Recent advances in nuclear and hybrid detection modalities for image-guided surgery

ABSTRACT

Introduction: Radioguided surgery is an ever-evolving part of nuclear medicine. In fact, this nuclear medicine sub-discipline actively bridges non-invasive molecular imaging with surgical care. Next to relying on the availability of radio- and bimodal-tracers, the success of radioguided surgery is for a large part dependent on the imaging modalities and imaging concepts available for the surgical setting. With this review, we have aimed to provide a comprehensive update of the most recent advances in the field.

Areas covered: We have made an attempt to cover all aspects of radioguided surgery: 1) the use of radioisotopes that emit γ, β⁺, and/or β⁻ radiation, 2) hardware developments ranging from probes to 2D cameras and even the use of advanced 3D interventional imaging solutions, and 3) multiplexing solutions such as dual-isotope detection or combined radionuclear and optical detection.

Expert opinion: Technical refinements in the field of radioguided surgery should continue to focus on supporting its implementation in the increasingly complex minimally invasive surgical setting, e.g. by accommodating robot-assisted laparoscopic surgery. In addition, hybrid concepts that integrate the use of radioisotopes with other image-guided surgery modalities such as fluorescence or ultrasound are likely to expand in the future.

KEYWORDS:

• Radioguided surgery
• image guided surgery
• nuclear medicine
• molecular imaging
• SPECT
• PET
• fluorescence
• surgical navigation

1. Introduction

Image-guided surgery is a key component in the realization of precision surgery, especially through the ability to intraoperatively identify disease based on its molecular properties. Radioguided surgery is one of the earliest and still most used forms of interventional molecular imaging. By intraoperatively exploring the use of radiopharmaceuticals that are embedded within the field of nuclear medicine, guidance can be facilitated towards the location and extent of the disease [1].

The concept of radioguided surgery originated about 6 decades ago. The first radiation detection probe system was evaluated by Selverstone et al. who reported in 1949 on the use of a handheld gaseous ionization detector (i.e. a Geiger-Müller tube) to localize suspected brain tumors that contained β⁻ emitting ³²P isotope [2]. In 1956, Harris et al. reported on the first use of probe based ¹³¹I isotope detection in a patient who underwent thyroidectomy [3]. From that moment onward, applications and new innovations for radioguided surgery have evolved substantially and many studies have reported on the introduction of new detection modalities, radiopharmaceuticals and clinical applications [4].

To date, radioguided surgery has been successfully applied in a plurality of clinical indications, mostly oncological (see Table 1). When examining this list, one soon realizes that the indications are highly dependent on the radiopharmaceutical used. In some cases, for example, in sentinel node imaging, radiopharmaceuticals are used specifically dedicated to surgical guidance. Here low dose to the patient and surgical staff and compatibility with scintigraphy or SPECT/CT are considered selection criteria. However, there are also multiple examples where radioguidance procedures can make use of radiopharmaceuticals that were originally designed to have a role in diagnostic PET/CT such as ¹⁸F-FDG. This ability to build on the well-established discipline of nuclear medicine and the plurality of clinical radiopharmaceuticals that have come available through decades of radiochemical developments occurring across the globe, drives the field of radioguided surgery and gives it a unique edge over other image-guided surgery approaches.

Table 1. Clinical application of nuclear detection modalities in radioguided surgery. (In vivo human use only.)

Clinical procedure	Indications	Radiopharmaceutical	Devices	References
Sentinel lymph node biopsy (SN)	Breast cancer, head & neck cancers, melanoma, prostate cancer, penile cancer, testicular cancer, vulvar cancer, cervix cancer, endometrial cancer, bladder cancer, esophagus cancer, colorectal cancer, anus cancer, gastric cancer, lung cancer, thyroid cancer	^99mTc-nanocolloid, ICG-^99mTc-nanocolloid, ^99mTc-Senti-Scint, ^99mTc-phytate colloid, ^99mTc-tin colloid, ^99mTc-sulfur colloid, ^99mTc-rhenium colloid, ^99mTc-antimony trisulfide, ^99mTc-Tilmanoscept, ^99mTc-dextran 500, ^89Zr-nanocolloid	Single device: Low-to-mid energy γ probe (open and (robot-assisted) laparoscopic surgery) High-energy γ probe (open surgery) Portable γ camera (open surgery), SPECT/CT navigation (open and laparoscopic surgery) fhSPECT navigation (open and laparoscopic surgery) Multiplexing/hybrid device: γ + Fluorescence probe (open surgery) γ + Fluorescence camera (open surgery) SPECT/CT navigation + Fluorescence (open and laparoscopic surgery) fhSPECT navigation + Fluorescence (open and laparoscopic surgery) fhSPECT navigation + Ultrasound (Percutaneous interventions)	[5–25,100,113,114,116,119,120,130,150,156,157,179,186–188,191,194–196,198,199,212,216,220,221,244,245,254]
Radioguided occult lesion localization (ROLL)	Pulmonary lesions (e.g. lung cancer), thyroid cancer, endometriosis, renal cancer, ovary cancer, colorectal cancer, breast cancer, melanoma, lymphoma	^99mTc-MAA, ICG-^99mTc-nanocolloid	Low-to-mid energy γ probe (open and laparoscopic surgery), Portable γ camera (open surgery), fhSPECT navigation (laparoscopic surgery)	[26–34,100,101,126,149,192,219]
Radioguided seed localization (RSL)	Breast cancer	^125I-seeds	Low-to-mid energy γ probe (open surgery), fhSPECT navigation (open surgery)	[35,36,102,189]
Metabolic targeted resections - FDG	Breast cancer, thyroid cancer, ovarian cancer, cervical cancer, gastric cancer, lung cancer, head & neck cancer, adrenocortical cancer, melanoma, squamous cell carcinoma, Colorectal cancer, lymphoma, Adenocarcinoma, endometrial carcinoma, plasmacytoma, urothelial carcinoma, sarcoma, eccrine porocarcinoma, testicular cancer, esophageal cancer	^18F-FDG	High-energy γ probe (open surgery), β^+probe (open surgery)	[37–43,122,123,125–127,140]
Metabolic targeted resections - L-DOPA	Neuroendocrine tumors	^18F-L-DOPA	High-energy γ probe (open surgery)	[44]
Metabolic targeted resection - Iodine or similar	Thyroidectomy, Parathyroid adenoma, Thyroid carcinoma	^99mTc-pertechenetate, ^201TlCl, ^131I, Na^123I	Low-to-mid energy γ probe (open surgery)	[3,45,46]
Metabolic targeted resections - Phosphorus	Glioma	^32P buffered phosphate ion solution	β^− probe (open surgery)	[2]
Physiological targeted resections	Thyroid cancer	^99mTc-DMSA	Low-to-mid energy γ probe (open surgery)	[47,48,105]
Hydroxyapatite targeted resections	Bone lesions	^99mTc-MDP, ^99mTc-HDP	Low-to-mid energy γ probe (open surgery) fhSPECT navigation (open procedure)	[49–53,201]
Mitochondrial uptake targeted resections	Breast cancer, Brain tumor, Parathyroid adenoma, Parathyroid hyperplasia, Parathyroid cancer,	^99mTc-sestamibi (MIBI)	Low-to-mid energy γ probe (open surgery) Portable γ camera (open surgery) SPECT/CT navigation (open surgery) fhSPECT navigation (open surgery)	[54–60,101,178]
Inflammatory targeted resections	Extranodal lymphoma, Granulomatous inflammation, Pancreatitis	^67Ga-citrate, ^18F-FDG	Low-to-mid energy γ probe (open surgery) High energy γ probe (open surgery)	[43,61,125]
PET-guided biopsy	Intrathoracic lesions, Bone lesions, Lymph nodes	^18F-FDG	PET/CT navigated robot arm PET/CT navigation (laparoscopic surgery)	[171,172,174]
Receptor targeted resections	Prostate	^99mTc-PSMA I&S, ^111In-PSMA I&T, ^111In-capromab pendetide, ^125I-B72.3	Low-to-mid energy γ probe (open and robot-assisted laparoscopic surgery), fhSPECT navigation (open surgery)	[62–65,104,108,121]
	Renal	^124I-cG250	High energy γ probe (open surgery) β^+ probe (open surgery)	[66,142]
	Colorectal cancer	^99mTc-IMMU-4 Fab’, ^111In-B72.3 (CYT-103), ^125/131I-B72.3, ^125I-CC49, ^125I-HuCC49ΔC^H2 ^125I-A5B7, ^125I-CL58, ^125I-17-1A, ^124I-Hu-A33	Low-to-mid energy γ probe (open surgery) High energy γ probe (open surgery) β^+ probe (open surgery)	[67–74,105,142]
	Gastric cancer	^125/131I-3H11, ^125I-B72.3	Low-to-mid energy γ probe (open surgery)	[75,76,105]
	Breast cancer	^125I-B72.3, ^125I-F023C5, ^125I-NR-LU-10	Low-to-mid energy γ probe (open surgery)	[105]
	Ovarian cancer	^99mTc-H17E2, ^99mTc- SM3, ^111In-B72.3 (CYT-103), ^125I-B72.3, ^125I-CC49, ^131I-OC125	Low-to-mid energy γ probe (open surgery)	[70,77,105]
	Pancreatic cancer	^125I-CC49	Low-to-mid energy γ probe (open surgery)	[105]
	Neuroendocrine tumors	^111In-pentetreotide, ^68Ga-DOTA-NOC, ^68Ga-DOTA-TATE, ^68Ga-DOTATOC, [^99mTc-EDDA/HYNIC]octreotate, ^125I-Tyr 3-octreotide, ^125I-Lanreotide, ^123/125/131I-MIBG	Low-to-mid energy γ probe (open surgery and laparoscopic), High-energy γ probe (open surgery), Portable γ camera (open surgery), SPECT/CT navigation (open surgery), fhSPECT navigation (open surgery)	[47,78–96,101,128,254]
Perfusion	Brain Tumors	^131I-diiodofluorescein	Low-to-mid energy γ probe (open surgery)	[97]
	Ureteral stent placement	^99mTc-DTPA	Low-to-mid energy γ probe (open surgery)	[98]

Next to its reliance on the availability of specific radiopharmaceuticals, the implementation of radioguided surgery is highly dependent on the availability of dedicated (intraoperative) tracing and imaging modalities. In the current review, we evaluate advances made in the engineering of detection modalities that have been specifically designed for the purpose of radioguided surgery. In doing so, we have made an attempt at placing new innovations within the perspective of existing technologies and clinical applications.

2. Overview radioguidance modalities

2.1. 1D nuclear detection probes

Handheld nuclear detection probes are 1D detector modalities designed to measure the number of incident γ photons or β particles within a small FOV and a specific time frame (see Figure 1). When small in size, such probes can be used to trace radioactivity even in small confined surgical spaces. Typically, audible and numerical feedback, provided in counts/s, describe the intensity of the radioactive signal that was measured. As a result, these devices have proven to be useful tools for the intraoperative localization of tissues with radiopharmaceutical uptake (e.g. cancerous tissue). Surgical nuclear detection probes are developed for either: (1) low-to-mid energy γ ray detection (≤400 keV), often simply called ‘gamma probes’, (2) high-energy γ ray detection (>400 keV), often called ‘high-energy gamma probes’, (3) β⁺ particle detection (i.e. positively charged electrons or positrons), often called ‘beta+ probes’, and (4) β⁻ particle detection (i.e. negatively charged electrons or negatrons), often called ‘beta- probes’.

Figure 1. 1D nuclear detection probes. (a) Open surgery low-to-mid energy gamma probe, with example during ROLL procedure with ICG-^99mTc-nanocolloid for recurrent melanoma (from [219]). (b) Laparoscopic surgery low-to-mid energy gamma probe, with example during SN procedure with ICG-^99mTc-nanocolloid for prostate cancer. (c) DROP-IN gamma probe for robot-assisted laparoscopic surgery, for example, during lymphatic salvage procedures in recurrent prostate cancer using ^99mTc-PSMA. (d) High energy gamma probe for open surgery, with example in head and neck squamous cell carcinoma showing ¹⁸F-FDG avid lymph node with metastases (from [127]). (e) Open surgery beta- probe, with example of ex vivo tumor with ⁹⁰Y-DOTATOC in meningioma (from [144]).

2.1.1. Gamma (γ) probes (≤400 kev)

Typical application of low-to-mid energy γ probes is tailored towards the use of ‘SPECT isotopes’ (see Table 2) and form factors are available for open, laparoscopic and even robot-assisted laparoscopic surgery (see Figure 1(a–c)) [99]. Compared to β emissions, γ rays have a high penetration depth of >10 cm. Today the γ probe is one of the most widely applied modalities for image-guided surgery. As can be seen from Table 1, the most common surgical applications are: sentinel node (SN) procedures using ^99mTc-labelled radiocolloids (e.g. melanoma, head and neck oncology, breast cancer, penile cancer, prostate cancer), radioguided occult lesion localization (ROLL) procedures using ^99mTc-labelled macro-aggregates (e.g. breast cancer, lung cancer, thyroid cancer) and radioguided seed localization (RSL) procedures using ¹²⁵I-seeds (e.g. breast cancer) [100–103]. Building on many proof-of-concept studies, receptor targeted tumor resections are also increasingly being performed with the use of γ probes (e.g. prostate specific membrane antigen (^99mTc or ¹¹¹In)) [104]. Below, we provide a short summary of the working principles for this well-established technology. However, a more detailed description can be found in more topic-specific reviews such as those of Heller et al. or Povoski et al. [105,106].

Table 2. Characteristics of radionuclides interesting for radioguided surgery.

Radioisotope	Half-life	Radiation	Energy
SPECT γ-emitting isotopes
^57Co	271.8 days	γ	14, 122, 136 keV
^67Ga	3.26 days	β^−	84 keV
		γ	93, 184, 300 keV
^99mTc	6.0 h	γ	141 keV
^111In	2.80 days	γ	171, 245 keV
^123I	13.2 h	β^−	23, 127 keV
		γ	27, 31, 159 keV
^125I	60.1 days	γ	27, 35 keV
^131I	8.02 days	β^−	606 keV
		γ	364 keV
^201Tl	73 h	γ	71, 167 keV
PET β^+-emitting isotopes
^18F	110 min	β^+	634 keV
		Annihilation γ	511 keV
^68Ga	67.7 min	β^+	1.90 MeV
		Annihilation γ	511 keV
^89Zr	78.4 h	β^+	389 keV
		γ	909 keV
		Annihilation γ	511 keV
^124I	4.18 days	β^+	1.5, 2.1 MeV
		γ	603, 1.69 MeV
		Annihilation γ	511 keV
Therapeutic β^–emitting isotopes
^31Si	2.62 h	β^−	1.49 MeV
^32P	14.3 days	β^−	1.71 MeV
^83Br	2.4 h	β^−	935 keV
^90Y	64 h	β^−	2.3 MeV
^97Zr	17 h	β-	1.92 MeV
		γ	743 keV
		Secondary β-	1.28 MeV
		Secondary γ	657 keV
^133I	20.8	β-	1.23 MeV
		γ	530 keV
^153Sm	46	β-	635, 704, 808 keV
		γ	103 keV
^188Re	17	β-	1.96, 2.12 MeV
		γ	155 keV

Emissions >10 keV and abundance >5% are included

2.1.1.1. Background and recent advances

Two main detector setups are in use for γ probes: (1) a scintillation detector, which consists of a scintillation crystal coupled (directly or via optical fiber [107]) to a photomultiplier tube (PMT) or photodiode, or (2) an ionization detector, which consists of a semiconductor crystal structure. Next to having real-time sample times (typically <1 s), γ probes have been shown to allow for the identification of lesions as small as 2 mm [108]. To allow for spatial resolution, some form of collimation is needed around the detector setup to only allow radiation originating from the front-side of the γ probe to be detected. To achieve collimation, shielding of the detector with a certain thickness of a high-atom-number material is required. Lead and tungsten, or some sort of alloy of these materials, are the most generally used materials in collimators [106]. Given the relative stopping powers, however, gold and platinum might even be better alternatives; relative stopping powers of 1 (lead), 1.2 (tungsten (8% copper)), 1.6 (gold) and 1.7 (platinum (iridium alloy)) [109]. The collimator material also reflects on the size and weight of the collimator, where a typical collimator diameter for low-energy γ probes ranges between 10 and 12 mm. Even with the collimator in place, lesions with low radiopharmaceutical uptake can still be hard to distinguish when located in close proximity to high-uptake background tissues, typically denoted as the ‘shine-through’ problem. To this end, some groups have experimented with blocking background radiation (e.g. injection site) with the intraoperative use of additional lead-shielding [110,111].

In the evolution of surgical techniques, more and more minimally invasive alternatives are being pursued, of which (robot-assisted) laparoscopic surgery is a prime example [112]. To enable the use of radioguidance during laparoscopic surgery, laparoscopic versions of the low-to-mid energy γ probe have been introduced. From an engineering perspective, this basically means the shaft of an open surgery probe has to be elongating so that it can be used through a trocar [113]. Unfortunately, with the trocar functioning as fixed rotation point, the maneuverability is drastically restricted, ultimately limiting the accuracy of lesion localization in anatomically difficult to reach locations [114,115]. In case of shine-through issues, this restricted maneuverability can especially be limiting when (low-uptake) lesions are located near high-uptake background tissues [116–118]. To help focus the probe FOV, alternative laparoscopic γ probe designs have incorporated a detection window at, e.g. 45° or 90° angles [119]. Because the angle of the detector would accommodate detection in specific anatomical locations, this could mean that different probe versions would be needed during a single procedure. When robot-assisted procedures are performed, next to the reduction in rotational freedom, the operating surgeon is also deprived of his/her ability to guide probe placement: based on verbal feedback provided by the surgeon, the bedside assistant takes care of the probe. Obviously, such placement issues become increasingly complicated when laparoscopic probes are used with angled detectors. To provide a solution for the challenges encountered during traditional laparoscopic radioguided surgery, and to optimally facilitate robot-assisted procedures, a small-sized tethered DROP-IN γ probe concept was introduced in 2016 (see Figure 1(c)) [99]. This probe, which essentially has a flexible shaft, was designed to allow the surgeon to independently manipulate the probe position using the surgical instruments (e.g. the wristed PROGRASP tool of the da Vinci robot). Gripping was designed so that it facilitates the identification of lesions in areas with a high background activity. Following technological evaluation in pigs [99], it was successfully translated to in-human use (n = 12 patients) during robot-assisted prostate cancer SN procedures (with ICG-^99mTc-nanocolloid [120]) and robot-assisted salvage resection of lymphatic metastases in recurrent prostate cancer (with ^99mTc-PSMA I&S [121]).

2.1.2. High-energy gamma (γ) probes (>400 kev)

High-energy γ probes are generally designed to detect the indirect 511 keV annihilation γ-emissions of PET isotopes (see Table 2), facilitating the surgical translation of diagnostic PET radiopharmaceuticals (see Figure 1(d)). Therefore, they are sometimes also called ‘PET probes’. From a technical point, these probes are very similar to traditional low-energy γ probes, but employ different materials and designs to facilitate the detection and collimation of high-energy γ rays (i.e. >400 keV). As seen from Table 1, the most common surgical application of these probes is during open surgical localization of ¹⁸F-FDG avid lesions (e.g. colorectal cancer, breast cancer, lymphoma, ovarian cancer) [122]. Topic-specific reviews are provided by Daghighian et al. and Povoski et al. [123,124].

2.1.2.1. Background and recent advances

Since ionization detectors typically are less sensitive for high-energy γ rays, scintillation-based detectors appear to be the preferred choice for high-energy γ probes [106]. In general, to provide enough stopping power for these γ rays, scintillation crystals are longer than those used in low-to-mid energy γ probes (typically >2 cm [124] and <1 cm [99], respectively).

Largely dependent on the probe collimator, the smallest lesion size as detected with a high-energy γ probe, was reported to be 5 mm [124]. High-energy γ probe collimators comprise of the same materials as chosen for low-to-mid energy γ probes, but since the 511 keV γ rays require more stopping power, the collimation surrounding the detector has to be substantially thicker. This also results in a substantially enlarged diameter of the end products: typically a probe-head diameter between 25–35 mm [124,125]. This also negatively influences the weight, where a high-energy γ probe is generally much heavier than a low-to-mid energy γ probe [126–129]. Therefore, both probe diameter and weight restrict the intraoperative utility of such probes [130]. Since minimal invasive laparoscopic surgery is slowly moving towards smaller trocar diameters (<12 mm), the typical 25–35 mm high-energy γ probe is simply not compatible. Still, a 15 mm diameter laparoscopic high-energy γ probe is reported in literature: a single case study (ovarian cancer) showed its success in 2005 [131], however, follow-up hasn’t been reported since and further preliminary studies (colorectal and lung cancer) suggest that collimation in this small design is inadequate for successful use [124].

Further refinements on intraoperative tracing of 511 keV emissions will most likely focus towards the design of innovative detector-collimator designs that allow for the engineering of more user-friendly probes [123]. One innovative detector design, already applied in-human trials, comprises an arrangement of multiple detectors, able to perform electronical collimation of the γ signal without the need of a heavy collimator [126,128,130,132]. Unfortunately, this multi-detector setup still renders the device rather big (~30 mm diameter probe-head). It has been suggested that use of K-alpha x-ray fluorescence could be used to fabricate much lighter, and possibly smaller, detectors [133,134].

2.1.3. Beta+ (β+) and beta- (β-) probes

Instead of detecting γ-rays, β particles (including β⁺ and β⁻), can be detected using β probes (see Figure 1(e)). Unlike γ-rays, such emissions have a very limited tissue penetration of a few mm rendering this a superficial detection technology [124,135]. The upside of this limitation is that β tracing is less likely to suffer from radiation ‘shine-through’ (see above), originating from high-uptake background tissues. Hence, the technology could help realize detailed examination of the resection planes with respect to clear tumor margins [136,137] and could potentially support lesion detection in high background areas [130]. Although most dedicated β probe systems can detect both β⁺ and β⁻ particles, there is a clear distinction; the systems are focused on isotopes with different emission characteristics. Similar to high-energy γ probes, β⁺ probes facilitate the intraoperative identification of PET-radiopharmaceuticals. Instead of detecting the secondary annihilation γ-rays, rather they directly detect the β⁺ particles emitted by these PET isotopes (see Table 2). Apart from ex vivo evaluation in breast cancer [124], melanoma [138] and cervical cancer [139], small-sized in vivo evaluations have been reported using ¹⁸F-FDG (colorectal cancer, melanoma, adenocarcinoma, thyroid cancer and breast cancer [140–255]). Studies have also been performed using ¹²⁴I-Hu-A33 (colorectal cancer [142]) and ¹²⁴I-cG250 (renal cancer [142]) (see Table 1).

Radioguidance based on β⁻ detection is based on the use of isotopes that have therapeutic properties (see Table 2). With this emission type, the high background of 511 keV annihilation γ rays are avoided. Although the use of β⁻ emitting isotopes in radioguided surgery was already explored in 1949 (³²P in brain tumor surgery) [2], instrumentation was not sensitive for routine implementation [136]. With the advance of modern technology, there has been a renewed interest for this surgical methodology. This has resulted in the first ex vivo experiments of modern β⁻ radioguided surgery using ⁹⁰Y-DOTATOC in meningioma [143]. Topic-specific literature is provided by Heller et al., Daghighian et al. and Camillocci et al. [106,124,136].

2.1.3.1. Background and recent advances

The most widely applied detector composition for β probes comprises a scintillation setup. Because of the short-range attenuation of β particles, minimal collimation is needed and probe designs can be relatively small and lightweight. The materials that are often applied are stainless steel [144], PVC [136] and ABS [143]. It should be noted that the sample times of β probes depend on the energy of the β particle, but values are often not clearly stated with respect to in vivo measurements.

Although the β probe plastic scintillators are relatively insensitive for γ rays, γ background signals can still render β tracing problematic. This is because both β⁺ and β⁻ particles can induce additional γ ray backgrounds within the human tissue. The first form is bremsstrahlung, produced by both β⁺ and β⁻ particles as they are decelerated within the tissue (emission probability of only 0.1%) [136]. According to Russomando et al., using a p-terphenyl based detector, the sensitivity to such bremsstrahlung can be reduced to a negligible <1% [145]. Contrary to pure β⁻ emitting isotopes, β⁺ emitting isotopes always come with high-energy γ rays due to the positron annihilation process. This high background of γ rays has been shown to be especially problematic when tracing low-energy β⁺ emissions such as that of ¹⁸F (635 keV) [256]. To solve this issue, most β⁺ detection probes implement a dual-detector design: a first detector for both β and γ radiation and a second detector for γ radiation only [124]. These detectors can either be placed next to or even behind each other. In this design the ‘γ only’ detector is shielded from β radiation by the first detector or some form of β collimation [124,144,146]. By correcting the ‘combined β and γ signal’ (first detector) with the ‘γ only signal’ (second detector), a background rejection can be implemented to drastically improve the signal-to-noise ratio. Since background subtraction is not needed for pure β⁻ isotopes, these probes do not feature a dual-detector setup.

Current β⁺ and β⁻ probes have mainly focused towards open surgical applications. However, a technical description of a laparoscopic β⁺ probe version [124] and a single case study in lung cancer using ¹⁸F-FDG have been reported [147]. Interestingly, due to the small sizes possible, β⁺ detectors have also been suggested for intravascular detection of ¹⁸F-FDG avid atheroma [148]. Next to experiments on laparoscopic versions of these probe technologies, future developments will most likely focus towards the realization of the first in vivo evaluations of the modern β⁻ probes.

2.2. 2D portable nuclear detection cameras

Nuclear detection cameras combine the output of a set of 1D detectors to form a 2D image of the radiopharmaceutical distribution within a specific FOV (see Figure 2). With that, they provide a logical evolution of the above-mentioned detection probe concepts. The image output of portable cameras can be considered to be more intuitive than the numerical and acoustic readout of probes. Furthermore, it may reduce localization time by allowing the mapping of a larger field of view. By using longer exposure times, the statistical noise can be reduced, but this comes at a cost for the ability to provide real-time feedback. Although full 3D insight is missing, the possibility to make an image from different directions can already help increase the diagnostic accuracy when lesions are located relatively deep within the anatomy or multiple lesions are overlapping. Unfortunately, the size of the bulkier detector can limit intraoperative maneuverability and mentally connecting the images displayed on a screen with the actual patient can be a demanding task. Furthermore, probe detection modalities are often found to be more sensitive than camera detection modalities [106]. Providing a map for the radiopharmaceutical distribution within a small surgical area (e.g. SN mapping), portable nuclear detection cameras have proven to be a useful tool, with clinical systems available for low-to-mid energy γ ray detection and experimental systems available for β⁺ particle detection.

Figure 2. 2D portable nuclear detection cameras. (a–b) Portable gamma camera imaging during SN procedure for head and neck melanoma with ICG-^99mTc-nanocolloid (from [253254]). (c–e) Augmented reality overlay of gamma camera findings within the anatomical context of the patient during head and neck cancer SN procedure (from [255]). (f) Setup of a portable beta+ camera for radioguided surgery, with evaluation in a tongue tumor rabbit model showing uptake in primary tumor (g) and lymph nodes (h) using ¹⁸F-FDG (from [162]).

2.2.1. Portable gamma (γ) cameras

Imaging the emitted γ rays, portable γ cameras are designed to image radiopharmaceutical uptake in a small FOV (typically around 50 × 50 mm²) during surgery (see Figure 2(a–b)). Most systems are designed to image γ ray energies between roughly 50–300 keV, making them compatible with traditional SPECT isotopes (e.g. ^99mTc) (see Table 2). Therefore, as seen from Table 1, portable γ cameras are mostly applied for open surgery SN procedures using ^99mTc-labelled radiocolloids (e.g. in head and neck cancer, breast cancer, melanoma or penile cancer) and ROLL procedures using ^99mTc-labelled macro-aggregates (e.g. breast cancer, thyroid cancer), but also in SNOLL procedures using ^99mTc-nanocolloid and ^99mTc-MAA (i.e. breast cancer), resection of neuroendocrine tumors using ¹²³I-MIBG (e.g. paraganglioma) and resection for thyroid disorders ^99mTc-MIBI [101,149]. To our knowledge, intraoperative usage with PET radiopharmaceuticals has not been shown in literature yet. Specific reviews reporting on portable γ cameras in more detail are provided by Tsuchimochi et al. and Hellingman et al. [150,151].

2.2.1.1. Background and recent advances

Similar to the γ probe technology, most γ camera detectors are either based on a scintillator system or an ionization system [150,152]. Effectively, camera exposure times used during surgery range between 5 and 60 s [106]. Typical system resolutions of a portable γ camera, at distances <5 cm to the targeted tissue, are found between roughly 1.5–10 mm [150,151]. Typical collimator designs are the parallel-hole and the pinhole collimators, fabricated out of lead or tungsten [153]. In a parallel-hole collimator, parallel septa of collimation material are used to prevent overflow of γ signal between individual pixels of the camera, only allowing what is in front of the specific pixel to be detected. Consequently, this fixes the size of the camera FOV. These parallel-hole collimators generally have a square or hexagonal pattern in front of the detector and often come in low energy high resolution or low energy high sensitivity configurations; for example, longer septa increase camera resolution, but decrease camera sensitivity. In a pinhole collimation configuration, a single focusing aperture is created with the collimation in front of the detector, very similar to photographic cameras used in daily life. When an object is close to the camera, this allows for a magnified image on the detector (i.e. higher resolution, smaller FOV) [154]. However, when an object is far from the camera, the image on the detector is miniaturized allowing for a larger FOV with lower resolution. Just as with a parallel-hole setup, the pinhole setup also allows for an interchangeable collimator configuration, where a smaller aperture allows for higher resolution, but lower sensitivity [155]. Literature is somewhat contradicting on this point, most likely due to differences in working distances, detector technologies, and collimator geometries used, parallel-hole is generally thought to provide higher sensitivity (especially at large distances), while resolution is higher with pinhole (especially at close distances) [106,151].

Portable γ cameras can be used as a handheld device (e.g. CrystalCam) or one that is mounted on an articulating arm (e.g. Sentinella) (see Figure 2(a)). The first model is more mobile and can be applied for investigations under difficult angles, but the second is more ergonomic over longer periods of time (typical camera weight 0.7–2.7 kg [150]) and can provide a sharper image when long exposure times are needed. A downside of using γ cameras is that these images traditionally only display the distribution of radioactive counts on a screen in the OR, and thus miss a connection to the anatomical context of the patient. To provide such a connection and make use of the system more intuitive, camera developments focus on integrating γ images with optical images of the area of interest via an augmented reality image overlay. This directly places the nuclear findings within the anatomical context of the patient (see Figure 2(c–e)) [156–159]. In the clinic, portable γ cameras are only used as open surgery systems (i.e. outside of the patient), however, experimental setups are devised allowing for the acquisition of γ images via a laparoscopic device as well [107].

2.2.2. Beta (β) cameras

Although intraoperative imaging of PET radiopharmaceuticals with a portable γ camera has not been shown yet, some research groups are pioneering this use with handheld β⁺ cameras (see Figure 2(e–g)) [124,160–164].

2.2.2.1. Background and recent advances

Similar as what was reported for β probes, background as a result of the high-energy annihilation γ’s limits the implementation of this camera technology [163]. Hence, like the probes, most β⁺ camera systems incorporate a dual-detector design. However, different from typical β⁺ probes reported, these β⁺ cameras do not use two separate detectors to determine the contribution of the individual signals, but rather use a single detector with two stacked scintillation materials in front: the first converting both β⁺ and γ signals to visible light and the second only converting the deeper penetrating γ rays to visible light. These light pulses can subsequently be separated based on shape [163]. Similar as with β⁺ probes, subtracting the γ-only signal from the signal of the first scintillator (i.e. γ and β⁺) allows for a γ rejection to be applied. Typically, the first scintillator is a relatively thin plastic scintillator (e.g. p-terphenyl), while the second scintillator is made of a thicker inorganic scintillator (e.g. LYSO or BGO). This scintillation stack is generally coupled to either a position-sensitive PMT, silicon photomultiplier (SiPM) detector arrays or an EMCCD. Current prototype systems hardly use any collimation, though it is suggested that shielding on the sides and back would be a requirement in vivo, preventing detector noise from lesion surrounding anatomies [160,162].

Most experimental systems are now targeted towards ¹⁸F-FDG; preliminary ex vivo (¹⁸F-FDG avid existed breast tumor [124]) or in vivo animal evaluations (¹⁸F-FDG avid rabbit tongue tumor [161,162]) indicate possible translation of this technology (see Figure 2(e–g)). As far as we know, portable β⁻ cameras have not been reported. That said, CMOS sensors have been suggested as relative simple detector for β⁻ particle imaging, without the need for a scintillation material [165].

2.3. 3D nuclear detection modalities

To provide full in-depth insight regarding the radiopharmaceutical distribution within the patient, some form of 3D imaging is required. For this purpose, SPECT/CT and PET/CT have become the golden standard for diagnostic molecular imaging. For interventional purposes, these scans can be used to provide a reference roadmap for planning of the procedure. Furthermore, similar as the use of nuclear detection probes (1D) and cameras (2D), SPECT- or PET-based imaging (3D) can also be of value during radioguided interventions, including interventional radiology and surgery (see Figure 3). Especially for surgical application, however, it is often not logistically and financially feasible to use a full-sized SPECT or PET system in the OR itself. Therefore, pre-interventional scans are used in a navigation workflow, whereby an augmented/mixed reality overlay on to the patient is shown or a virtual reality navigation environment is provided, directing the interventional instruments towards the lesions with high radiopharmaceutical uptake [166]. Such navigation procedures have been pursued during PET-guided biopsy and PET- and SPECT-guided intraoperative lesion localization. As result of innovative use of a surgical navigation setup, intraoperatively acquired freehand SPECT has also been introduced. This technology provides a method to acquire a patient roadmap in the operating room. The biggest challenge with navigated approaches in general are tissue-induced deformations, which degrade the registration between the patient and the PET- or SPECT-based patient map [167]. Real-time confirmation with an intraoperative detection device can help correct for such inaccuracies.

Figure 3. 3D nuclear detection modalities for radioguided interventions. (a–b) Setup for navigated ¹⁸F-FDG PET-biopsy using a registered robotic biopsy arm (from [257]). (c–d) Example of trajectory planning in patient with suspected lymphoma. (e) Setup for SPECT/CT-based surgical navigation in head and neck cancer SN procedure, showing near-infrared (NIR) tracking of patient and instrument positions for registration with the patient scans. (f) Augmented reality overlay of SPECT/CT scan in the operating room for a penile cancer SN procedure (from [180]). (g) Virtual reality navigation towards SN in breast cancer using the SPECT/CT patient data (from [101]). (h) Intraoperative creation of 3D freehand SPECT images using a tracked portable gamma camera, including subsequent augmented reality overlay (i) and virtual reality navigation (j) during a head and neck cancer SN procedure.

2.3.1. Navigated PET- or SPECT-guided biopsy

Image-guided percutaneous biopsy followed by pathology plays an essential role in the management of oncological patients. Biopsies provide detailed molecular and genetic information of the disease and are critical for both diagnosis and staging. A non-successful biopsy, which occurs in 5–31% of the oncological cases, demands a repeating biopsy or even a conversion to open (surgical) procedures, which can postpone diagnosis and lead to additional costs, patient pain and anxiety [168,169]. Image-guided percutaneous biopsies are commonly performed using morphological imaging (e.g. fluoroscopy, US, CT, and MR imaging). In some cases, morphological changes are not predictive for the disease progression, which can lead to inconclusive findings [170]. Here targeting of molecular features as identified on, e.g. SPECT/CT or PET/CT can help decrease the number of inconclusive biopsies. One of the main advantages of such a radioguided biopsy approach is the ability to specifically target the lesion(s) with highest radiopharmaceutical uptake (see Table 2).

2.3.1.1. Background and recent advances

Intra-procedural ¹⁸F-FDG PET/CT-guided biopsy using an automated robot arm has been reported [171,172]. Here, positioning of the biopsy needle and tissue sampling was fully automated using a registered robot arm based on lesion coordinates defined in the PET/CT images (see Figure 3(a–d)). Fixation of the patient with a vacuum-immobilization device helped preventing inaccuracies due to patient movement. Radhakrishnan et al. reported this led to 100% successful diagnostic biopsies in 25 patients with intrathoracic lesions [172] and Kumar et al. reported a diagnostic yield of 98.6% in 73 patients with bone lesions [171]. A down-side of such procedures is that they are time-consuming and can increase the radiation burden to the patient and medical staff [171]. SPECT/CT-guided biopsies have also been suggested, using, for example, ^99mTc-MIBI [173]. Navigated approaches of this method were not found in literature yet, but the manual method already provided a 100% diagnostic yield (n = 12) in intrathoracic lesions.

2.3.2. Navigated PET- or SPECT-guided surgery

Similar as to navigated biopsies, 3D PET and SPECT images have also proven their ability to guide surgical lesion localization via a surgical navigation workflow in vivo (see Figure 3(e)).

2.3.2.1. Background and recent advances

¹⁸F-FDG PET/CT navigation of a laparoscope was demonstrated during lymph node salvage surgery for breast cancer and recurrent lymphoma [174]. SPECT/CT navigation has been applied more often, with navigation of a γ probe during open surgery SN procedures using (ICG-)^99mTc-nanocolloid (e.g. penile cancer, melanoma, breast cancer, thyroid cancer and prostate cancer [101,175–177]), the resection of neuroendocrine tumors using ¹²³I-MIBG (e.g. paraganglioma [101]) and parathyroid adenoma using ^99mTc-MIBI [178]. All intraoperative studies so far were based on the same underlying technology: an intraoperative navigation system with near-infrared optical tracking and optical tracking fiducials attached to both the patient and the navigated instruments (see Figure 3(e)). This tracking setup allowed for a registration between the preoperative PET- or SPECT-based patient maps and the intraoperative instruments. During surgery, this allowed for more accurate positioning of the surgical instruments (see Figure 3(f–g)). However, these studies also indicated that navigation to soft tissues based on preoperative images can suffer from inaccuracies due to tissue deformations. By navigating a γ probe or fluorescence camera, the real-time feedback provided could partially correct for such inaccuracies [175,176,179–181].

2.3.3. 3D intraoperative freehand imaging and subsequent navigation

Rather than rely on preoperatively acquired 3D scans, also intraoperative 3D scans can be obtained using a so-called freehand imaging technology. This technology makes innovative use of nuclear detection modalities already available in the OR to create 3D images of the radiopharmaceutical distribution within the patient. Freehand SPECT (fhSPECT) is the most common form of nuclear freehand 3D imaging available in the OR [182,183] (see Figure 3(h–j) and is the only form evaluated in vivo during radioguided surgery so far.

2.3.3.1. Background and recent advances

Using a surgical navigation system, the position and orientation of a γ probe or camera can be followed during γ tracing in de OR. While freely moving the γ probe or camera around the tissue of interest, this navigation system tracks the detector position relative to the patient, and at the same time, the read-out of the detector in each different position is recorded. Subsequently, dedicated signal processing software is able to create a 3D scan of the tracer distribution as related to the tracked patient [182,184,185]. The quality of this fhSPECT scan depends on the radiopharmaceutical uptake (i.e. signal intensity) and the number of positions and orientations (i.e. angular coverage) scanned around the tissue of interest [156,183]. Acquisition times can vary, but in general total scanning time should be kept roughly below 5 min [156,182,186].

Since the clinical introduction in 2010, fhSPECT has shown to be useful for several nuclear detection modalities, including open surgery γ probes [187–189], open surgery portable γ cameras [156,186,190], laparoscopic γ probes [179,191,192] and even the recently introduced DROP-IN γ probe [193]. As a result, this technology has already been evaluated during many different radioguided surgery procedures, such as SN in breast cancer [156,182,187], RSL in breast cancer [189], SN in head and neck cancers [186,188,194–197], SN in melanoma [186,198,199], SN in prostate cancer [179], SN in penile cancer [179], SN in gynecology [191], ROLL for pulmonary lesions [192], PSMA-targeted prostate salvage procedures [108], parathyroid adenoma [178], NET tumors [200] and various bone lesions [201].

Apart from using γ detection modalities, some have experimented with using β⁺ probes to create freehand β⁺ surface mapping [137,202]. Though proven successful in the laboratory, this concept has not been performed in vivo yet.

2.4. Multiplexing modalities

Despite the strong advantages provided for radioguided surgery, it is obvious to all that each individual detection signal (i.e. γ or β emissions) also has weaknesses. One way to overcome such weaknesses is to include the use of complementing guidance technologies during the same procedure. This multiplexing of the complementary information of different signatures in to a single procedure yields so-called ‘hybrid’, ‘dual-modality’ or ‘multi-modal’ procedures. The exploration of multiplexing concepts within the framework of radioguided surgery has substantially increased during the last 10 years. Multiplexing concepts have made use of dual-isotope detection (i.e. γ emissions with different energies or a combination of γ and β emissions), combined nuclear and optical detection (i.e. a combination of γ and fluorescence emissions or γ and Cerenkov emissions), combined use of β detection and optical coherence tomography and combined use of γ detection and ultrasound imaging. While procedures that rely on two signatures are more challenging from a technical perspective, from a clinical point-of-view, guidance towards targeted lesions may be optimized and logistics can be simplified.

2.4.1. Dual-isotope detection

Where the use of multiple radiopharmaceuticals for a single surgical guidance procedure is rare, dual-isotope multiplexing has been applied for the use of ¹²⁵I-seeds and ^99mTc-radiocolloid pharmaceuticals. Both low-to-mid energy γ probes [102] and γ cameras [116] have shown to be capable of such multiplexing.

2.4.1.1. Background and recent advances

Every radioactive isotope comes with a characteristic emission spectrum based on emission type (i.e. γ photon or β particle) and emission energy (see Table 2). Such a defined emission spectrum can consist of a single type and energy, but often consists of a combination of multiple types and/or energies. These defined emissions allow for the differentiation between multiple radiopharmaceuticals, each harboring a complementing radioactive isotope [203,204].

γ detectors typically describe detection events as an electrical pulse, where height of the pulse is a reflection of the γ ray energy. However, energy resolution of the detector determines how accurate this energy estimation is. By optimally classifying detection events within chosen energy ‘windows’, a differentiation can be made between different isotopes, provided that both are individually detectable with the device. The more unique the emission spectra of the radioactive isotopes are (i.e. no overlap of energy peaks), the more trivial such differentiation becomes.

To this extend, low-to-mid energy γ probes have been used to support combined use of the SN procedure (using ^99mTc) and the RSL procedure (using ¹²⁵I) in open breast cancer surgery [205]. Individual isotope tracing was achieved using a single γ probe that allows for switching between a ^99mTc and ¹²⁵I energy window (i.e. a window either around 140 or 27 keV, respectively). Similar energy discrimination even allows simultaneous imaging of a ^99mTc radiopharmaceutical distribution with respect to the ¹²⁵I-seed location. For portable γ cameras, the dual-isotope concept has been used to realize more convenient γ probe placement during laparoscopic SN procedures [114,116,206]. This concept was realized by placing a ¹²⁵I seed on the tip of the laparoscopic γ probe able to detect the radiopharmaceutical ^99mTc-nanocolloid, while monitoring the location of this tip with respect to the targeted lesion. However, some groups report a certain level of additional background is present during ¹²⁵I detection with both γ probe and camera, due to the ^99mTc originating scattered γ rays [102].

Next to multiplexing several γ ray energies, it has also been suggested to use a combination of β⁺ and γ detection during surgery [141,207]. Such joint emissions are common for all PET isotopes (e.g. ¹⁸F), producing both β⁺ particles and annihilation γ rays (see Table 2). In this setup, the γ-signal could be used for initial localization of the targeted lesion, while the β⁺ signal enables examination of, for example, tumor margins. As discussed in the β⁺ probe section, these nuclear emissions can be discriminated using a dual-detector setup: one sensitive to both β⁺ and γ and another sensitive to γ only. Despite being technically possible, to the best of our knowledge, hybrid γ and β⁺ detection has only been pursued in a single in vivo study for recurrent melanoma using ¹⁸F-FDG yet [255]. This study describes the use of a nuclear detection probe in five patients, capable of switching between β⁺ and γ detection via a footswitch pedal.

2.4.2. Optical emissions – fluorescence

To provide the surgeon with the best guidance as currently possible, many recent advances focus on the use of optical and nuclear detection modalities within a single surgical workflow [153,208,209]. Within the field of image-guided surgery, fluorescence imaging is rapidly gaining popularity, often providing detailed real-time visualization of targeted tissues within their anatomical context [210]. Unfortunately, despite the intuitive use of this technology, it remains a superficial technique (<1 cm) [211]. Therefore, in the case of targeted resections, a combination with nuclear medicine approaches is preferred. The hybrid (i.e. fluorescent and radioactive) radiopharmaceutical indocyanine green (ICG)-^99mTc-nanolloid has been successfully applied during, among others, SN procedures performed across different indications [212] including breast cancer [213], cervical cancer [214], penile cancer [215], prostate cancer [216] and head and neck cancers [217,218]. The same hybrid concept also has demonstrated value during ROLL procedures performed in melanoma and lymphoma patients [219].

2.4.2.1. Background and recent advances

Fluorescence imaging is an optical method that exploits the nature of fluorescent dyes: under excitation with a dye specific wavelength of light (typically between 400 and 800 nm), these substances emit light with a lower energy themselves (typically between 500 and 900 nm). Due to this shift in energy, optical filters can be used to separate excitation from emission light, allowing for precise visual localization of the fluorescent pharmaceutical. Of all the hybrid detection systems described for radioguided surgery, the combination of γ and fluorescence is the one most addressed in clinical literature. The optonuclear probe is a hybrid version of the traditional γ probe (see Figure 4(a–d)), providing both low-to-mid energy γ tracing and ICG fluorescence tracing in a single device [220–222]. This functionality is achieved by extending a γ probe design with two optical fibers, one coupled to an ICG excitation laser and the other coupled to an optically filtered (>810 nm) PMT. It has been used during both open and laparoscopic surgery for SN procedures in head and neck cancers, penile cancer, breast cancer, melanoma and cervical cancer [220–222]. Recently, it was shown that an integration of this hybrid detection probe with a surgical navigation system was even capable of producing 3D fluorescence tomography reconstructions (i.e. freehand Fluorescence scans) in addition to the above described fhSPECT modality [258]. This hybrid imaging and navigation technology was evaluated in ex vivo prostate cancer samples using ICG-99mTc-nanocolloid. KleinJan et al. investigated the use of image-based hybrid modalities in vivo (i.e. penile cancer SN procedure), by using a tailored bracket to physically connect either a γ probe or portable γ camera to a fluorescence camera system [154]. Here, the in-depth information of radioguidance provided the ability to more accurately position the fluorescence camera. A portable and fully integrated hybrid γ and fluorescence camera has only been studied in preclinical evaluations [223]. In this system, γ and fluorescent emissions are both collected at the front of the device, but in the camera are separated through an angled mirror (45°) to allow for separate detection. With an innovative wavelength division-based multiplexing method, Kang et al. propose an integrated hybrid laparoscope for simultaneous γ and fluorescence imaging in a laparoscopic setting [107]. In this system, γ, white light and fluorescent emissions are all collected through the same tungsten pinhole collimator. Subsequently, all emissions are passed through a gadolinium oxyorthosilicate (GSO) scintillator, converting only the γ rays to visible blue light (~400–500 nm). Hereafter all emissions are transported via de laparoscope imaging fiber bundle and collected with three different cameras based on wavelength. However, usability of this system still has to be determined.

Figure 4. Multiplexing modalities for radioguided surgery combining gamma and fluorescence detection. (a) Optonuclear probe design with detection elements for both low-to-mid energy gamma tracing and ICG fluorescence tracing (from [220]). Application during open surgery breast cancer (b–c) and laparoscopic surgery cervix cancer (d) SN procedure using ICG-^99mTc-nanocolloid (from [221]). (e) Position tracking and navigation of an open surgery fluorescence camera during a penile cancer SN procedure using ICG-^99mTc-nanocolloid. (f) Similar navigated fluorescence camera setup for a laparoscopic prostate cancer SN procedure (from [179]). (g–h) The fluorescence laparoscope is guided towards the lesion locations via augmented reality overlays of the freehand SPECT scans. (i) Fluorescence confirmation of the lesion of interest.

Next to the use of fully integrated hybrid detection modalities, hybrid surgical navigation concepts have been used to successfully integrate nuclear guidance (i.e. SPECT/CT or fhSPECT) with fluorescence guidance in vivo [175,179–181]. In this approach, the surgical targets (e.g. SNs) are defined based on the 3D preoperative SPECT/CT or intraoperative fhSPECT scans. Hereafter, the tracked fluorescence camera is navigated towards these targets, using virtual or augmented reality displays of the SPECT findings in the fluorescence video display (see Figure 4(e–i)). In this way, fluorescence guidance is extended to deeper lying lesions (>1 cm), while <1 cm inaccuracies of the navigation workflow are corrected via the real-time fluorescence feedback. Promising evaluations of this approach were shown in open surgery penile SN and laparoscopic prostate SN procedures.

2.4.3. Optical emissions – cerenkov

An alternative means to combine nuclear with optical imaging is provided by Cerenkov imaging (see Table 2). Ciarrocchi et al., Das et al. and Spinelli et al. provide comprehensive overviews regarding the current status of clinical Cerenkov imaging [224–226].

2.4.3.1. Background and recent advances

Cerenkov radiation is a phenomena first described and explained in literature by Pavel Cerenkov in 1934 [227]. It is an optical emission that occurs when charged particles, such as β⁺ and β⁻ particles, travel through a dielectric medium with a phase velocity higher than the speed of light in that medium [225,228]. By passing through the medium at such velocities, the charged particles create an asymmetric polarization of the medium along their traveled path, which promotes the emission of (ultra)violet (~250–450 nm) light and to a lower extend visible light (<25% emission >450 nm) [229,230]. The amount of light coming from these types of emissions increases with the particle energy and amount of particles (i.e. radiation dose). The total light yield at conventional clinical ¹⁸F-FDG conditions is unfortunately relatively low, being roughly an order of 3 to 4 less in intensity as compared to typical fluorescence-guided surgery [231]. To increase intensity of the faint signal, a higher amount of the β emitting radiopharmaceutical could be injected, though increasing the dose to the patients and possibly the surgical staff. Although ¹⁸F-FDG appears to be the generally used tracer, this isotope is actually rated as a low to moderate Cerenkov emitter, where isotopes such as the β⁻ emitting ⁹⁰Y provide a much higher Cerenkov intensity (factor 23) due to the higher β particle energy [232].

Theoretically, instrumentation to detect Cerenkov radiations is rather straightforward, where only an optical camera is needed to capture the light emitted in the tissue as a result of the injected radiopharmaceutical. Practically, due to the low signal intensity, a controlled light-tight environment is needed (i.e. blocking the ambient light) to accommodate detection by a highly sensitive (cooled) (EM)CCD camera with typically long exposure times (1–5 min). These practical features limit current Cerenkov-guided surgery, making it understandable that most work with this technology is performed in a preclinical setting so far [233]. Nevertheless, there have been some nice examples of in-human use (see Figure 5(g–l)): non-surgical imaging of ¹⁸F-FDG avid lymph nodes in the axilla [234], non-surgical imaging of thyroid radiation therapy using ¹³¹I [235], non-surgical imaging of external beam radiation therapy in breast cancer [236] and intraoperative imaging using ¹⁸F-FDG in rectal cancer endoscopic surgery [237]. Furthermore, ex vivo analysis of surgical specimens within the OR has also been suggested for direct margin evaluation [224]. Although no research is reported on this format yet, one could imagine a hybrid application where γ rays are used for lesion localization and Cerenkov imaging is used for margin evaluation [208].

Figure 5. Multiplexing modalities for radioguided monitoring and interventions using various detection signals. (a) Setup for a SN biopsy based on the fhSPECT-ultrasound fusion (from [208]). (b–c) fhSPECT-US fusion images for breast cancer SN localization (from [248]). (d–f) Combined use of beta+ and OCT for ex vivo localization of ¹⁸F-FDG avid ovarian cancer lesions, showing increased radiopharmaceutical uptake with a beta+ distribution map (d), anatomical microstructure details using OCT (e) and histopathological evaluation (f) (from [240]). (g) ¹⁸F-FDG avid axilla lymph nodes as shown with PET/CT can successfully be imaged with Cerenkov imaging (h) as well (from [236]). (i) Similar Cerenkov imaging during thyroid therapy using ¹³¹I (from [237]). (j) Intraoperative Cerenkov imaging of ¹⁸F-FDG in endoscopic surgery of rectal cancer (from [239]). (k–l) Augmented reality overlay of Cerenkov images with an example of tumor tissue (k) and normal tissue (l).

2.4.4. Optical coherence tomography

β⁺ imaging has also been proposed in combination with optical coherence tomography (OCT) [238]. OCT is a technique often compared to ultrasound. However, instead of sound pulses emitted and received by the ultrasound probe, an OCT probe typically emits near-infrared light pulses in to the tissue and detects the back-reflected light [259]. Spatial resolution of this technique is in the order of μm’s. Similar as β⁺ detection, OCT is a superficial technique with a penetration depth of only a few mm’s. In a combined setup, 2D β⁺ imaging is suggested to be used for localization of the lesions with high radiopharmaceutical uptake, while OCT provides anatomical imaging to investigate the tissue microstructures [239]. So far, only a single prototype system is reported, where the detection head consists of a single OCT fiber, surrounded by multiple β scintillators. Preliminary ex vivo results illustrate the potential of this technique (see Figure 5(d–f)); ex vivo ovarian cancer samples (using ¹⁸F-FDG) showed detailed morphological features with OCT that could potentially be used for detection of early malignant cancer [238].

2.4.5. Ultrasound

Interventional use of nuclear medicine technologies with ultrasound (US) imaging has also been pursued. In such a setup, nuclear detection modalities such as γ cameras and fhSPECT identify lesions with high radiopharmaceutical uptake, while ultrasound can be used to provide anatomical detail of the surrounding tissue.

2.4.5.1. Background and recent advances

Pani et al. describe a handheld ultrasound probe with an integrated small FOV γ camera [240]. By placing a piezoelectric US crystal in front of, and partially overlapping with, a custom γ collimator, this device can simultaneously image ultrasound and γ information, which can be displayed as a fused image. Partial overlap of the detectors combined with a custom software algorithm allows for <1 mm error in image registration. Using a slit model collimator design, combined with the NaI(Tl) scintillator and position sensitive PMTs, the resulting high γ counting efficiency allows for real-time acquisition of γ images. This in turn ensures that the fused γ/US images can be displayed in a real-time fashion. Unfortunately, a hard acquisition time is not mentioned. The reported resolution (<2 mm) was acceptable for a γ camera but is quite poor for an US device. In vivo evaluation has still to be shown.

Integration of US and γ images are also shown via a surgical navigation setup [241]. In this setup, the 3D molecular imaging capabilities of fhSPECT are acquired and subsequently fused with the real-time US information by tracking the position of both the patient and the US probe (see Figure 5(a–c)). Registration of this US-fhSPECT fusion has shown to be accurate for various (para)thyroid diseases [242,243] using ^99mTc-MIBI or ^99mTcO₄⁻. Mapping of sentinel lymph nodes was also shown for breast cancer, melanoma, cutaneous lesions, vulva cancer and head and neck cancers [244–246]. In these cases, the potential of US-fhSPECT fusion was further supported, facilitating sentinel lymph node identification if lymph nodes were not well visible with US or when various lymph nodes were located in close proximity to each other. However, to allow for an accurate fhSPECT-US registration (i.e. order of mm’s) in these procedures, specific attention was needed to minimize patient repositioning and tissue deformations.

3. Expert opinion

In this article, we’ve provided a comprehensive overview of nuclear detection modalities for image-guided surgery, specifically placing new developments within the framework of existing technology. During the last years, dedicated detection modalities have become available for specific medical applications such as the tethered DROP-IN γ probe for robot-assisted laparoscopic surgery. Also, use of a wide range of nuclear emissions has been explored: γ radiation (low-to-mid or high energy), β radiation (β⁺ and β⁻). Table 3 displays a simplified and generalized summary of all modalities discussed.

Table 3. Simplified general overview of detection modalities available for radioguided surgery, including human use only.

Characteristic	Low-to-mid energy γ probe	High energy γ probe	β^+ probe	β^− probe	Portable γ camera	Portable β^+ camera	Surgical navigation	fhSPECT
Signal dimensions	1D	1D	1D	1D	2D	2D	3D	3D
Radiopharmaceuticals	SPECT	PET	PET	Therapeutic	SPECT	PET	SPECT and PET	SPECT
Detected emissions	γ (≤400 keV)	γ (511 keV)	β^+, γ (511 keV)	β^−	γ (50–300 keV)	β^+, γ (511 keV)	γ (≤400 keV), γ (511 keV)	γ (≤400 keV)
Form factors	Open, laparoscopic and tethered DROP-IN	Open surgery	Open surgery	Open surgery	Open surgery	Open surgery	Open and laparoscopic surgery	Open and laparoscopic surgery
Signal display	Numeric and acoustic	Numeric and acoustic	Numeric and acoustic	Numeric and acoustic	Image (& AR overlay with optical image)	Image	AR overlay with optical image & VR environment	AR overlay with optical image & VR environment
Dose exposure to patient	+	-	-	-	+	-	+	+
Dose exposure to staff	+	-	-	++	+	-	+	+
Signal penetration through tissue	cm’s	cm’s	mm’s	mm’s	cm’s	mm’s	cm’s	cm’s
Resolution	mm’s	<cm	mm’s	mm’s	mm’s	mm’s	mm’s	mm’s
Acquisition time	<second	seconds	seconds	seconds	Tens of seconds	Tens of seconds	Tens of minutes	minutes
Multiplexing combinations for radioguided surgery	Fluorescence	Cerenkov, β^+	High energy γ, OCT, Cerenkov	Cerenkov	Fluorescence, US	Cerenkov	Fluorescence	Fluorescence, US

+ = low dose exposure; - = high dose exposure

From a clinical perspective, the main advantages of using low-to-mid energy γ detection are the ease of use (e.g. low sampling time), the great availability of (hybrid) detection devices for different surgical techniques and the relative low dose to patient and surgical staff. Based on this, one can argue there is a clinical demand for the development of more receptor-specific SPECT radiopharmaceuticals. Contradictory to this, the main advantages of using either high energy γ or β⁺ detection is the availability of a plurality of PET radiopharmaceuticals. For the exploration of available PET radiopharmaceuticals, further engineering of high energy γ and β⁺ detection modalities is required to improve ease of handling and promote integration in laparoscopic surgery. Considering that PET isotopes come with high-energy γ rays, decrease of radiopharmaceutical dosing would also be desired, decreasing radiation dose to patient and surgical staff. Since detection of pure β⁻ isotopes demands the use of therapeutic radiopharmaceuticals, more detailed evaluations are needed to decide on the potential role of this approach. Specific challenges lie with preoperative lesion mapping since β particles have low penetration depth, and radiation dose to the patient.

Though the use of radioactive isotopes in medicine is only expected to grow, it does not mean there aren’t shortcomings and disadvantages to its use in surgery. The limitations of conventional radioguided surgery approaches have resulted in an increasing tendency to apply radioguidance in combination with other imaging signatures (e.g. fluorescence, Cerenkov, OTC, and US) or together with software-based guidance solutions (e.g. surgical navigation and augmented/mixed/virtual reality displays). With all the research available on investigating hybrid surgical devices [153,208,209], especially the link between radioguidance and fluorescence guidance appears to be important for surgical interventions. Here, the complementary advantages of both techniques will provide a valuable roadmap for surgery, were nuclear information is used for diagnostics (e.g. SPECT or PET), surgical planning (e.g. SPECT/CT) and intraoperative translation and coarse localization (e.g. γ probe or portable camera), while fluorescence information provides high-resolution visual confirmation and delineation of the targeted lesions during excision [260]. With the many successful evaluations of ICG-^99mTc-nanocolloid [212], we are under the opinion that this field will rapidly expand when more hybrid radiopharmaceuticals will make their way in to the clinic.

3.1. Five-year view

Radioguided surgery is already standard for image-guided surgery procedures such as the SN, ROLL and RSL and it is likely that the clinical impact of radioguided surgery will increase through the expanding clinical availability of disease-specific radiopharmaceuticals. The recent example of lymphatic salvage procedures in recurrent prostate cancer that make use of PSMA I&S (^99mTc or ¹¹¹In) provides a great example how innovations in the area of radiopharmaceutical design impact the field of radioguided surgery [247]. Here it should be noted that efforts towards the realization of hybrid radiopharmaceuticals are likely to promote the use of multiplexing approaches. Examples of potential future hybrid procedures are: prostate cancer (PSMA I&F) [248], neuroendocrine tumors (Cy5-¹¹¹In-DTPA-Tyr3-octreotate) [249], breast cancer ([¹¹¹In]-DTPA-trastuzumab-IRDye800) [250] and renal cancer (¹¹¹In-girentuximab-IRDye800CW) [251].

From a modality perspective, significant improvements are to be expected for high-energy γ detection modalities (e.g. improved ergonomics) and β detection modalities (e.g. first in vivo evaluations of the role of modern β⁻ detection). Nevertheless, we think the main focus of radioactive isotopes for surgery will probably remain confined to the more traditional low- and mid-energy γ detection (i.e. ^99mTc and ¹¹¹In). A combination of factors still makes this kind of nuclear detection dominant during surgery: (1) a clear connection to preoperative total body molecular imaging (i.e. SPECT/CT) available, (2) in-depth information offered for lesion localization and confirmation, (3) ease of use due to low sample times (<1 s) and plurality of form factors possible with relative lightweight and small dimensions, and (4) a relative low dose to patient and surgical staff [254].

In the pursue of minimal invasive interventions, ensuring radical excisions while decreasing surgical complications, thereby improving patient outcome and quality of life, an ever more amount of surgical interventions will be pushed towards the realm of robot-assisted (laparoscopic) surgery. This will push the development of dedicated technologies such as the tethered DROP-IN γ probe [99,120,121]. At the same time, the technological evolution of the field is expected to provide a platform for integration of augmented-, mixed- or virtual-reality displays and navigation in routine procedures [167].

Article highlights

• One-dimensional (1D) γ-detection probes provide the technical fundament of radioguided surgery.

• Additionally, nuclear imaging during interventions has been evolving towards the detection of alternative signals (e.g. β radiation) or signal combinations (e.g. γ and fluorescence) as well. These efforts not only expand toward two-dimensional (2D) and three-dimensional (3D) imaging, but even include augmented- and virtual-reality approaches.

• Key issues of performance for such image guidance modalities are:

  1. Sensitivity, which determines the ability to detect low radiopharmaceutical uptake and allows for short sample times. To facilitate surgical implementation, sample times have to be pushed towards real-time (<1 s) detections.

  2. Spatial resolution, which describes the ability to distinguish between lesions in close proximity to each other.

  3. Specificity, which defines the ability to discriminate the target tissue from background, sometimes called contrast.

  4. Ease of handling, which is determined by the ability of the surgeon to maneuver the nuclear detection device in an ergonomic and intuitive fashion.

  5. Rotational freedom during lesion localization.

  6. Signal representation, which determines how the surgeon needs to interpret the findings during lesion localization (e.g. audible, numerical or via image display).

• These key issues of performance are not defined by a single aspect of the nuclear detection modality, but rather are a result of the complete design, applied working distance and integration within the surgical methodology. The latter underlines that the surgical procedure will influence the choice of device.

• Clinically, a balance has to be created between the radiation dose that comes with a specific procedure (risk) and the benefit it creates (outcome). From the perspective of the patient, clinical outcome should outweigh the risk of accumulating dose.

• For the medical staff, legally allowed annual dose exposure boundaries may limit the number of procedures that can be performed by individual surgeons. Most important dose factors are energy of the emitted γ or β particles (i.e. lower energy gives lower dose) and the amount of radioactivity left at the procedure (which is a combination of injected activity, isotope half-life and time after injection).

• Uniquely, provided proper handling, use of β⁻ radiation hardly results in any dose risk to the surgical staff; β⁻ radiation has a limited penetration of only a few mm’s. Unfortunately, radiation dose to the patient does increase.

Declaration of interest

FWB van Leeuwen is a consultant for Hamamatsu photonics and is Chief Innovation Officer at the ORSI Academy surgical training center. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by an NWO-TTW-VICI grant (grant no. TTW 16141).