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Diagram shows the clinical management algorithm for patients with infiltrative glioma. The role of the index test (MRP) for differentiating LGGs and HGGs at first presentation is shown with alternative tests (MRS, DWI, PET). These advanced MRI techniques are also used to identify progression or recurrence during interval scanning and are included, although they are outside the scope of this review. *May or may not be offered, depending on institutional/regional practice.Abbreviations: LGG: Low‐grade glioma, HGG: High‐grade glioma,MRP: Magnetic resonance perfusion, MRS: magnetic resonance spectroscopy, DWI: Diffusion‐weighted imaging, PET: Positron emission tomography
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Figure 1

Diagram shows the clinical management algorithm for patients with infiltrative glioma. The role of the index test (MRP) for differentiating LGGs and HGGs at first presentation is shown with alternative tests (MRS, DWI, PET). These advanced MRI techniques are also used to identify progression or recurrence during interval scanning and are included, although they are outside the scope of this review. *May or may not be offered, depending on institutional/regional practice.

Abbreviations: LGG: Low‐grade glioma, HGG: High‐grade glioma,MRP: Magnetic resonance perfusion, MRS: magnetic resonance spectroscopy, DWI: Diffusion‐weighted imaging, PET: Positron emission tomography

Flow diagram.
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Figure 2

Flow diagram.

Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study using QUADAS 2 tool, applied on study design and included patient data
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Figure 3

Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study using QUADAS 2 tool, applied on study design and included patient data

Risk of bias and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies
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Figure 4

Risk of bias and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies

Coupled forest plots of included studies using rCBV threshold of < 1.75 for differentiating low grade gliomas from high‐grade gliomas.
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Figure 5

Coupled forest plots of included studies using rCBV threshold of < 1.75 for differentiating low grade gliomas from high‐grade gliomas.

Summary ROC Plot of DSC MR perfusion using rCBV threshold of 1.75 for differentiating low grade gliomas from high‐grade gliomas. In this review, a positive test or rCBV < 1.75 implied an LGG diagnosis, while a negative test or rCBV > 1.75 suggested an HGG diagnosis. In the SROC plot, each study is represented by an open circle with emanating lines, representing the sensitivity and specificity with their confidence intervals. The size of the open circle is proportional to the study sample size. The shaded circle represents the pooled sensitivity and specificity surrounded by a 95% confidence ellipse (dotted line), which in this case is 0.830 (95% CI 0.657, 0.926) and 0.479 (95% CI 0.086, 0.900), respectively.
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Figure 6

Summary ROC Plot of DSC MR perfusion using rCBV threshold of 1.75 for differentiating low grade gliomas from high‐grade gliomas. In this review, a positive test or rCBV < 1.75 implied an LGG diagnosis, while a negative test or rCBV > 1.75 suggested an HGG diagnosis. In the SROC plot, each study is represented by an open circle with emanating lines, representing the sensitivity and specificity with their confidence intervals. The size of the open circle is proportional to the study sample size. The shaded circle represents the pooled sensitivity and specificity surrounded by a 95% confidence ellipse (dotted line), which in this case is 0.830 (95% CI 0.657, 0.926) and 0.479 (95% CI 0.086, 0.900), respectively.

rCBV ‐ Law Threshold.
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Test 1

rCBV ‐ Law Threshold.

Summary of findings Summary of findings table

Population

Almost all adults

Setting

Mostly university hospitals, employing exclusively 1.5T or 3T MRI scanners

Index test

Dynamic susceptibility contrast MR perfusion (commonly gradient echo rather than spin echo sequence acquisition), usually without contrast preload, typically using arterial input function or gamma variate function post‐processing algorithms, and preferentially using region‐of‐interest method to obtain Max rCBV values (CBV ratio of tumour: contralateral normal appearing white matter)

Importance

For solid and non‐enhancing brain tumours with low rCBV, patients with no or little neurologic deficit may opt for conservative management over surgery to avoid early neurologic disability. Meanwhile, patients with high rCBV could favour early treatment for better tumour control.

Reference standard

All with histologic examinations, majority with resection.

Studies

Mostly prospective cross sectional studies (no case‐control studies)

Positive Test

Summary accuracy
(95% CI) using bivariate model

No. of study participants / selected patients
(No. of studies)

Prevalence

Implications

Quality of studies
(Based on QUADAS‐2 applied on study design and selected patients)

Comments

rCBV threshold <1.75 indicates LGG

Sensitivity

(proportion of LGG detected by MR perfusion)

0.83

(0.66, 0.93)

Specificity

(proportion of HGG detected by MR perfusion)

0.48

(0.09 to 0.90)

392 patients /

115 with solid non‐enhancing Grade II‐IV gliomas who underwent tissue sampling within 2 months of MR perfusion

(7 studies)

In a hypothetical population of solid and non‐enhancing Grade II‐IV gliomas, the prevalence of LGGs and HGGs is 72% and 28%, respectively.

Given 100 patients with solid and non‐enhancing infiltrative gliomas, 72 will have LGG and 28 with HGG.

Of 72 patients with LGG, it is expected 12 patients will be misclassified to have HGG (but this could potentially be between 5 to 24 patients) and may undergo surgery, thus risking early neurologic deterioration. Meanwhile, of 28 patients with HGG, 15 will be misclassified to have LGG (but this could be between 3 to 25 patients), which may lead to a delay in treatment that can potentially adversely affect outcomes.

Generally low risk of bias in the patient selection domain, excepting 2 out of 7 studies with unclear patient sampling and inappropriate exclusion of small tumours.

High risk of bias in the index test domain, mainly because 6 out of 7 studies did not use a pre‐specified threshold. However this did not affect meta‐analysis as we used a common rCBV threshold of 1.75.
Generally low risk of bias in the reference standard domain, excepting 2 out of 7 studies with unclear method of histologic confirmation and/or presence of blinding.
Low risk of bias in the flow and timing domain.

Low concerns of applicability for the patient selection, index test and reference standard domains by using patient‐level data.

Low numbers (4 to 48) with target and alternative conditions per study and only 2 studies had >20 patients.

In general, individual studies had heterogeneous sensitivity and specificity, both with wide confidence intervals.

Only 1 study had low risk of bias and low concern of applicability across all domains.

Five studies were considered good quality (i.e., with low risk of bias in the domains of reference standard and flow & timing). Their sensitivity analysis yielded sensitivity 0.80 (95% CI 0.61 to 0.91) and specificity 0.67 (95% CI 0.07 to 0.98).

Subgroup analysis showed sensitivity/specificity of [0.92 (95% CI 0.55 to 0.99)/ 0.42 (95% CI 0.02 to 0.95) in astrocytomas and 0.77 (95% CI 0.46 to 0.93)/0.53 (95% CI 0.14 to 0.88) in oligodendrogliomas + oligoastrocytomas.

Data were too sparse to investigate any differences across subgroups.

HGG: high‐grade glioma, LGG: low‐grade glioma, rCBV: relative cerebral blood volume

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Summary of findings Summary of findings table
Table 1. World Health Organization (WHO) Grading of Brain Tumors*

WHO Grade

Tumour histology

I**

Pilocytic astrocytoma

Subependymal giant cell astrocytoma

Pleomorphic xanthoastrocytoma

Ganglioglioma

Ependymoma

II

Diffuse astrocytoma

Oligodendroglioma

Oligoastrocytoma

III

Anaplastic astrocytoma

Anaplastic oligodendroglioma

Anaplastic oligoastrocytoma

IV

Glioblastoma multiforme

Gliomatosis cerebri

* Partial listing and specific to the tumour histology types relevant to this review.

**These tumours are included in this table for reference only and are not part of the review.

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Table 1. World Health Organization (WHO) Grading of Brain Tumors*
Table 2. rCBV per tumour grade and per tumour histology

Included studies

LGG

(Grade II)

HGG

(Grade III+IV)

DA

OA

OG

AA

AOA

AOG

Cuccarini 2016

1.15 ± 0.95

1.18 + 0.8

1.19 ± 0.76

1.12 ± 1.13

1.22 ± 0.57

1.15 ± 0.53

1.33 ± 0.98

Falk 2014

1.30 + 0.48

1.76 + 0.93

1.48 + 0.69

1.20 + 0.21

1.19 + 0.32

2.22 + 1.18

0.86

1.76

Guzman de Villoria 2014

1.07 + 0.79

0.75

0.98 + 0.29

1.24 ±1.33

0.75

Koob 2016

0.8 + 0.04

0.8 + 0.6

[0.77]

0.82

[0.41]

1.28

Kudo 2016

3.1 ± 1.19

3.83 ± 2.34

2.31 ±1.23

3.88 ±.46

3.8 + 2.3

Maia 2004

1.16 ± 0.63

3.2 ± 0.35

0.9 ±.43

1.98 ± 0.57

1.27

3.24 ± 0.37

2.99

Yang 2002

1.29 ± 0.17

1.76 ± 0.08

1.29 ± 0.17

1.81

1.7

LGG: Low‐grade glioma, HGG: high‐grade glioma, DA: diffuse astrocytoma, OA: oligoastrocytoma, OG: oligodendroglioma, AA: anaplastic astrocytoma, AOA: Anaplastic oligoastrocytoma, AOG: anaplastic oligodendroglioma.

Nearly all HGGs are Grade III, except for one case of Grade IV/glioblastoma from Cuccarini 2016, with rCBV of 0.3. Bracketed values in Koob 2016 are included for completion but represent unspecified gliomas, with no reported histology.

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Table 2. rCBV per tumour grade and per tumour histology
Table Tests. Data tables by test

Test

No. of studies

No. of participants

1 rCBV ‐ Law Threshold Show forest plot

7

115

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Table Tests. Data tables by test