, et al.; European Journal of Cancer. 2022; 162:221-236; doi: 10.1016/j.ejca.2021.09.046.

4. DNA methylation-based classification of sinonasal tumors. P. Jurmeister, … , M. Lechner, ... , D. Capper. Nature Communications. 2022; 13(1):7148. doi: 10.1038/s41467-022-34815-3..

5. International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System. M. Lechner, et al. Journal of Neurological Surgery—Part B: Skull Base. 2022; DOI: 10.1055/s-0042-1750178

6. C. Schatz, … , M. Lechner, M. Hermsen, J. Haybaeck. Dysregulation of Translation Factors EIF2S1, EIF5A and EIF6 in Intestinal-Type Adenocarcinoma (ITAC). Cancers (Basel). 2021 Nov 11;13(22):5649. doi: 10.3390/cancers13225649. PMID: 34830804; PMCID: PMC8616251.

7. SSTR2 in Nasopharyngeal Carcinoma: Relationship with Latent EBV Infection and Potential as a Therapeutic Target. O. Emanuel, J. Liu, V.H. Schartinger, W.L. Nei, Y.Y. Chan, C.M. Tsang,
H. Riechelmann, L. Masterson, J. Haybaeck, U. Oppermann, S.M. Willems, M.L. Ooft, G. Wollmann, D. Howard, B. Vanhaesebroeck, V.J. Lund, G. Royle, M.L.K. Chua, K.W. Lo, P. Busson, and M. Lechner; Cancers. 2021; 13(19), 4944; https://doi.org/10.3390/cancers13194944

8. Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy. M. Lechner, et al.; Nature Communications. 2020; 12(1):117. doi: 10.1038/s41467-020-20308-8.

9. Precision medicine in rare tumors and the need for multicenter trials and international collaboratives: Sinonasal cancer as paradigm. P. Bossi, M. Hermsen, M. Lechner, A. Franchi. Oral Oncology. 2020;104737. doi:10.1016/j.oraloncology.2020.104737

European Network for Sinonasal Cancer Research (EUSICA)

EUSICA is a collaboration of centres across Europe, the UK and Ireland, working together to advance the diagnosis and treatment of patients with cancers of the nose, sinuses, and skull base.

EUSICA

Sinonasal cancers arise from the nasal cavities and paranasal sinuses and comprise of a wide spectrum of histologically and clinically distinct disease entities, with a total incidence between 0.5-1.0 cases per 100,000 men and women per year. Diagnosis can be challenging particularly because there are plenty of histological subtypes with overlapping characteristics.

Treatment includes surgery and postoperative radiotherapy, in some cases combined with neoadjuvant and adjuvant chemotherapy. Clinical approaches for recurrent and metastatic disease are even more limited.

Overall, clinical outcomes have remained unchanged over recent years and there is a clear need for new therapeutic options and, hence, we established the European Network for Sinonasal Cancer Researc h, (EUSICA).

EUSICA is a non-hierarchical, multi-disciplinary, multi-national collaboration of centres across Europe, the UK and Ireland, offering a platform for collaboration and a cross university/ cross disciplinary research enterprise and training programmes. EUSICA works closely with partners across Europe and the globe, including EURACAN.

EUSICA has also recently signed a Memorandum of Understanding with the Cole-Reagins Registry for Sinonasal Cancer (CORSICA) which has been ratified at the 4th EUSICA Board meeting. The aim of this collaboration is to harmonise prospective data collection for a global analysis of data in years to come, with the establishment of core facilities across Europe which allow us to harmonise biomarker development.

2nd EUSICA and 1st COST-initiative meeting will take place on the 3rd and 4th of May 2023 in Copenhagen, Denmark. For more information, please visit www.eusica.org.

Funding support:

Head and Neck Cancer Domain of the 100,000 Genomes Project and translation into the NHS
(National GeCIP Co-Lead: Matt Lechner)

Matt has served as Co-Lead of the Genomics England Head and Neck Domain since 2016
This includes two projects which are currently ongoing:

Retrospective analysis of already collected 100k Head and Neck WGS data
Prospective study planning of clinical translation of the project

HPV awareness and rationale for early detection of HPV-associated Oropharyngeal Cancer

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HPV and Oropharyngeal Cancer

Although still a rare cancer, HPV-associated oropharyngeal squamous cell cancer (OPSCC) has one of the most rapidly rising incidences of any cancer in high income countries, having overtaken cervical cancer in the UK (M. Lechner, et al. Nature Reviews of Clinical Oncology. 2022 and M. Lechner, et al. Lancet Infect. Dis. 2019; 19: 131-132) and in the US. The increasing rates of HPV-positive OPSC will have a tremendous healthcare cost, with estimated overall cost for treatment in the UK amounting to £2 billion over the next twenty years (in men only). Taking into account broader societal costs, we estimate that HPV-positive OPSCC will cost the UK more than £18 billion over the next twenty years (M. Lechner et al.; Lancet. 2019; 393: 2123). A similar study is currently conducted for the US (M. Lechner et al., in preparation).

HPV-positive OPSCC is distinct from its HPV-negative counterpart, which is largely caused by tobacco use and predominantly affects older men. In contrast, HPV-positive OPSCC is caused by oncogenic HPV infection and tends to impact younger men, with a distinct and unique molecular profile. Importantly, HPV positivity confers an improved prognosis. However, positive clinical outcome is hindered by a lack of effective prevention and early detection measures, which is exacerbated by low awareness of the link between HPV infection and OPSCC, particularly in men. Of 1,200 respondents in a UK-wide, population-based survey (649 [54.1%] female), only 444 (37.0%; 95% CI 34.3–39.7) had ever heard of HPV. Of these, 309 (69.6%; 65.2–73.7) knew that HPV could be transmitted during sex, 172 (38.7%; 34.3–43.3) recognized HPV as a risk factor for oropharyngeal squamous cell cancer, and 283 (63.7%; 59.2–68.1) knew that a preventive vaccine existed. Women were almost twice as likely to be aware of HPV as were men (290 [44.7%] vs 154 [27.9%]; p<0.001) (M. Lechner et al.; Lancet Infectious Diseases. 2019; 19(2):131-132). This is important as OPSCC is often detected at a late stage, which directly impacts clinical outcome and survival. Improving public awareness of the cancer risk as well as educating individuals on symptoms would not only reduce the incidence but also aid in earlier detection. Importantly, Primary care physicians (GPs) are at the nexus of the general public and our healthcare systems and have the ability to promote public health initiatives. In survey across primary care physicians, we found that while 74% of primary care physicians recognised HPV as a risk factor for OPSCC, less than half were aware that being male was a risk factor for HPV-associated OPSCC (M. Lechner, et al. BMJ Open. 2018; 8: e023339).

In an effort to improve awareness, we are developing a questionnaire, which would function as an educational tool as well as enable risk stratification of participants for a future screening program for persistent HPV infection and oropharyngeal cancer. We are investigating the role of various lifestyle factors, such as tobacco, marijuana and alcohol use as well as education, age and sex as potential stratification markers in addition to better understanding knowledge of OPSCC and HPV.

HPV-positive OPSCC is treated in much the same way as HPV-negative disease and centers on surgery and chemoradiotherapy. There are ongoing efforts to de-escalate treatment due to the high incidence of treatment-related adverse events and reduced post-treatment quality of life. However, there is much need for an improved understanding of the molecular profile of these tumours as well as the identification of clinically important risk factors in order to properly stratify patients and allocate treatment accordingly. This will further add to the identification of therapeutic targets and the development of precision medicine, including the paramount task of identifying biomarkers for early detection.

Publications

1. HPV-associated Oropharyngeal Cancer; M. Lechner et al.; Nature Reviews of Clinical Oncology. 2022 ; 19(5):306-327. doi: 10.1038/s41571-022-00603-7. Epub 2022 Feb 1. PMID: 35105976; PMCID: PMC8805140.

2. S. Basyuni, …, M. Lechner, … A. Schache. Value of p53 sequencing in the prognostication of head and neck cancer: a systematic review and meta-analysis. Scientific Reports. 2022. 1;12(1):20776. doi: 10.1038/s41598-022-25291-2.

3. A. Chakravarthy, …, M. Lechner, …, T.R. Fenton. Integrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance. Nature Communications. 2022;13(1):5818. doi: 10.1038/s41467-022-33544-x.

4. Awareness of Human Papillomavirus (HPV) and HPV Vaccination amongst the General Population in Germany: Lack of Awareness and Need for Action. S.J. Sharma, ... , M. Lechner, U. Wieland, J.P. Klussmann. Oncol Res Treat. 2022; 45(10):561-567. doi: 10.1159/000525697.

5. Reply to 'HPV-associated oropharyngeal cancer - discussion points'. Lechner M, Liu J, Masterson L, Fenton TR. Nature Reviews of Clinical Oncology. 2022 Jun;19(6):422-423. doi: 10.1038/s41571-022-00627-z. PMID: 35351994.

6. Public awareness of the association between human papillomavirus and oropharyngeal cancer. F. Verhees, I. Demers, L.J. Schouten, M. Lechner, E.M. Speel, B. Kremer. Eur J Public Health. 2021 Oct 26;31(5):1021-1025. doi: 10.1093/eurpub/ckab081. PMID: 34233355; PMCID: PMC8565482.Targeting key groups using a low-cost strategy to increase HPV awareness and vaccine uptake. O. Jones, C. Vassie, O. Emanuel & M. Lechner; Vaccine. 2020; 38(25):4059. doi:10.1016/j.vaccine.2020.02.022

7. Early detection strategies urgently needed to limit HPV-associated OPSCC morbidity, mortality and cost. M. Lechner et al.; Lancet. 2019; 393(10186):2123.

8. Gender-neutral HPV vaccination in the UK, rising male oropharyngeal cancer rates, and lack of HPV awareness. M. Lechner et al.; Lancet Infectious Diseases. 2019; 19(2):131-132.

9. A Cross-Sectional Survey of Awareness of Human Papillomavirus-associated Oropharyngeal Cancers among General Practitioners in the UK. M. Lechner, et al.; BMJ Open. 2018; 8(7): e023339

10. Pan-cancer deconvolution of tumour composition using DNA methylation. A. Chakravarthy, A. Furness, K. Joshi, E. Ghorani, K. Ford, M.J. Ward, E.V. King, M. Lechner, T. Marafioti, S.A. Quezada, G.J. Thomas, A. Feber, T.R. Fenton. Nature Communications. 2018; 13;9(1): 3220.

11. Frequent HPV-independent p16/INK4A overexpression in head and neck cancer. M. Lechner, A.R. Chakravarthya, V. Walter, L. Masterson, A. Feber, A. Jay, P.M. Weinberger, R. McIndoe, C.T. Forde, K. Chester, N. Kalavrezos, P. O'Flynn, M. Forster, T.M. Jones, F. Vaz, N. Hayes, T.R. Fenton; Oral Oncology. 2018; 83: 32-37

12. Until eradication, awareness. O.S. Jones, C. Vassie, R. Gilson, M. Lechner; Lancet Infectious Diseases. 2017, 17(4): 368-369

13. Expanding the benefits of HPV vaccination to boys and men. L. Masterson, J. O'Mahony, M. Lechner; Lancet. 2017, 388(10063):2992

14. Human papillomavirus drives tumor development throughout the head and neck: Improved prognosis is associated with an immune response largely restricted to the oropharynx. A. Chakravarthy, S. Henderson, S.M. Thirdborough, C.H. Ottensmeier, X. Su, M. Lechner, A. Feber, G.J. Thomas, T. Fenton; Journal of Clinical Oncology. 2016, 34(34):4132-4141

15. The Genomics, Epigenomics, and Transcriptomics of HPV-Associated Oropharyngeal Cancer - Understanding the Basis of a Rapidly Evolving Disease. M. Lechner et T. Fenton; Advances in Genetics; 2016, 93: 1-56.

16. CD8+ T cell response to human papillomavirus 16 E7 is able to predict survival outcome in oropharyngeal cancer. L. Masterson, M. Lechner, S. Loewenbein, H. Mohammed, C. Davies-Husband, T. Fenton, H. Sudhoff, P. Jani, P. Goon, J. Sterling; European Journal of Cancer. 2016, 67:141-151.

17. Health policy: HPV vaccination in boys - will the UK join the fight? L. Masterson and M. Lechner; Nature Reviews of Clinical Oncology. 2016, 13(12):721-722

18. Deregulation of SYCP2 predicts early stage HPV+ oropharyngeal carcinoma – a prospective whole transcriptome analysis. L. Masterson, F. Sorgeloos, D. Winder, M. Lechner, A. Marker, S. Malhotra, H. Sudhoff, P. Jani, P. Goon, J. Sterling; Cancer Science; 2015, 106(11):1568-75.

19. Exploring the implications of HPV infection for head and neck cancer; N. Field & M. Lechner; Sexually Transmitted Infections; 2015, 91(4):229-30.

20. Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer; A. Feber, M. Arya, P. De Winter, M. Saqip, R. Nigam, P. Malone, W.S. Tan, S. Rodney, M. Lechner, A. Freeman, C. Jameson, A. Muneer, S. Beck, J.D. Kelly; Clinical Cancer Research, 2015, 21(5):1196-206

21. Using high-density DNA methylation arrays to profile copy number alterations; A. Feber, P. Guilhamon, M. Lechner, T. Fenton, G.A. Wilson, C. Thirlwell, A.M. Flanagan, A.E. Teschendorff, J.D. Kelly, S. Beck; Genome Biology. 2014, 15(2): R30

22. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing; G.M. Frampton, A. Fichtenholt, G.A. Otto, K. Wang, S.R. Downing, J. He, M. Schnall-Levin, J. White, E.M. Sanford, P. An, J. Sun, F. Juhn, K. Brennan, K. Iwanik, A. Maillet, J. Buell, E. White, M. Zhao, S. Balasubramanian, S. Terzic, T. Richards, V. Banning, L. Garcia, K. Mahoney, Z. Zwirko, A. Donahue, H. Beltran, J.M. Mosquera, M.A. Rubin, S. Dogan, C.V. Hedvat, M.F. Berger, L. Pusztai, M. Lechner, C. Boshoff, M. Jarosz, C. Vietz, A. Parker, V.A. Miller, J.S. Ross, J. Curran, M.T. Cronin, P.J. Stephens, D. Lipson, R. Yelensky; Nature Biotechnology. 2013, 10.1038/nbt.2696.

23. Integrated virus-host methylome analysis in head and neck squamous cell carcinoma; G.A. Wilson & M. Lechner, A. Koeferle, H. Caren, L.M. Butcher, A. Feber, T. Fenton, A. Jay, C. Boshoff, S. Beck; Epigenetics. 2013, 18:8(9).

24. Targeted Next-generation Sequencing of Head and Neck Squamous Cell Carcinoma identifies novel genetic alterations in HPV+ and HPV- tumours. M. Lechner, G. Frampton, T. Fenton, A. Feber, G. Palmer, A. Jay, N. Pillay, M. Forster, M.T. Cronin, D. Lipson, V.A. Miller, T.A. Brennan, S. Henderson, F. Vaz, P. O'Flynn, N. Kalavrezos, R. Yelensky, S. Beck, P.J. Stephens, C. Boshoff; Genome Medicine. 2013, 5(5): 49.

25. Identification and Functional Validation of HPV-mediated Hypermethylation in Head and Neck Squamous Cell Carcinoma. M. Lechner, T. Fenton, J. West, G. Wilson, A. Feber, S. Henderson, C. Thirlwell, H.K. Dibra, A. Jay, L. Butcher, A.R. Chakravarthy, F. Gratrix, N. Patel, F. Vaz, P. O'Flynn, N. Kalavrezos, A.E. Teschendorff, C. Boshoff, S. Beck; Genome Medicine. 2013, 5(2): 15.

26. One-stop Triple-Imaging: The way forward in Head and Neck Cancer management? P. Randhawa, J. Jie, M. Lechner, J. Rimmer, T. Beale, S. Morley, F. Vaz; Bulletin of The Royal College of Surgeons of England. 2013, 95(5): 1-4.

27. A Beta-Mixture Quantile Normalisation method for correcting probe design bias in Illumina Infinium 450k DNA methylation data. A.E. Teschendorff, F. Marabita, M. Lechner, T. Bartlett, J. Tegner, D. Gomez-Cabrero and S. Beck; Bioinformatics. 2013, 29(2): 189-96.

28. Comments on: Interpretation of genome-wide infinium methylation data from ligated DNA in formalin-fixed paraffin-embedded paired tumor and normal tissue. C. Thirlwell, A. Feber, M. Lechner, A.E. Teschendorff, S. Beck; BMC Research Notes. 2012, 13(5): 631.

29. Genome-wide DNA methylation analysis of archival formalin-fixed paraffin-embedded tissue using the Illumina Infinium HumanMethylation27 BeadChip. C. Thirlwell, M. Eymard, A. Feber, A.E. Teschendorff, K. Pearce, M. Lechner, M. Widschwendter, S. Beck; Methods. 2010, 52(3):248-54.

30. Cancer Epigenome. M. Lechner, C. Boshoff, S. Beck; Advances in Genetics. 2010, Vol. 70, Chapter 9; pages 247-276.

Novel treatment approaches for HPV-associated Oropharyngeal Cancer

HPV-associated oropharyngeal squamous cell cancer (OPSCC) has one of the most rapidly rising incidences of any cancer in high income countries, having overtaken cervical cancer in the UK (M. Lechner, et al. Nature Reviews of Clinical Oncology. 2022 and M. Lechner, et al. Lancet Infect. Dis. 2019; 19: 131-132). The increasing rates of HPV-positive OPSC will have a tremendous healthcare cost, with estimated overall cost for treatment in the UK amounting to £2 billion over the next twenty years (in men only). Taking into account broader societal costs, we estimate that HPV-positive OPSCC will cost the UK more than £18 billion over the next twenty years (M. Lechner et al.; Lancet. 2019; 393: 2123). A similar study is currently conducted for the US. Treatment options are still limited.

In collaboration with other UCL researchers we are currently developing novel agents to target HPV viral proteins via the Interdisciplinary programme for PROTAC development for virally-induced head and neck cancers (David Selwood, Rob Sellar, David Shorthouse, Matt Lechner)

MRes Drug Design: Israt Choudhury
MSc Cancer: Yujia Liu (HPV-associated oropharyngeal cancer)
MSc Cancer: Inés Loranca Delgado (EBV-associated nasopharyngeal cancer)

RHINOGENIUS project

In collaboration with Wellcome / EPSRC Centre for Interventional and Surgical Sciences (WEISS)

NPC1000 study (multicentre study on nasopharyngeal cancer) and UCL Shenzhen collaboration (CAMS) for novel treatment approaches for NPC

The highest incidence rates of nasopharyngeal cancer worldwide are reported in Shenzhen and Guangdong province with a population of 110 million people. Recently we published exciting work on the role of SSTR2 in NPC and its impact on prognosis, imaging and therapy. The collaboration with the CAMS (Prof Gary Royle, UCL) allows us to translate these findings into clinical practice for the benefits of patients in one of the most highly affected regions in the world. Moreover, the NPC1000 study aims to comprehensively evaluate the role of EBV and HPV in NPC and is based on our recent Nature Communications publication, including 402 patients.

Publications

1. Cancer of the Nasopharynx. M. Chua, M. Lechner, B. Ma; Cancer: Principles & Practice of Oncology (12th edition)

2. Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy. M. Lechner, et al.; Nature Communications. 2020; 12(1):117. doi: 10.1038/s41467-020-20308-8.

3. SSTR2 in Nasopharyngeal Carcinoma: Relationship with Latent EBV Infection and Potential as a Therapeutic Target. O. Emanuel, J. Liu, V.H. Schartinger, W.L. Nei, Y.Y. Chan, C.M. Tsang, H. Riechelmann, L. Masterson, J. Haybaeck, U. Oppermann, S.M. Willems, M.L. Ooft, G. Wollmann, D. Howard, B. Vanhaesebroeck, V.J. Lund, G. Royle, M.L.K. Chua, K.W. Lo, P. Busson, and M. Lechner; Cancers. 2021; 13(19), 4944; https://doi.org/10.3390/cancers13194944

4. Clinical Outcomes, Kadish-INSICA Staging and Therapeutic Targeting of SSTR2 in Olfactory Neuroblastoma. M. Lechner, et al.; European Journal of Cancer. 2022; 162:221-236; doi: 10.1016/j.ejca.2021.09.046.

Novel surgical instruments for frontal sinus surgery

In collaboration with Wellcome / EPSRC Centre for Interventional and Surgical Sciences (WEISS)

Betel nut-induced oral cancer

UCL – DMH – AGA-ENT Memorandum of Understanding (MoU) signed in 2016. Betel nut is the seed of Areca catechu, a fruit-bearing tropical palm tree commonly cultivated in Asian countries. It is chewed alone or can form the basic ingredient to a variety of chewed products, including betel quid which is prepared with areca nut, betel leaf, slaked lime and spices, with or without tobacco (Gupta et al., 1980). it is chewed by approximately 10% of the world’s population (Figure 1) which makes betel nut the fourth most common psychoactive substance after tobacco, alcohol and caffeine (Gupta & Warnakulasuriya, 2002).

Beat Betel

Betel nut is an addictive substance chewed by one-tenth of the global population and is a known cause of mouth cancer. In a study conducted in Pune, India, we found that 40% of individuals chew betel nut and those who chew were significantly less likely to be aware of its cancer risk, compared to non-chewers. In the UK, we have found that over half of respondents chew betel more than once per year and are also significantly less aware of its cancer risk. Additionally, more than one quarter of GPs were unaware of betel nut being a risk factor for throat cancer. It is evident that this is an issue on both the national and global scale.

One of the main limiting factors to poor survival in mouth cancer is late detection of disease. No validated biomarkers are in clinical use and targeted therapies are lacking. We have sought to advance this field by conducting targeted genomic sequencing of tumor specimens, which we collected in Pune, India, in partnership with Deenanath Mangeshkar Hospital and Foundation Medicine (Cambridge, US). This was based on a previous partnership with Foundation Medicine on the analysis of HPV-associated oropharyngeal cancer (published in Genome Medicine). This analysis enabled us to determine a panel of genes which are frequently mutated in the tumor cohort and may serve as a potential diagnostic or prognostic biomarker.

Publications

1. Betel nut chewing in high-income countries – lack of awareness and regulation. M. Lechner, et al. The Lancet Oncology. 2019; 20: 181-183.

2. Genomic analysis of betel nut-induced oral squamous cell carcinoma. M. Lechner, et al., in preparation

3. Betel nut chewing and global oral cancer burden - lack of awareness and need for action. M. Lechner, et al. submitted for publication

Chronic rhinosinusitis, allergic rhinitis, snoring/OSA, including clinical trials

Allergic Rhinitis (AR) and Chronic Rhinosinusitis (CRS) are common conditions throughout the world, affecting up to 40% and 12% of the general population, respectively. While not associated with severe morbidity nor mortality, both place a substantial burden on healthcare systems and incur large societal costs associated with loss of productivity and consumption. In the US, the direct cost for the management of CRS is up to $13 billion per year and indirect costs exceeding $20 billion per year. For AR, the total economic burden of disease is estimated to be $24.8 billion.

Allergic Rhinitis and Chronic Rhinosinusitis

Matt is local PI of the MACRO trial and the Express study (Exploring Endotypes in Chronic Rhinosinusitis) at his NHS Trust. The MACRO Programme of research has been designed to establish the most effective treatments for CRS patients within the NHS and the Express study aims to analyse intranasal cytokines from patients suffering from chronic rhinosinusitis. Moreover, Matt is Chief Investigator of the COVANOS-2 and COPANOS trial after having successfully delivered the COVANOS UK trial. He runs clinics for patients with both nose /sinus problems and patients with smell dysfunction and offers them a personalised treatment approach and also a personalised approach when offering them to participate in trials depending on their underlying disease pathology.

Publications

2. The burden of olfactory dysfunction during the COVID-19 pandemic in the United Kingdom. M. Lechner, et al. Rhinology. 2022; doi: 10.4193/Rhin22.232.

3. The COVANOS trial – insight into post-COVID olfactory dysfunction and the role of smell training. M. Lechner, et al. Rhinology. 2022; doi: 10.4193/Rhin21.470.

8. Anosmia and hyposmia in health-care workers with undiagnosed SARS-CoV-2 infection. M. Lechner et al.; The Lancet Microbe. 2020, 1(4): e150.

Funding (past and present)

Rhinology And Laryngology Research Fund
Nan Blofeld Fellowship Committee

Interdisciplinary Rhinology, Sinus/Skull Base Surgery and Head & Neck Cancer Programme

Group Leader: Matt Lechner
MD PhD FRCS (ORL-HNS) FHEA, Associate Professor of Surgery