Prognostic Potential of Olfactory Function in Glioblastoma: a Prospective Observational Study

Background: Olfactory impairment is frequent in glioblastoma and is associated with poor overall survival. However, earlier studies were limited by confounding of important predictive factors and the lack of long-term olfactory assessments to evaluate treatment-related neurotoxicity.

Aim: To determine whether olfactory function is an independent prognostic marker for survival, quality of life and neurocognitive outcome in glioblastoma.

Design: Prospective, multicenter cohort study with 64 glioblastoma patients and 64 comparable controls without tumor disease. Patients were stratified by baseline olfactory status, extent of resection, radiologic involvement of olfactory regions,O6-methylguanine DNA methyltransferase (MGMT) promoter methylation, age, and Karnofsky performance status.

Methods: Olfactory function will be serially assessed from diagnosis to treatment using Sniffin' Sticks (identification and threshold tests). Psychosocial assessments, neurocognitive testing and quality of life assessments will be performed at intervals. Coronal T2- and T1-weighted MRI scans will be evaluated independently by blinded neuroradiologists to identify olfactory involvement.

Next-generation sequencing will be used to investigate molecular correlates of hyposmia. As part of a parallel translational study, blood samples will be taken to analyze extracellular vesicles.

Olfactory testing:

In the identification test, 12 sniffin sticks are presented, which the patient has to name using a selection card with four terms each. Both nostrils are tested individually at each visit during the identification test. A correct answer scores one point. A maximum of 12 points is possible.

The threshold test consists of 16 dilution levels. Each level contains one sniffin stick with odor and two blanks. All three sniffin sticks of a dilution level are presented to the patient one after the other with eyes closed. The patient must indicate which of the three sticks contains an odor. Depending on whether the patient gives the correct answer, the three sniffin sticks in the next higher or next lower level are presented next. A maximum of 16 points is possible.

• olfactory testing (threshold and identification test) (Diagnostic test): In the identification test, 12 sniffin sticks are presented, which the patient has to name using a selection card with four terms each. Both nostrils are tested individually at each visit during the identification test. A correct answer scores one point. A maximum of 12 points is possible. The threshold test consists of 16 dilution levels. Each level contains one sniffin stick with odor and two blanks. All three sniffin sticks of a dilution level are presented to the patient one after the other with eyes closed. The patient must indicate which of the three sticks contains an odor. Depending on whether the patient gives the correct answer, the three sniffin sticks in the next higher or next lower level are presented next. A maximum of 16 points is possible.

Primary outcomes

• Overall survival [From tumor diagnosis to death (usually 6 to 24 months)]: Overall survival in relation to olfactory function

Secondary outcomes

• Progression free survival [From date of first surgery until the date of first progression (MRI)]: Progression free survival in relation to olfactory function
• Neurocognition [From enrollment to 2 years after the end of radiotherapy]: Neurocognition in relation to olfactory function The following tests are used for neurocognition testing: * Immediate and delayed story recall from the Rivermead Behavioural Memory Test * Number span (forward and backward) and block span (forward and backward) from the Wechsler Memory Scale * Phonemic word fluency from the Regensburg Word Fluency Test (phonemic) * Trail Making Test A and B
• Quality of Life (QoL) [From enrollment to 2 years after the end of radiotherapy]: Quality of Life in relation to olfactory function The following questionnaires are used to assess quality of life: * EORTC QLQ-C30 (Version 3.0; Part A with 28 questions on a Likert scale, 28 to 112 points, Higher score means lower quality of life; Part B with 2 questions on a Likert scale, 2 to 14 points, Lower score means lower quality of life ) * EORTC QLQ-BN20 (20 questions on a Likert scale; 20 to 80 points; Higher score means lower quality of life)
• Psychological condition [From enrollment to 2 years after the end of radiotherapy]: Psychological well-being in relation to olfactory function The following psychiatric questionnaires are used: * Patient Health Questionnaire-8 (PHQ-8): 8 questions on a Likert scale, score 0 to 24, higher score indicate more depression * Generalized Anxiety Disorder 7 (GAD-7): 7 questions on a Likert scale, score 0 to 21, higher score indicate more anxiety * National Comprehensive Cancer Network (NCCN) Distress Thermometer: Score 1 to 10, higher score indicate more distress

Sex: All, ages: 18 Years to any, accepts healthy volunteers

Inclusion Criteria:

* At least 18 years of age
* Newly-diagnosed glioblastoma (IDH wild-type)
* Never received prior chemotherapy
* Never received radiotherapy to the head or neck before
* KPS ≥ 70
* No history of severe head or brain trauma requiring ICU admission or classified as Glasgow Coma Scale grade 3
* No respiratory infection at the time of inclusion
* No significant aphasia

Exclusion Criteria:

* Presence of Neurodegenerative diseases (e.g. Parkinson's disease, Alzheimer's disease, Huntington's disease, Korsakoff's syndrome, Pick's disease, Shy-Drager syndrome)
* History of invasive tumors or surgery in the head or neck area, except for surgeries for non-invasive skin tumors (e.g. basal cell carcinomas)
* Permanent olfactory impairment following infections (e.g., influenza, coronavirus)
* Conditions that, in the examiner's judgment, could interfere with the participant's study compliance (e.g., schizophrenia)
* Language barriers likely to interfere with participation or comprehension of study procedures.

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• Results publication: Oster C, Matyar A, Schmidt T, Hummel T, Hattingen E, Jokisch M, Jokisch D, Grieger J, Cappello G, Kizina K, Lazaridis L, Ahmadipour Y, Rauschenbach L, Stuschke M, Pottgen C, Guberina N, Tertel T, Giebel B, Dreizner GL, Barbato F, Skoda EM, Scheffler B, Muther M, Herrmann K, Kleinschnitz C, Sure U, Deuschl C, Glas M, Kebir S. Decoding glioblastoma survival: unraveling the prognostic potential of olfactory function in a prospective observational study. Neurol Res Pract. 2025 Jul 24;7(1):51. doi: 10.1186/s42466-025-00410-2. PMID 40708059