Old Discovery Leading to New Era: Metabolic Imaging of Cancer with Deuterium MRI

Round 1

Reviewer 1 Report

The authors provide a short overview of recent work using 2H as label for metabolic imaging using in vivo MRS(I). The Opinion manuscript concludes with suggestions of what is needed for this technique to become a valuable method for use in imaging of cancer in clinical settings.  

Here some suggestions for additions/improvements/corrections:

L34: technically incorrect since FDG is trapped in its phosphorylated form...

L44: reference "4": not exactly the most suited reference for hyp13C: a preclinical study in brain of healthy mouse...

L55: reference "10": this paper also mentions the use of 2H-labeled substrates for study of metabolism in the Discussion. 

L61: outer volume suppression: could be added that this is specific for brain applications

L71: alpha-ketoglutarate

L82: that's not exactly a very accurate description of the Warburg effect: a shift from oxidative to glycolytic glucose metabolism in the presence of sufficient oxygen. Lower glucose could be a consequence but this is not necessarily the case. 

Fig.1 panel 3: suggest to change textbox to "acquisition of 2H MRSI..."; figure legend title: Workflow of a DMI study

L101: De Feyter instead of Feyter

L103: studies were in mice, not rats

L102: DMI instead of MRI?

L122: studies were in mice, not rats

L140: This section omits the use of fumarate to detect dead cells, see work by Kevin Brindle's lab. That would be a useful addition. 

L150 - 161: given the goal of the manuscript to discuss DMI as a promising tool for use in the clinic, this in vitro example could be omitted from the manuscript. 

L208: De Graaf instead of Graaf

L242: typo: Glx

L254-256: Without a scientific paper describing these coils, this information on modular RF receive arrays seems a bit out of place. Further, how does transmission take place?

L267: this section: Especially for low frequency X-nuclei it is beneficial to go to high field because the increase in SNR has a supralinear relation with magnetic field strength. 

Many argue that the only relevant field strength for clinical applications is 3T, given its widespread use. The extremely high field examples are a bit out of place in this context, but could benefit research, of course. 

 

 

 

Author Response

L34: technically incorrect since FDG is trapped in its phosphorylated form...

L34: changed to 'However, 18F-FDG-PET is affected by several factors including altered blood glucose levels, duration of fasting, muscle activation such as exercise and steroids.'

L44: reference "4": not exactly the most suited reference for hyp13C: a preclinical study in brain of healthy mouse...

L44: reference "4" changed to 'Ma J, Pinho MC, Harrison CE, et al. Dynamic ¹³ C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans. Magn Reson Med. 2022;87(3):1136-1149. doi:10.1002/mrm.29049'

L55: reference "10": this paper also mentions the use of 2H-labeled substrates for study of metabolism in the Discussion. 

L55: changed to 'In 1987, ²H MRS was developed with deuterated water as a tracer to measure blood flow and tissue perfusion; its potential for metabolism study was also briefly discussed.'

L61: outer volume suppression: could be added that this is specific for brain applications

L61: changed to 'These relaxation properties favour rapid scanning which enhances the sensitivity of ²H MRI for brain applications by outer volume suppression.'

L71: alpha-ketoglutarate

L71: changed to 'Labelled acetyl coenzyme A enters tricarboxylic acid cycle and produce intermediates such as alpha-ketoglutarate which consequently lead to production of [4,4′-²H₂]-glutamate and [4,4′-²H₂]-glutamine. '

L82: that's not exactly a very accurate description of the Warburg effect: a shift from oxidative to glycolytic glucose metabolism in the presence of sufficient oxygen. Lower glucose could be a consequence but this is not necessarily the case. 

L82: changed to 'According to Warburg effect, instead of oxidative glucose metabolism like in normal tissue, tumour cells shift to glycolytic metabolism in the presence of sufficient oxygen ¹⁵. Tracking of lactate and Glx can generate a Warburg effect (Lac/Glx) map and was used in the study of De Feyter et al ⁶ to show pronounced metabolic differences between tumour and normal tissue.'

Fig.1 panel 3: suggest to change textbox to "acquisition of 2H MRSI..."; figure legend title: Workflow of a DMI study

Fig.1 panel 3 text changed to 'acquisition of ²H MRSI and processing into DMI'; figure legend title changed to Workflow of a DMI study

L101: De Feyter instead of Feyter

L101: changed to 'De Feyter'

L103: studies were in mice, not rats

L103: changed to 'Markovic et al. ¹⁶ induced pancreatic ductal adenocarcinoma (PDAC) in mice with two different mutations to mimic the diversity of human pancreatic cancer aetiology. '

L102: DMI instead of MRI?

L102 changed to 'The DMI acquisitions were carried out with slice-selective 2D chemical-shift imaging (CSI) and a repetition time of 95 ms. '

L122: studies were in mice, not rats

L122: changed to 'Veltien et al. ¹⁸ performed 3D DMI for renal tumours in mice at 11.7T field and was able to obtain high nominal resolution of 8 µL in 37 min. '

L140: This section omits the use of fumarate to detect dead cells, see work by Kevin Brindle's lab. That would be a useful addition. 

Following the referee’s recommendation, start from L145, section is added: ' Measurements of ²H labelled fumarate conversion to ²H-labeled malate can be used to detect tumor cell death, as demonstrated by the in vivo study from Hesse et al ²². DMI at 7 T could detect the increase in malate production in necrotic tumour tissue. The malate/fumarate ratio increased more than 10 folds in murine lymphoma, human breast and colorectal xenografts after drug treatment and was correlated with increased levels of tumour cell death measured in excised tumor sections. Similar results can be obtained using ¹³C MRS ²³. However, since DMI technique does not require a hyperpolarizer, it is a less expensive option. For possible future clinical implementation, detection of fumarate and malate at 3 T should be tested and the safe dosage of fumarate needs further investigation.'

L150 - 161: given the goal of the manuscript to discuss DMI as a promising tool for use in the clinic, this in vitro example could be omitted from the manuscript. 

this section is deleted

L208: De Graaf instead of Graaf

L208 changed to: 'De Graaf et al. ³³ showed that with optimal multi-receiver arrays, a nominal 1 mL resolution DMI acquisition is feasible at 7 T and proposed that clinical use field strength of 3 T should allow for a nominal 4 – 8 mL DMI acquisition. '

L242: typo: Glx

L242 changed to 'However, Kaggie et al. ³⁴ suggested that when DMI is compared with hyperpolarized ¹³C MRSI, ¹³C MRSI could probe early rapid lactate production, and DMI probe the later slower production of Glx.'

L254-256: Without a scientific paper describing these coils, this information on modular RF receive arrays seems a bit out of place. Further, how does transmission take place?

Following the referee’s suggestion, extra information has been incorporated into the manuscript to provide more details on the modular RF array. 'Figure 2 shows an example of a multi-purpose, modular transmit/receive RF array which supports ²H DMI/DMS. This is an extension of previous developments tailored for ¹H MRI but uses hexagonal building blocks to form an array. Each building block comprises 4 RF elements. It can be driven in the parallel transmission mode but also supports excitation using a single-feeding RF channel. For the latter, fixed phase settings are used for each element for transmission field (B₁⁺) shaping depending on the target anatomy. Phase setting can be conveniently changed and hardware adapted by replacing the phase shifter module of the universal interface which is used to connect the RF array with the MR scanner.'

L267: this section: Especially for low frequency X-nuclei it is beneficial to go to high field because the increase in SNR has a supralinear relation with magnetic field strength. 

Following the referee’s recommendation, the extra text has been added to the manuscript to outline the value of the supra-linear SNR gain for lowering detection levels and for reducing scan times in x-nuclear MR including 2H MR.

'Low-frequency X-nuclei MR such as ²H MR would particularly benefit from the signal-to-noise ratio (SNR) gain at higher magnetic fields because SNR scales supra-linearly with the magnetic field strength. This would help to lower detection levels and reduce scan times. An SNR gain of two would translate into a scan time reduction of a factor of four.'

Many argue that the only relevant field strength for clinical applications is 3T, given its widespread use. The extremely high field examples are a bit out of place in this context but could benefit research, of course. 

We agree that explorations into 7.0 T MR and higher magnetic field strengths are a steam engine for basic research and innovation in biomedical MR research and clinical science. We agree that there is a large body of literature which demonstrates that many technologies now being used at 3.0 T were triggered by the unmet needs of ultrahigh field MR. Recent examples include parallel transmission technology as well as transmission field mapping algorithms, SAR management using virtual observation points, progress in RF pulse design, B1+shimming techniques to name a few. Of course, transfer of this technology is not always easy but recent MR history shows that moving technology from lower clinical fields strengths such as 1.5 T to 3.0 T turned out to be not the best solution. Therefore there is a paradigm shift which means that technology transfer is – to a large extent – being done by adapting technology developed at 7.0 T to the needs of lower magnetic fields strengths commonly used in a clinical setting.

 

 

 

 

 

 

 

 

Reviewer 2 Report

This opinion piece is focused on the recent emergence of deuterium magnetic resonance spectroscopy and imaging (DMS and DMI) for metabolic imaging of diseases. The article provides a short review of deuterium MR history, current state and future perspectives of this unique imaging modality.  Overall, this review reads well and should be of a great interest to the field of molecular/metabolic imaging.

There are a few ambiguous statements, however, mainly in the abstract and the first paragraph. Perhaps, this is not the authors’ field of expertise. They are as follows:

It is not clear what it means by “metabolic compartments involved in the survival, growth, and invasion of tumors”. It appears that the term “metabolic compartments” is incorrectly used.

Line 27, page 1: revise the following statement “malignant cells need all the energy stored in ATP”

Author Response

Thank you for the advice.

The term 'metabolic compartments' is changed to 'metabolic processes'

Line 27, page 1: the statement 'malignant cells need all the energy stored in ATP' is changed to ''malignant cells need more energy for aggressive proliferation'

Reviewer 3 Report

Well written article that makes the case for 2H MRI and MRS in cancer diagnostics. The authors also states the need for future development of 2H  technology. The authors should state any conflict of interest and source of funding

Author Response

Thank you for the comment. The editor has been informed of the conflict of interest and the source of funding.