A first-in-human study of [68Ga]Ga-CDI: a positron emitting radiopharmaceutical for imaging tumour cell death.

PURPOSE: This study assesses human biodistribution, radiation dosimetry, safety and tumour uptake of cell death indicator labelled with 68Ga ([68Ga]Ga-CDI), a novel radiopharmaceutical that can image multiple forms of cell death. METHODS: Five participants with at least one extracranial site of solid malignancy > 2 cm and no active cancer treatment in the 8 weeks prior to the study were enrolled. Participants were administered 205 ± 4.1 MBq (range, 200-211 MBq) of [68Ga]Ga-CDI and 8 serial PET scans acquired: the first commencing immediately and the last 3 h later. Participants were monitored for clinical, laboratory and electrocardiographic side effects and adverse events. Urine and blood radioactivity was measured. Spherical volumes of interest were drawn over tumour, blood pool and organs to determine biodistribution and calculate dosimetry. In one participant, tumour specimens were analysed for cell death using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. RESULTS: [68Ga]Ga-CDI is safe and well-tolerated with no side effects or adverse events. [68Ga]Ga-CDI is renally excreted, demonstrates low levels of physiologic uptake in the other organs and has excellent imaging characteristics. The mean effective dose was 2.17E - 02 ± 4.61E - 03 mSv/MBq. It images constitutive tumour cell death and correlates with tumour cell death on histology. CONCLUSION: [68Ga]Ga-CDI is a novel cell death imaging radiopharmaceutical that is safe, has low radiation dosimetry and excellent biodistribution and imaging characteristics. It has potential advantages over previously investigated radiopharmaceuticals for imaging of cell death and has progressed to a proof-of-concept trial. TRIAL REGISTRATION: ACTRN12621000641897 (28/5/2021, retrospectively registered).

Imaging of cell death in malignancy: Targeting pathways or phenotypes?

Cell death is fundamental in health and disease and resisting cell death is a hallmark of cancer. Treatment of malignancy aims to cause cancer cell death, however current clinical imaging of treatment response does not specifically image cancer cell death but assesses this indirectly either by changes in tumor size (using x-ray computed tomography) or metabolic activity (using 2-[18F]fluoro-2-deoxy-glucose positron emission tomography). The ability to directly image tumor cell death soon after commencement of therapy would enable personalised response adapted approaches to cancer treatment that is presently not possible with current imaging, which is in many circumstances neither sufficiently accurate nor timely. Several cell death pathways have now been identified and characterised that present multiple potential targets for imaging cell death including externalisation of phosphatidylserine and phosphatidylethanolamine, caspase activation and La autoantigen redistribution. However, targeting one specific cell death pathway carries the risk of not detecting cell death by other pathways and it is now understood that cancer treatment induces cell death by different and sometimes multiple pathways. An alternative approach is targeting the cell death phenotype that is "agnostic" of the death pathway. Cell death phenotypes that have been targeted for cell death imaging include loss of plasma membrane integrity and dissipation of the mitochondrial membrane potential. Targeting the cell death phenotype may have the advantage of being a more sensitive and generalisable approach to cancer cell death imaging. This review describes and summarises the approaches and radiopharmaceuticals investigated for imaging cell death by targeting cell death pathways or cell death phenotype.

Incidental finding of tall cell variant papillary thyroid carcinoma on prostate-specific membrane antigen PET CT scan.

Prostate-specific membrane antigen (PSMA) PET CT is widely used for staging and restaging of prostate cancer. Thyroid and other non-prostatic pathology may be incidentally identified by this imaging modality. Such findings warrant further investigation given their malignant potential. We describe the first reported case of PSMA avid T cell-variant papillary thyroid carcinoma incidentally detected on PSMA PET CT.

Novel 5-point 18-FDG-PET/CT visual scoring system for assessing treatment response in patients with oesophageal or gastro-oesophageal junction carcinoma.

INTRODUCTION: The purpose of this study was to investigate the prognostic utility and reproducibility of a qualitative 5-point 18-fluorodeoxyglucose (FDG)-PET primary visual score (PVS) in patients with oesophageal and gastro-oesophageal junction (GOJ) cancer. METHODS: This was a retrospective review of patients with histologically proven oesophageal or GOJ cancer who received curative intent therapy. Clinical, pathological and imaging data were extracted from electronic medical records. Patients were required to have pre-treatment and post-treatment FDG-PET scans, that were evaluated with a 5-point primary visual score (prePVS, postPVS). The changes in PVS (ΔPVS) were correlated with progression-free survival and overall survival. Interobserver variability was assessed using Cohen's Kappa intraclass correlation and agreement. RESULTS: Sixty-seven patients were retrospectively identified. Two (3%), 36 (54%) and 29 (43%) of the patients had stage I, II and III disease respectively. Twenty-five (37%) patients had squamous cell carcinoma. Thirty-seven (55%) patients proceeded onto surgical resection. postPVS was associated with both PFS (P = 0.013) and OS (P = 0.0002). ΔPVS predicted for PFS (P = 0.002) and OS (P = 0.0003). When thresholds of response were considered, agreement was 80.6% (K = 0.78) and 74.6% (K = 0.69) for postPVS and ΔPVS respectively. CONCLUSION: Qualitative assessment of oesophageal and GOJ cancers utilising FDG-PET is reproducible and may be able to prognosticate outcomes in patients undergoing treatment. Prospective validation is required.

Concordant PET/CT and ICG positive lymph nodes in endometrial cancer: a case of mistaken identity.

Endometrial carcinoma is the most common gynecological malignancy in developed countries. In early stage endometrial cancer, routine systemic pelvic lymphadenectomy showed no survival benefits and results in increased morbidity. The role of PET/CT imaging for the pre-operative detection of lymph node metastases in endometrial cancer is unclear. Sentinel lymph node (SLN) mapping may reduce the surgical staging morbidity while maintaining prognostic information of the lymph node status. Recently, indocyanine green (ICG) SLN mapping has been utilized to detect nodal metastasis in endometrial cancer. Endosalpingiosis is defined as the presence of tubal-like epithelium outside of the fallopian tube and can sometimes be misinterpreted as cancer metastasis. Here, we discuss a patient with newly diagnosed endometrial cancer who had pelvic and para-aortic lymph nodes with high glucose avidity on PET/CT, and ICG positivity on SLN mapping, suspected clinically to be metastatic adenocarcinoma, but with the pathological finding of endosalpingiosis only.

Influence of X-ray computed tomography (CT) exposure and reconstruction parameters on positron emission tomography (PET) quantitation.

BACKGROUND: The CT of PET CT provides diagnostic information, anatomic localisation and attenuation correction (AC). When only AC is required, very lose dose CT is desirable. CT iterative reconstruction (IR) improves image quality with lower exposures however there is little data on very low dose IR CT for AC of PET. This work assesses the impact of CT exposure and reconstruction algorithm on PET voxel values. METHOD: An anthropomorphic torso phantom was filled with physiologically typical [18]F concentrations in heart, liver and background compartments. A 17-mm-diameter right lung "tumour" filled with [18]F was included (surrounding lung contained no 18[F]). PET was acquired followed by 24 CT acquisitions with varying CT exposures (15-50 mAs, 80-120 kVp, pitch 0.671 or 0.828). Each CT was reconstructed twice using filtered back projection (FBP) or IR and these used for AC of PET. The reference PET reconstruction (RR) used CT acquired at 50 mAs, 120 kVp, pitch 0.828, IR, all others were test PET reconstructions (TR). Regions of interest (ROIs) were drawn in the liver, soft tissue and over "tumour" on each TR and compared with the RR. Voxel values in each TR were compared to the RR using a paired t test and by calculating which and what proportion of voxels in each TR differed by a quantitatively significant difference (QSD) from the RR. RESULTS: TRs reconstructed using lower dose CTs underestimated mean and maximum ROI activity relative to the RR; greater with IR than FBP. Once CT dose index (CTDI) increased to 1 mGy, differences were less than QSD. On voxel analysis, all TRs were significantly different to the RR (p < 0.0001). TRs reconstructed at the lowest CT exposure with IR had 6% of voxels that differed by greater than QSD. Differences were reduced with increasing CTDI and FBP reconstruction. Voxels which exceeded the QSD were spatially localised to regions of high activity, interfaces between different attenuation and areas of CT beam hardening. CONCLUSIONS: Very low dose CT exposures are feasible for accurate PET AC. Scanner- and reconstruction-specific validation should be employed prior very low dose CT AC for PET.

Biodistribution and imaging of an hsp90 ligand labelled with 111In and 67Ga for imaging of cell death.

BACKGROUND: 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated at the γ-glutamyl residue with fluorophores and radio-isotopes is able to image dead and dying cells in vitro and in vivo by binding to intracellular 90-kDa heat shock proteins (hsp90) when cell membrane integrity is compromised. The ability to image cell death has potential clinical impact especially for early treatment response assessment in oncology. This work aims to assess the biodistribution and tumour uptake of diethylene triamine pentaacetic acid GSAO labelled with 111In ([111In]In-DTPA-GSAO) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid GSAO labelled with 67Ga ([67Ga]Ga-DOTA-GSAO) in a murine subcutaneous tumour xenograft model and estimate dosimetry of [67Ga]Ga-DOTA-GSAO. RESULTS: There was good tumour uptake of both [111In]In-DTPA-GSAO and [67Ga]Ga-DOTA-GSAO (2.44 ± 0.26% injected activity per gramme of tissue (%IA/g) and 2.75 ± 0.34 %IA/g, respectively) in Balb c nu/nu mice bearing subcutaneous tumour xenografts of a human metastatic prostate cancer cell line (PC3M-luc-c6). Peak tumour uptake occurred at 2.7 h post injection. [111In]In-DTPA-GSAO and [67Ga]Ga-DOTA-GSAO demonstrated increased uptake in the liver (4.40 ± 0.86 %IA/g and 1.72 ± 0.27 %IA/g, respectively), kidneys (16.54 ± 3.86 %IA/g and 8.16 ± 1.33 %IA/g) and spleen (6.44 ± 1.24 %IA/g and 1.85 ± 0.44 %IA/g); however, uptake in these organs was significantly lower with [67Ga]Ga-DOTA-GSAO (p = 0.006, p = 0.017 and p = 0.003, respectively). Uptake of [67Ga]Ga-DOTA-GSAO into tumour was higher than all organs except the kidneys. There was negligible uptake in the other organs. Excretion of [67Ga]Ga-DOTA-GSAO was more rapid than [111In]In-DTPA-GSAO. Estimated effective dose of [67Ga]Ga-DOTA-GSAO for an adult male human was 1.54 × 10- 2 mSv/MBq. CONCLUSIONS: [67Ga]Ga-DOTA-GSAO demonstrates higher specific uptake in dead and dying cells within tumours and lower uptake in normal organs than [111In]In-DTPA-GSAO. [67Ga]Ga-DOTA-GSAO may be potentially useful for imaging cell death in vivo. Dosimetry estimates for [67Ga]Ga-DOTA-GSAO are acceptable for future human studies. This work also prepares for development of 68Ga GSAO radiopharmaceuticals.

Positron emission tomography changes management, improves prognostic stratification and is superior to gallium scintigraphy in patients with low-grade lymphoma: results of a multicentre prospective study.

PURPOSE: Positron emission tomography (PET) was evaluated in low-grade non-Hodgkin lymphoma (NHL) to determine its impact on staging and management and to compare PET and gallium scans. METHODS: PET resulted in management plan changes in 74 patients with untreated low-grade NHL stages I to III. Patient outcomes to 12 months were documented. RESULTS: PET identified additional lesions in 50% of patients, led to a change in stage in 32%, and had a significant impact on management in 34%. Inferior progression-free survival was noted in patients with additional lesions detected by PET (p=0.001) and in the 28% of patients upstaged by PET to stage III or IV (p=0.024). In a subset of 16 patients undergoing both PET and gallium scans, PET was found to be superior. CONCLUSION: PET has a major role in the management of low-grade NHL in addition to its proven role in aggressive lymphoma.

Preparation of a Dithiol-Reactive Probe for PET Imaging of Cell Death.

Conjugates of 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid (GSAO) with optical or radionuclide probes are able to image cell death in vivo. GSAO conjugates are retained in the cytosol of dying and dead cells via the formation of covalent bonds between the As(III) ion and the thiol groups of proximal cysteine residues. Here we describe the method for preparing a NODAGA-GSAO conjugate and its radiolabeling with gallium-68 (68Ga-NODAGA-GSAO) for positron-emission tomography (PET) imaging of cell death.

Imaging in cutaneous melanoma.

Cutaneous melanoma (CM) is a common malignancy and imaging, particularly lymphoscintigraphy (LS), positron-emission tomography with 2-fluoro-2-deoxyglucose (FDG-PET), ultrasound, radiography computed tomography (CT) and magnetic resonance imaging have important roles in staging and restaging, surgical guidance, surveillance and assessment of recurrent disease. This review aims to summarize the available data regarding these and other imaging modalities in CM and provide the basis for subsequent formulation of guidelines regarding the use of imaging in CM. PubMed and Medline searches were performed and reference lists from publications were also searched. The published data were reviewed and tabulated. There is level I evidence supporting the use of LS and sentinel lymph node biopsy in nodal staging for CM. There is level III evidence demonstrating the superiority of ultrasound to palpation in the assessment of lymph nodes in CM. There is level IV evidence supporting FDG-PET in American Joint Committee on Cancer stage III/IV and recurrent CM and that FDG-PET/CT may be superior to FDG-PET. Level IV evidence also supports the use of CT in the same group of patients and the role of CT appears to be complementary to FDG-PET. Various imaging modalities, especially LS/sentinel lymph node biopsy and FDG-PET/CT, add incremental information in the management of CM and the various modalities have complementary roles depending on the clinical situation.

Guidelines for imaging in cutaneous melanoma.

The preceding article reviewed the available data on imaging modalities in cutaneous melanoma. Based on this review, this article aims to provide guidelines for the use of the various imaging modalities in cutaneous melanoma and to indicate the level of supporting evidence and strength of recommendation with associated explanatory notes.

Comparison of pinhole and SPECT 99mTc-MIBI imaging in primary hyperparathyroidism.

OBJECTIVE: This study aims to compare dual tracer, dual phase pinhole technetium-99m labelled 2-methoxyisobutylisonitrile (Tc-MIBI) imaging (including oblique imaging), with single photon emission computed tomography (SPECT) and dual phase planar Tc-MIBI images, and combined SPECT, dual phase planar Tc-MIBI images and anterior pinhole thyroid images for the localization of parathyroid adenomas in the neck in primary hyperparathyroidism. METHODS: Sixty-two patients underwent Tc-MIBI dual phase, anterior and anterior oblique pinhole images of the neck, anterior planar images of the neck and chest and early phase neck/chest SPECT followed by [Tc] pertechnetate anterior and anterior oblique pinhole thyroid images. Images were reviewed by consensus in three combinations - dual phase anterior and anterior oblique pinhole Tc-MIBI images and pinhole thyroid images; SPECT and dual phase planar Tc-MIBI images and combined SPECT, dual phase planar Tc-MIBI images and anterior pinhole thyroid images. RESULTS: For 52 parathyroid adenomas in 50 patients, the sensitivity of dual phase anterior and anterior oblique pinhole Tc-images and pinhole thyroid images was 81%. Significantly lower sensitivities were observed with SPECT and dual phase planar Tc-MIBI images (54%, P=0.0005) and combined SPECT, dual phase planar Tc-MIBI images and anterior pinhole thyroid images (65%, P=0.0209). The positive predictive value for all imaging combinations was 88-92%. CONCLUSION: Dual phase anterior and anterior oblique pinhole Tc-MIBI images and pinhole thyroid images are significantly more sensitive than imaging combinations that included SPECT and remains the optimal imaging protocol for the localization of parathyroid adenomas in the neck in primary hyperparathyroidism.

SPECT/CT imaging using a spiral CT scanner for anatomical localization: Impact on diagnostic accuracy and reporter confidence in clinical practice.

PURPOSE: To evaluate the incremental benefit in routine clinical practice of computed tomography (CT) scans acquired for anatomical localization on an integrated SPECT/CT which incorporates a spiral CT scanner, in comparison with conventional planar and SPECT scanning. METHODS: The first 50 studies acquired on the integrated system were evaluated by two experienced nuclear medicine physicians who were aware of the patient's clinical history. These included bone scans, gallium scans, octreotide scans, sestamibi parathyroid scans and MIBG scans. For each patient study, abnormalities were assessed on planar and SPECT images for location and provisional diagnosis and a quantitative scale was used to assess reporter confidence. The fused SPECT/CT images were then reviewed and the location and provisional diagnosis noted and reporter confidence was assessed using the same quantitative scale. RESULTS: There were 129 abnormalities detected in 50 patient studies. For localization of abnormalities, the inclusion of the CT resulted in a minor change in 16% of cases and a significant change in 11% over planar/SPECT imaging alone. The confidence of localization was improved moderately in 19% and improved significantly in 6%. For diagnosis, SPECT/CT resulted in a minor change in 10% and a significant change in 9% over planar/SPECT imaging. The confidence of diagnosis was improved moderately in 10% and improved significantly in a further 10% of cases. For the final scan interpretation, there would have been no change in 44% patients, a minor change in 30% and a significant change in 26% with the use of SPECT/CT. CONCLUSION: Use of integrated SPECT/CT with a high spatial resolution, spiral CT used for anatomical localization improves accuracy and reporter confidence in clinical practice. As a result, final reports were different in 56% of the cases, including being significantly different in 26% patients compared to reporting with planar/SPECT alone.

Application of novel quantitative techniques for fluorodeoxyglucose positron emission tomography/computed tomography in patients with non-small-cell lung cancer.

AIM: Flurodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is routinely used in non-small-cell lung cancer. This study aims to assess the prognostic value of quantitative FDG-PET/CT parameters including standard uptake value (SUV), metabolic tumor volume (MTV) and total lesional glycolysis (TLG) in non-small-cell lung cancer. METHODS: A retrospective review of 92 nonsurgical patients with pathologically confirmed stage I-III non-small-cell lung cancers treated with radical dose radiotherapy (≥50 Gy) was conducted. Metabolically active tumor regions on FDG-PET/CT scans were contoured manually. SUV, MTV and TLG were calculated for primary, nodal and whole-body disease. Univariate and multivariate (adjusting for age, sex, disease stage and primary tumor size in centimeters) Cox regression modeling were performed to assess the association between these parameters and both overall and progression-free survival (PFS). RESULTS: On univariate analysis, overall survival (OS) was significantly associated with primary MTV (P = 0.03), whole-body MTV (P = 0.02), whole-body maximum SUV (P = 0.05) and whole-body TLG (P = 0.03). PFS was significantly associated with primary MTV (P = 0.01), primary TLG (P = 0.04), whole-body MTV (P < 0.01) and whole-body TLG (P = 0.01). On multivariate analysis, OS was significantly associated with whole-body MTV (P = 0.05). PFS was significantly associated with whole-body MTV (P = 0.02) and whole-body TLG (P = 0.05). CONCLUSIONS: Whole-body MTV was significantly associated with overall and PFS, and whole-body TLG was significantly associated with PFS on multivariate analysis. These two parameters may be significant prognostic factors independent of other factors such as stage. SUV was not significantly associated with survival on multivariate analysis.

Impact of FDG-PET on lung cancer delineation for radiotherapy.

PURPOSE: The purpose of this study is to assess the impact of fused diagnostic F-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) and planning FDG-PET/CT scans on voluming of lung cancer for radiotherapy. METHODS: Five radiation oncologists (ROs), five radiation oncology trainees and a radiologist contoured five cases of non-small cell lung cancer. The CT alone, the diagnostic FDG-PET/CT and planning FDG-PET/CT each registered to the CT, were used to contour three volumes. The concordance index (CI) was used to compare each volume with a reference RO. RESULTS: Although there was considerable inter-observer variability in CT contouring, there was no significant difference between mean volumes of the gross tumour volume for the RO and radiation oncology trainees using any technique. There was no increase in CI with the addition of PET/CT, either diagnostic or planning, for the RO. However, the volumes of the radiation oncology trainees showed a significant increase in CI from 65.8% with CT alone to 68.0% and 72.3% with diagnostic PET/CT and planning PET/CT, respectively (P = 0.028). Mean variation at the tumour/mediastinum interface was significantly reduced with addition of registered PET/CT. CONCLUSIONS: The concordance of RO with the reference RO did not significantly increase with use of integrated FDG PET/CT images. However, the contouring of radiation oncology trainees' became more concordant with the reference.

Diagnostic and staging impact of radiotherapy planning FDG-PET-CT in non-small-cell lung cancer.

BACKGROUND AND PURPOSE: To evaluate whether FDG-PET performed for radiotherapy (RT) planning can detect disease progression, compared with staging PET. MATERIALS AND METHODS: Twenty-six patients with newly-diagnosed non-small-cell lung cancer underwent planning PET-CT for curative RT within 8 weeks (mean: 33±14days) of staging PET-CT. Progressive disease (PD) was defined as >25% increase in tumour size (transaxial) or volume, as delineated by SUV threshold of 2.5, or new sites (SUV>2.5). RESULTS: The planning PET detected PD in 16 patients (61%), compared to four patients (15%) by CT component of PET-CT. The mean scan interval was longer in patients with progression: 40±12days, compared to 22±11days without progression. Planning PET detected PD in 13/17 (76%), 12/14 (86%) and 7/7 patients if the interval was ≥4, 5 and 6 weeks, respectively, compared with 3/9 patients if interval <4 weeks. Planning PET detected PD in primary metabolic volume in seven patients, 20 new nodal sites in 12 new nodal stations and nine patients, five extra-nodal sites in five patients. This resulted in upstaging in nine patients (35%): stage IIIA in three, IIIB in three and IV in three. CONCLUSIONS: RT-planning FDG-PET can provide incremental diagnostic information and may impact on staging in a significant number of patients.

Positron emission tomography in non-medullary thyroid cancer.

While iodine scanning is the mainstay of functional imaging in differentiated thyroid cancer, there is now a significant body of literature regarding positron emission tomography with 2-fluoro-2-deoxy glucose in thyroid cancer. This clinical review will examine the evidence supporting the use of 2-fluoro-2-deoxy glucose-positron emission tomography throughout the diagnosis and management of thyroid cancer, and provide suggestions for its clinical use and potential future roles.