**4. Neuro-radiological updates for high-grade gliomas**

The updated aims of the working group of the Response Assessment in Neuro-Oncology (RANO) continue to provide guidelines for a uniform criteria for the assessment of determin‐ ing the progression and treatment response of high-grade gliomas [12]. RANO guidelines will be discussed in detail here, as it is imperative to emphasize the clinical need for consistency and standardization of imaging, for a reliable assessment of tumor burden and progression.

The RANO guidelines refer to the reliability of imaging data and reproducibility of the acquired results to be undertaken no later than 72 hours postsurgical resection and is deter‐ mined by the standardization of gadolinium dose, slice thickness ≥5 mm or no more than twice the thickness of a measurable lesion. We now describe RANO guidelines nomenclature as per the updated guidelines [12, 13]:


Furthermore, there are four RANO categories to treatment response:

**•** Complete response

**2. Twenty-first century epidemiological trends**

**3. The genetic risk of glioma**

270 Neurooncology - Newer Developments

Caucasians, and only 5.1% of patients survive five years after diagnosis.

considered on the molecular IDH marker status of the tumor [10].

The most recent 2015 Statistical Report of the Central Brain Tumor Registry [1] documents the epidemiology of glioblastomas from 2008 to 2012. Glioblastomas remain the most common malignant histology (46.1%) of all primary malignant brain tumors, with an age-proportion‐ al incidence peaking at the ninth decade of life (age range 75-84 years). Of interest, glioblas‐ tomas have been shown to be 1.6 times more common in males, twice as common in

The lifetime risk of gliomas is 4-5 per 1000 of the general population. Thus, inheriting of one of the low penetrance glioma risk variants may increase the risk by 20-40% to approximately 6 per 1000 [2]. The risk loci of glioma variants have been identified as ten inherited variants near eight genes, 2 with stratification leading to an increase in the risk of developing gliomas. The common inherited variants are named for the nearby genes of TERC, TERT, EGFR, CDKN2B, PHLDB1, CCDC26, TP53 and RTEL1, and are not directly involved in protein coding [3]. Of interest, these variants increase the odds ratio of gliomagenesis on a scale of 1.2– 1.4. TERT, TERC, and RTEL1 are involved in telomere maintenance, and it has been hypothe‐ sized that a longer telomere length may possibly contribute to risk of gliomas [4, 5]. Additionally, of note, is the predictive and prognostic value of gliomas with TERT gene promoter mutations in association with isocitrate dehydrogenase (IDH) mutations and loss of heterozygosity of 1p/19q [4]. The less common risk loci are noted to correlate with higher odds ratios, and these are located near TP53 (2.4-fold increase in relative risk) and CCDC26 (6.3-fold increase in relative risk) especially in the presence of an IDH mutation or an oligodendro‐ glial component. Moreover, the UCSF Adult Glioma Study noted that population screening for the risk loci near the CCDC26 yielded significantly more false positives than true posi‐ tives, and hence the yield for undertaking this screening test of risk loci was extremely low [2]. At this point, with our current knowledge arsenal, the authors advise the following three acquired molecular glioblastoma markers to be identified and then further correlate to survival and outcome: IDH mutation, 1p/19q, and TERT promoter mutation. These molecular glio‐ blastoma markers are then further subdivided into five glioma subgroups to further elicit the pathways of gliomas in pathways: TERT mutated only (most common in approximately half of the cases), IDH mutated only, TERT and IDH mutation (least common), triple negative and triple positive [6, 7]. Of note, the IDH mutation status was analyzed in the BELOB trial, which showed a lower median overall survival for patients with wild-type IDH (8 months) com‐ pared with median survival of 20 months for patients with an IDH mutational status [8]. We also note here, in our clinical role as Neurosurgical Oncologists, of the recent landmark paper associating a definite survival benefit after maximal surgical resection, including both enhancing and nonenhancing tumor, resulting in an improved prognosis observed in the IDH1 mutant subgroup [9]. Thus, individualized surgical strategies for high-grade gliomas must be

This refers to the lack of all enhancing lesions for a minimum of four weeks and the appearance of new lesions, this should be married to the patients' clinical picture of stability or response, whilst weaning or off steroids.

**•** Partial response

This refers to no progression of nonmeasurable lesions and no new lesions. Specifically, this is defined as ≥50% decrease in sum of all products of diameters (SPD) of all target lesions with stable clinical symptomatology and a stable steroid dose.

**•** Progressive disease

This differs from partial response with having ≥25% increase in the sum of target lesions, with significant increase in nonenhancing lesions, with clinical deterioration with no decrease in steroid dose and/or a new radiological lesion.

**•** Stable disease

This is the radiological diagnosis of exclusion of neither complete nor partial response, with lack of progression seen.

*As per the RANO guidelines, criteria for progressive disease is met when the majority of new enhancement is noted beyond the 80% isodose line of radiotherapy or on histopathological confirmation. This is an important point for us to bear in mind, as a third of glioblastoma patients may be reported on as undergoing pseudoprogression, thus this term needs to be utilized in accordance with the RANO guidelines. Also of importance, is the pseudoresponse seen post-antiangiogenic therapy (anti-vascular endothelial growth) which decrease the permeability of the blood-brain barrier thereby decreasing the gadolinium enhancement* [14]. *Radiological surveillance with T2/FLAIR is sensitive in identifying vasogenic edema and used in combination with DWI is a increases the likelihood of identifying tumor burden* [15]. *An improvement in T2/FLAIR is associated with improved survival and decreased mortality, DWI remains an independent predictor of progression free survival at 6 months* [12, 15].

RANO guidelines state that all radiological responses must persist for four weeks prior to be considered 'true' progression or response: this is the crux of the RANO guidelines.
