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Doctoral school

PhD in Neuroscience

Logo di PhD in Neuroscience

Francesco Bruno

Phd thesis

Introduction

Primary central nervous system lymphoma (PCNSL) is a rare aggressive non-Hodgkin lymphoma confined to the central nervous system (CNS) and the eye.1,2 Elderly patients significantly prevail among those with PCNSL, and they are more prone to developing severe neurotoxicity from treatments, and tend to have a worse prognosis.3 Confusion, attention and memory impairment, behavioural changes, executive disorders are often early symptoms in elderly PCNSL patients, and may progress over time. Remarkably, high-dose methotrexate (MTX)-based chemotherapy and/or whole brain radiotherapy (WBRT), which represent the standard treatment, may exacerbate cognitive deterioration, especially in case of prolonged survival.4–6 Therefore, it is critical to monitor neurocognitive functions, and possibly avoid reversible causes of neurotoxicity and neurodegeneration in elderly PCNSL patients following treatments.

There is some evidence suggesting that liquid biopsy of the cerebrospinal fluid (CSF) and blood may be useful to detect bioumoral markers of neurodegeneration in PCSNL patients.7 Also, liquid biopsy in PCNSLs may be used to monitor disease control and response to treatments as well: for instance, it has been suggested that the presence of MYD88L265P mutation, which may be found in up to 60-70% of PCNSLs tissue samples, may be investigated in the CSF and blood to confirm the diagnosis before surgery and – potentially – along the disease trajectory to assess the response to treatments.8,9

 

Aims

With this project, we aim to better characterise the patterns of damage to neuronal and glial structure in PCNSL elderly patients undergoing high-dose MTX chemotherapy or WBRT. We will investigate prospectively the neurocognitive features, the presence of markers of neurodegeneration in both CSF and serum, and neuroradiological findings (such as white and grey matter changes) of a clinical cohort of elderly PCNSL patients from the diagnosis throughout the different treatments.

Moreover, we will assess the feasibility of MYD88L265P detection in the tumour tissue, cerebrospinal fluid (CSF), and peripheral blood of patients with suspected PCNSL, and to investigate its use as a potential disease biomarker.

 

References

  1. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncology. 2021;23(8):1231-1251. doi:10.1093/neuonc/noab106
  2. Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014–2018. Neuro-Oncology. 2021;23(Supplement_3):iii1-iii105. doi:10.1093/neuonc/noab200
  3. Liu Y, Yao Q, Zhang F. Diagnosis, prognosis and treatment of primary central nervous system lymphoma in the elderly population (Review). Int J Oncol. 2021;58(3):371-387. doi:10.3892/ijo.2021.5180
  4. Berlin C, Lange K, Lekaye HC, et al. Long-term clinically relevant rodent model of methotrexate-induced cognitive impairment. Neuro-Oncology. 2020;22(8):1126-1137. doi:10.1093/neuonc/noaa086
  5. Gibson EM, Nagaraja S, Ocampo A, et al. Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. Cell. 2019;176(1):43-55.e13. doi:10.1016/j.cell.2018.10.049
  6. Thiel E, Korfel A, Martus P, et al. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. The Lancet Oncology. 2010;11(11):1036-1047. doi:https://doi.org/10.1016/S1470-2045(10)70229-1
  7. Elens I, Dekeyster E, Moons L, D’Hooge R. Methotrexate Affects Cerebrospinal Fluid Folate and Tau Levels and Induces Late Cognitive Deficits in Mice. Neuroscience. 2019;404:62-70. doi:10.1016/j.neuroscience.2019.01.024
  8. Nayyar N, White MD, Gill CM, et al. MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas. Blood Advances. 2019;3(3):375-383. doi:10.1182/bloodadvances.2018027672
  9. Hiemcke-Jiwa LS, Minnema MC, Radersma-van Loon JH, et al. The use of droplet digital PCR in liquid biopsies: A highly sensitive technique for MYD88 p.(L265P) detection in cerebrospinal fluid. Hematological Oncology. 2018;36(2):429-435. doi:10.1002/hon.2489

Research activities

CAREER SUMMARY

In July 2016 I graduated in Medicine.

In December 2021 I completed the residency in Neurology.

Since 01/11/2022 I am PhD Student in Neuroscience (38th cycle), with the project: "Neurodegeneration in Primary Central Nervous System Lymphomas (PCNSL) of Elderly Patients Following Multimodal Treatments". Since then, I have been attending the Division of Neuro-Oncology of the University and City of Heatlh and Science Hospital on a daily basis, being involved in both clinical and research activity.

 

Research activity (November 2022 - up to September 2023)

 

  1. Clinical research activity (main projects)

I am personally involved in data collection / analysis process of the following clinical projects:

  • PhD project (see above): collection of clinical and CSF/blood data of PCNSL patients and preliminary analysis on the role of the MYD88 L265P mutation as a diagnostic and predictive marker of response to treatments along the disease trajectory (see the 2023 Annual report for details).

 

  • New entities of diffuse gliomas according to the 2021 WHO Classification: two different datasets have been created and are being prospectively filled with clinical and MRI data of patients with i) IDH-mutant grade 4 astrocytomas / lower-grade oligodendrogliomas with CDKN2A/B homozygous deletion; ii) IDH-wildtype astrocytomas with molecular features of glioblastoma. The purpose of this observational prospective study is to better clarify the clinical / MRI characteristics and role of surgery and adjuvant treatments among patients with those rare tumours. This is an AINO (Italian Association of Neuro-Oncology) project, and involves several other Institutions across Italy.

 

  • Brain tumour-related epilepsy: two retrospective studies have been performed which investigate the factors correlated with the natural course of seizures among i) IDH-mutant lower-grade diffuse gliomas; ii) brain metastases. Preliminary data have been presented in different national, European and international congresses, and two papers will be finalised soon with the definitive results.

 

  • Intracranial ependymomas of the adult: a retrospective / prospective data collection and analysis of the clinical features and impact of treatments across (the recently defined) molecular subgroups of patients with very rare intracranial ependymomas (in collaboration with Besta Institute).

 

  • Response Assessment in Neuro-Oncology (RANO) projects. RANO is an international multidisciplinary board aiming to define standard criteria to assess response to treatments in brain tumour patients. I am an active member of two RANO groups (RANO resect; RANO seizures). With the RANO resect group, we identified new prognostic criteria based on the volume analysis of the residual tumour in glioblastoma patients after both first and second surgery (see Publications); with the RANO seizures group we are aiming to identify new tools (e.g., questionnaires) to collect data on seizure control along the disease trajectory in glioma patients, and integrate this information together with the MRI response.

 

  • Prospective collection of data of patients from leptomeningeal spread from primary and secondary brain tumours.

 

  • Prospective collection of data of patients with rare molecular alterations with therapeutic interest for precision medicine.

 

  1. Clinical trials activity

I am Sub-Investigator of the following clinical trials currently ongoing in our Institution:

  • AG881 “INDIGO” phase 3 trial
  • APL-101-01 phase 1/2 trial
  • FIGHT 209 trial

 

  1. PhD Educational activity
  • Welcome meeting 38th cycle and 1st Enrica Marzola award ceremony (Turin, 07/12/2022).
  • Toolbox Course (Complementary Training): Introduction to research methodology - prof. Daniele Romano (10-17-24/02/2023)

 

  1. Participation to scientific societies
  • Member of the European Association of Neuro-Oncology (EANO) Youngster group from November 2022 (activity: monthly online meetings; Journal Club; organisation of the annual EANO meeting).
  • Member of the Italian Association of Neuro-Oncology (AINO) Youngster group from November 2022 (activity: monthly online meetings; Journal Club; webinars; organisation of the annual EANO meeting).
  • Member of the Italian Society of Neurology (SIN).
  • Member of the European Academy of Neurology (EAN).
  • Member of the American Society for Neuro-Onoclogy (SNO)

 

  1. Congresses / Webinars
  • Annual national congress of the Italian Association of Neuro-Oncology (AINO) (role: speaker) (Padua, Italy, 10-12/11/2022).
  • Annual meeting of the Society for Neuro-Oncology (SNO) congress (role: speaker) (Tampa, USA, 16-20/11/2022).
  • Annual national congress of the Italian Society of Neurology (SIN) (role: speaker) (Milan, Italy, 03-06/12/2022).
  • Joint AINO-SINCh (Italian Society of Neurosurgery) webinar (speaker) (03/05/2023).
  • Annual congress of the European Academy of Neurology (EAN) (role: speaker) (Budapest, 01-04/07/2023).
  • Annual meeting of the European Association of Neuro-Oncology (EANO) (role: speaker; chair) (Rotterdam, 21-24/09/2023)

 

  1. Awards
  • “Carla Russo” award for the best clinical publication on an International journal on diffuse gliomas (for the paper: Bruno et al., IDH wild-type grade 2 diffuse astrocytomas: prognostic factors and impact of treatments within molecular subgroups, Neuro Oncol. 2021;noab239, https://doi.org/10.1093/neuonc/noab239).
  • SIN award 2022.
  • SNO award 2023 (for the oral contribution: “Seizure outcome across disease trajectory in IDH-mutant grade 2 gliomas: which is the impact of standard antineoplastic treatments?”)

 

PUBLICATIONS (up to 20/09/2023)

 

Karschnia P, Dietrich J, Bruno F, et al., Surgical management and outcome of newly diagnosed glioblastoma without contrast enhancement ('low grade appearance') - a report of the RANO resect group. Neuro Oncol, 2023, noad160. Advance online publication. https://doi.org/10.1093/neuonc/noad160

 

Soffietti R, Pellerino A, Bruno F, Mauro A, Rudà R. Neurotoxicity from Old and New Radiation Treatments for Brain Tumors. Int. J. Mol. Sci. 2023, 24, 10669. https://doi.org/10.3390/ijms241310669

 

Caccese M, Desideri I, Padovan M, Bruno F et al. Association between thyroid function and regorafenib efficacy in patients with relapsed wild-type IDH glioblastoma: a large multicenter study. J Neurooncol (2023). https://doi.org/10.1007/s11060-023-04356-w

 

Pellerino A, Bruno F, Soffietti R et al. Antiangiogenic Therapy for Malignant Brain Tumors: Does It Still Matter?. Curr Oncol Rep 25, 777–785 (2023). https://doi.org/10.1007/s11912-023-01417-1

 

Karschnia P, Dono A, Young J S, Juenger ST, Teske N, Häni L, Sciortino T, Mau CY, Bruno F, Nunez L, Morshed RA, Haddad AF, Weller M, van den Bent M, Beck J, Hervey-Jumper S, Molinaro AM, Tandon N, Rudà R, Vogelbaum MA, … Tonn JC (2023). Prognostic evaluation of re-resection for recurrent glioblastoma using the novel RANO classification for extent of resection: A report of the RANO resect group. Neuro Oncol. 2023, noad074. Advance online publication. https://doi.org/10.1093/neuonc/noad074

 

Rudà R *, Bruno F *, Pellerino A, Pronello E, Palmiero R, Bertero L, Crasto S, Polo V, Vitaliani R, Trincia E, Internò V, Porta C, Soffietti R. Observational real-life study on regorafenib in recurrent glioblastoma: does dose reduction reduce toxicity while maintaining the efficacy? J Neurooncol. 2022 Oct 30. doi: 10.1007/s11060-022-04155-9. Epub ahead of print. PMID: 36309895. * equal contribution

 

Karschnia P, Young JS, Dono A, Häni L, Juenger ST, Sciortino T, Bruno F, Teske N, Morshed RA, Haddad AF, Zhang Y, Stoecklein S, Vogelbaum MA, Beck J, Tandon N, Hervey-Jumper S, Molinaro AM, Rudà R, Bello L, Schnell O, Esquenazi Y, Ruge MI, Grau SJ, van den Bent M, Weller M, Berger MS, Chang SM, Tonn JC. TERT promotor status does not add prognostic information in IDH-wildtype glioblastomas fulfilling other diagnostic WHO criteria: A report of the RANO resect group. Neurooncol Adv. 2022 Sep 29;4(1):vdac158. doi: 10.1093/noajnl/vdac158. PMID: 36325373; PMCID: PMC9616057.

 

Karschnia P, Young JS, Dono A, Häni L, Sciortino T, Bruno F, Juenger ST, Teske N, Morshed RA, Haddad AF, Zhang Y, Stoecklein S, Weller M, Vogelbaum MA, Beck J, Tandon N, Hervey-Jumper S, Molinaro AM, Rudà R, Bello L, Schnell O, Esquenazi Y, Ruge MI, Grau SJ, Berger MS, Chang SM, van den Bent M, Tonn JC. Prognostic validation of a new classification system for extent of resection in glioblastoma: a report of the RANO resect group. Neuro Oncol. 2022 Aug 12:noac193. doi: 10.1093/neuonc/noac193. Epub ahead of print. PMID: 35961053.

 

Saaid A, Monticelli M, Ricci AA, Orlando G, Botta C, Zeppa P, Bianconi A, Osella-Abate S, Bruno F, Pellerino A, Rudà R, Cassoni P, Garbossa D, Cofano F, Bertero L. Prognostic Analysis of the IDH1 G105G (rs11554137) SNP in IDH-Wildtype Glioblastoma. Genes (Basel). 2022 Aug 12;13(8):1439. doi: 10.3390/genes13081439. PMID: 36011350; PMCID: PMC9408597.

 

Bruno F, Pellerino A, Pronello E, Palmiero R, Bertero L, Mantovani C, Bianconi A, Melcarne A, Garbossa D, Rudà, R. Elderly Gliobastoma Patients: The Impact of Surgery and Adjuvant Treatments on Survival. A Single Institution Experience. Brain Sci. 2022, 12, 632. https://doi.org/10.3390/brainsci12050632

 

Pellerino A, Bruno F, Palmiero R, et al. Clinical Significance of Molecular Alterations and Systemic Therapy for Meningiomas: Where Do We Stand?. Cancers (Basel). 2022;14(9):2256. Published 2022 Apr 30. doi:10.3390/cancers14092256

 

Rudà R, Bruno F, Pellerino A, Soffietti R. Ependymoma: Evaluation and Management Updates [published online ahead of print, 2022 Apr 6]. Curr Oncol Rep. 2022;10.1007/s11912-022-01260-w. doi:10.1007/s11912-022-01260-w

 

Mo F, Meletti S, Belcastro V, Quadri S, Napolitano M, Bello L, Dainese F, Scarpelli M, Florindo I, Mascia A, Pauletto G, Bruno F, Pellerino A, Giovannini G, Polosa M, Sessa M, Conti Nibali M, Di Gennaro G, Gigli GL, Pisanello A, Cavallieri F, Rudà R. Lacosamide in monotherapy in BTRE (brain tumor-related epilepsy): results from an Italian multicenter retrospective study. J Neurooncol. 2022 Apr 9. doi: 10.1007/s11060-022-03998-6. Epub ahead of print. PMID: 35397759.

 

Bruno F, Pellerino A, Palmiero R, Bertero L, Mantovani C, Garbossa D, Soffietti R, Rudà R. Glioblastoma in the Elderly: Review of Molecular and Therapeutic Aspects. Biomedicines. 2022 Mar 10;10(3):644. doi: 10.3390/biomedicines10030644. PMID: 35327445; PMCID: PMC8945166.

 

Rudà R*, Bruno F*, Ius T et al, IDH wild-type grade 2 diffuse astrocytomas: prognostic factors and impact of treatments within molecular subgroups, Neuro Oncol. 2021;noab239, https://doi.org/10.1093/neuonc/noab239 * equal contribution

 

Pellerino A, Soffietti R, Bruno F, Manna R, Muscolino E, Botta P, Palmiero R, Rudà R. Neratinib and Capecitabine for the Treatment of Leptomeningeal Metastases from HER2-Positive Breast Cancer: A Series in the Setting of a Compassionate Program. Cancers 2022, 14, 1192. https://doi.org/10.3390/cancers14051192

 

Cremascoli R, Sparasci D, Giusti G, Cattaldo S, Prina E, Roveta F, Bruno F et al. Effects of Circadian Phase Tailored Light Therapy on Sleep, Mood, and Cognition in Alzheimer's Disease: Preliminary Findings in a Pivotal Study. Front Physiol. 2022;12:755322. Published 2022 Jan 6. doi:10.3389/fphys.2021.755322

 

Bruno F, Pellerino A, Bertero L et al. Targeted Therapies in Rare Brain Tumours. International Journal of Molecular Sciences. 2021; 22(15):7949. https://doi.org/10.3390/ijms22157949

 

Bruno F, Palmiero RA, Ferrero B et al, Pembrolizumab-Induced Isolated Cranial Neuropathy: A Rare Case Report and Review of Literature. Front  Neurol. 2021;12:669493. https://doi: 10.3389/fneur.2021.669493

 

Bruno F, Pellerino A, Bertero L et al, Long-term survival of a sacro-coccygeal myxopapillary ependymoma with extra-neural metastases: case report and review of the literature. Neurol Sci. 2020;41, 1955–1957. https://doi.org/10.1007/s10072-020-04269-w

 

Diamanti L, Picca A, Bini P, Gastaldi M, Alfonsi E, Pichiecchio A, Rota E, Rudà R, Bruno F et al, Characterization and management of neurological adverse events during immune-checkpoint inhibitors treatment: an Italian multicentric experience. Neurol Sci. 2021. https://doi.org/10.1007/s10072-021-05561-z

 

Pellerino A, Bruno F, Rudà R et al. Systemic Therapy for Lung Cancer Brain Metastases. Curr. Treat. Options in Oncol. 2021;22, 110. https://doi.org/10.1007/s11864-021-00911-7

 

Pellerino A, Bruno F, Internò V et al, Current clinical management of elderly patients with glioma, Expert Rev Anticancer Ther (2020). 20:12, 1037-1048. https://doi.org/10.1080/14737140.2020.1828867

 

Rudà R, Bruno F, Soffietti R et al, What Have We Learned from Recent Clinical Studies in Low-Grade Gliomas?. Curr Treat Options Neurol. 2018;20, 33 (2018). https://doi.org/10.1007/s11940-018-0516-3

 

Rudà R, Pellerino A, Franchino F, Bertolotti C, Bruno F et al. Lacosamide in patients with gliomas and uncontrolled seizures: results from an observational study. J Neurooncol. 2018;136, 105–114. https://doi.org/10.1007/s11060-017-2628-0

 

Last update: 25/09/2023 13:00
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