AR and PI3K Genomic Profiling of Cell-free DNA Can Identify Poor Responders to Lutetium-177-PSMA Among Patients with Metastatic Castration-resistant Prostate Cancer.

Lutetium-177 prostate-specific membrane antigen radioligands (177Lu-PSMA) are new therapeutic agents for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We evaluated the prognostic value of circulating tumour DNA (ctDNA) profiling in patients with mCRPC starting treatment with 177Lu-PSMA I&T. Between January 2020 and October 2022, patients with late-stage mCRPC (n = 57) were enrolled in a single-centre observational cohort study. Genomic alterations in the AR gene, PI3K signalling pathway, TP53, and TMPRSS2-ERG were associated with progression-free survival (PFS) on Kaplan-Meier and multivariable Cox regression analyses. Median PFS of 3.84 mo (95% confidence interval [CI] 3.3-5.4) was observed, and 21/56 (37.5%) evaluable patients experienced a prostate-specific antigen response of ≥50% during treatment. Among 46 patients who provided a blood sample for profiling before 177Lu-PSMA treatment. ctDNA was detected in 39 (84.8%); higher ctDNA was correlated with shorter PFS. Genomic structural rearrangements in the AR gene (hazard ratio [HR] 9.74, 95% confidence interval [CI] 2.4-39.5; p = 0.001) and alterations in the PI3K signalling pathway (HR 3.58, 95% CI 1.41-9.08; p = 0.007) were independently associated with poor 177Lu-PSMA prognosis on multivariable Cox regression. Prospective evaluation of these associations in biomarker-driven trials is warranted. Patient summary: We examined cell-free DNA in blood samples from patients with advanced metastatic prostate cancer who started treatment with lutetium-177-PSMA, a new radioligand therapy. We found that patients with genetic alterations in the androgen receptor gene or PI3K pathway genes did not experience a lasting benefit from lutetium-177-PSMA.

A systematic review and meta-analysis on the radiation dose of computed tomography in hybrid nuclear medicine imaging.

BACKGROUND: While diagnostic reference levels (DRLs) are well-established for the radiopharmaceutical part, published DRLs for the CT component of positron emission tomography/computed tomography (PET/CT) and single photon emission computed tomography/computed tomography (SPECT/CT) are limited. This systematic review and meta-analysis provides an overview of the different objectives of CT in hybrid imaging and summarizes reported CT dose values for the most common PET/CT and SPECT/CT examinations. Also, an overview of already proposed national DRLs is given. METHODS: A systematic literature search was performed to identify original articles reporting CT dose index volume (CTDIvol), dose-length product (DLP) and/or national DRLs for the most frequently performed PET/CT and/or SPECT/CT examinations. Data were grouped according to the clinical objective: diagnostic (D-CT), anatomical localisation (AL-CT) or attenuation correction (AC-CT) CT. Random-effects meta-analyses were conducted. RESULTS: Twenty-seven articles were identified of which twelve reported national DRLs. For brain and tumour PET/CT imaging, CTDIvol and DLP values were higher for a D-CT (brain: 26.7 mGy, 483 mGy cm; tumour: 8.8 mGy, 697 mGy cm) than for an AC/AL-CT (brain: 11.3 mGy, 216 mGy cm; tumour: 4.3 mGy, 419 mGy cm). Similar conclusions were found for bone and parathyroid SPECT/CT studies: D-CT (bone: 6.5 mGy, 339 mGy cm; parathyroid: 15.1 mGy, 347 mGy cm) results in higher doses than AL-CT (bone: 3.8 mGy, 156 mGy cm; parathyroid: 4.9 mGy, 166 mGy cm). For cardiac (AC-CT), mIBG/octreotide, thyroid and post-thyroid ablation (AC/AL-CT) SPECT/CT pooled mean CTDIvol (DLP) values were 1.8 mGy (33 mGy cm), 4.6 mGy (208 mGy cm), 3.1 mGy (105 mGy cm) and 4.6 mGy (145 mGy cm), respectively. For all examinations, high variability in nuclear medicine practice was observed. CONCLUSION: The large variation in CT dose values and national DRLs highlights the need for optimisation in hybrid imaging and justifies the clinical implementation for nuclear medicine specific DRLs.

PSMA expression on neovasculature of solid tumors.

The use of prostate specific membrane antigen (PSMA) binding agents, labelled with diagnostic and therapeutic radio-isotopes is opening the potential for a new era of personalized management of prostate carcinoma. A wide variety of immunohistochemistry studies have shown PSMA also to be upregulated on the endothelial cells of the neovasculature of a wide variety of other solid tumors where it may facilitate endothelial cell sprouting and invasion through its regulation of lytic proteases that have the ability to cleave the extracellular matrix. Similar to the introduction of PSMA-targeting theranostics in prostate carcinoma, overexpression of PSMA on newly formed tumor vessels may serve as a target for imaging and subsequent treatment of cancer through the use of agents that are capable of blocking PSMA in its function or through PSMA-mediated delivery of chemotherapeutics or radiation agents. In this review, the available data on PSMA expression on tumor neovasculature in human solid tumors assessed by using immunohistochemistry are discussed.

Quantification of 18F-fluorodeoxyglucose uptake to detect residual nodal disease in locally advanced head and neck squamous cell carcinoma after chemoradiotherapy: results from the ECLYPS study.

BACKGROUND: The Hopkins criteria were introduced for nodal response evaluation after therapy in head and neck cancer, but its superiority over quantification is not yet confirmed. METHODS: SUVbody weight thresholds and lesion-to-background ratios were explored in a prospective multicenter study of standardized FDG-PET/CT 12 weeks after CRT in newly diagnosed locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients (ECLYPS). Reference standard was histology, negative FDG-PET/CT at 12 months after treatment or ≥ 2 years of negative follow-up. Area under the receiver operator characteristics curves (AUROC) were estimated and obtained thresholds were validated in an independent cohort of HNSCC patients (n = 127). RESULTS: In ECLYPS, 124 patients were available for quantification. With a median follow-up of 20.4 months, 23 (18.5%) nodal neck recurrences were observed. A SUV70 threshold of 2.2 (AUROC = 0.89; sensitivity = 79.7%; specificity = 80.8%) was identified as optimal metric to identify nodal recurrence within 1 year after therapy. For lesion-to-background ratios, an SUV50/SUVliver threshold of 0.96 (AUROC = 0.89; sensitivity = 79.7%; specificity = 82.8%) had the best performance. Compared with Hopkins criteria (AUROC = 0.81), SUV70 and SUV50/SUVliver provided a borderline significant (p = 0.040 and p = 0.094, respectively) improvement. Validation of thresholds yielded similar AUROC values (SUV70 = 0.93, SUV50/SUVliver = 0.95), and were comparable to the Hopkins score (AUROC = 0.91; not statistically significant). CONCLUSION: FDG quantification detects nodal relapse in LAHNSCC patients. When using EARL standardized PET acquisitions and reconstruction, absolute SUV metrics (SUV70 threshold 2.2) prove robust, yet ratios (SUV50/SUVliver, threshold 0.96) may be more useful in routine clinical care. In this setting, the diagnostic value of quantification is comparable to the Hopkins criteria. TRIAL REGISTRATION: US National Library for Medicine, NCT01179360. Registered 11 August 2010, https://clinicaltrials.gov/ct2/show/NCT01179360.

PSMA-Targeting Positron Emission Agents for Imaging Solid Tumors Other Than Non-Prostate Carcinoma: A Systematic Review.

Despite its name, prostate-specific membrane antigen (PSMA) has been shown using immunohistochemistry (IHC) to also be over-expressed in the tumor neovasculature of a wide variety of solid tumors other than prostate carcinoma. Accordingly, positron-emitting radiolabeled small molecules targeting PSMA, initially developed for positron emission tomography in prostate carcinomas, are currently being explored for their staging and restaging potential as an alternative imaging modality in other solid tumor types where 18-F-fluorodeoxyglucose (FDG)-PET imaging has low diagnostic accuracy. In this paper, the currently available literature in this field is reviewed. Preliminary, mainly retrospective studies are encouraging, with evidence of improved diagnostic sensitivity and specificity in clear cell renal carcinoma, glioma, and hepatocellular carcinoma, leading to a change in patient management in several patients. However, the results published thus far warrant confirmation by larger prospective studies additionally assessing the longitudinal impact on patient outcomes.

Impact of PET reconstruction protocols on quantification of lesions that fulfil the PERCIST lesion inclusion criteria.

BACKGROUND: The aim of this study was to compare liver and oncologic lesion standardized uptake values (SUV) obtained through two different reconstruction protocols, GE's newest clinical lesion detection protocol (Q.Clear) and the EANM Research Ltd (EARL) harmonization protocol, and to assess the clinical relevance of potential differences and possible implications for daily clinical practice using the PERCIST lesional inclusion criteria. NEMA phantom recovery coefficients (RC) and SUV normalized for lean body mass (LBM), referred to as SUV normalized for LBM (SUL), of liver and lesion volumes of interest were compared between the two reconstruction protocols. Head-to-toe PET/CT examinations and raw data from 64 patients were retrospectively retrieved. PET image reconstruction was carried out twice: once optimized for quantification, complying with EARL accreditation requirements, and once optimized for lesion detection, according to GE's Q.Clear reconstruction settings. RESULTS: The two reconstruction protocols showed different NEMA phantom RC values for different sphere sizes. Q.Clear values were always highest and exceeded the EARL accreditation maximum for smaller spheres. Comparison of liver SULmean showed a statistically significant but clinically irrelevant difference between both protocols. Comparison of lesion SULpeak and SULmax showed a statistically significant, and clinically relevant, difference of 1.64 and 4.57, respectively. CONCLUSIONS: For treatment response assessment using PERCIST criteria, the harmonization reconstruction protocol should be used as the lesion detection reconstruction protocol using resolution recovery systematically overestimates true SUL values.

Patient-specific lean body mass can be estimated from limited-coverage computed tomography images.

OBJECTIVE: In PET/CT, quantitative evaluation of tumour metabolic activity is possible through standardized uptake values, usually normalized for body weight (BW) or lean body mass (LBM). Patient-specific LBM can be estimated from whole-body (WB) CT images. As most clinical indications only warrant PET/CT examinations covering head to midthigh, the aim of this study was to develop a simple and reliable method to estimate LBM from limited-coverage (LC) CT images and test its validity. PATIENTS AND METHODS: Head-to-toe PET/CT examinations were retrospectively retrieved and semiautomatically segmented into tissue types based on thresholding of CT Hounsfield units. LC was obtained by omitting image slices. Image segmentation was validated on the WB CT examinations by comparing CT-estimated BW with actual BW, and LBM estimated from LC images were compared with LBM estimated from WB images. A direct method and an indirect method were developed and validated on an independent data set. RESULTS: Comparing LBM estimated from LC examinations with estimates from WB examinations (LBMWB) showed a significant but limited bias of 1.2 kg (direct method) and nonsignificant bias of 0.05 kg (indirect method). CONCLUSION: This study demonstrates that LBM can be estimated from LC CT images with no significant difference from LBMWB.

Evaluation of CT-based SUV normalization.

The purpose of this study was to determine patients' lean body mass (LBM) and lean tissue (LT) mass using a computed tomography (CT)-based method, and to compare standardized uptake value (SUV) normalized by these parameters to conventionally normalized SUVs. Head-to-toe positron emission tomography (PET)/CT examinations were retrospectively retrieved and semi-automatically segmented into tissue types based on thresholding of CT Hounsfield units (HU). The following HU ranges were used for determination of CT-estimated LBM and LT (LBMCT and LTCT): -180 to -7 for adipose tissue (AT), -6 to 142 for LT, and 143 to 3010 for bone tissue (BT). Formula-estimated LBMs were calculated using formulas of James (1976 Research on Obesity: a Report of the DHSS/MRC Group (London: HMSO)) and Janmahasatian et al (2005 Clin. Pharmacokinet. 44 1051-65), and body surface area (BSA) was calculated using the DuBois formula (Dubois and Dubois 1989 Nutrition 5 303-11). The CT segmentation method was validated by comparing total patient body weight (BW) to CT-estimated BW (BWCT). LBMCT was compared to formula-based estimates (LBMJames and LBMJanma). SUVs in two healthy reference tissues, liver and mediastinum, were normalized for the aforementioned parameters and compared to each other in terms of variability and dependence on normalization factors and BW. Comparison of actual BW to BWCT shows a non-significant difference of 0.8 kg. LBMJames estimates are significantly higher than LBMJanma with differences of 4.7 kg for female and 1.0 kg for male patients. Formula-based LBM estimates do not significantly differ from LBMCT, neither for men nor for women. The coefficient of variation (CV) of SUV normalized for LBMJames (SUVLBM-James) (12.3%) was significantly reduced in liver compared to SUVBW (15.4%). All SUV variances in mediastinum were significantly reduced (CVs were 11.1-12.2%) compared to SUVBW (15.5%), except SUVBSA (15.2%). Only SUVBW and SUVLBM-James show independence from normalization factors. LBMJames seems to be the only advantageous SUV normalization. No advantage of other SUV normalizations over BW could be demonstrated.

False-Positive Axillary Lymph Nodes Due to Silicone Adenitis on (18)F-FDG PET/CT in an Oncological Setting.

The case of a 49-year-old transgender individual with a history of bilateral silicone breast implants and a right lung mass proven by biopsy to be a non-small cell lung cancer is presented. In addition to the primary malignancy, a positron emission tomography/computed tomography scan showed contralateral hypermetabolic adenopathy in the left axilla that was suggestive of nodal metastatic disease. Additional imaging and histological examination of the lymph nodes indicated silicone breast implant leakage and silicone adenitis as the underlying cause of the hypermetabolic axillary lymph node.

Review of clinically accessible methods to determine lean body mass for normalization of standardized uptake values.

With the routine use of 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scans, metabolic activity of tumors can be quantitatively assessed through calculation of SUVs. One possible normalization parameter for the standardized uptake value (SUV) is lean body mass (LBM), which is generally calculated through predictive equations based on height and body weight. (Semi-)direct measurements of LBM could provide more accurate results in cancer populations than predictive equations based on healthy populations. In this context, four methods to determine LBM are reviewed: bioelectrical impedance analysis, dual-energy X-ray absorptiometry. CT, and magnetic resonance imaging. These methods were selected based on clinical accessibility and are compared in terms of methodology, precision and accuracy. By assessing each method's specific advantages and limitations, a well-considered choice of method can hopefully lead to more accurate SUVLBM values, hence more accurate quantitative assessment of 18F-FDG PET images.

Preclinical validation of automated dual-energy X-ray absorptiometry and computed tomography-based body composition measurements.

BACKGROUND: The aim of this study was to determine and validate a set of Hounsfield unit (HU) ranges to segment computed tomography (CT) images into tissue types and to test the validity of dual-energy X-ray absorptiometry (DXA) tissue segmentation on pure, unmixed porcine tissues. METHODS: This preclinical prospective study was approved by the local ethical committee. Different quantities of porcine bone tissue (BT), lean tissue (LT) and adipose tissue (AT) were scanned using DXA and CT. Tissue type segmentation in DXA was performed via the standard clinical protocol and in CT through different sets of HU ranges. Percent coefficients of variation (%CV) were used to assess precision while % differences of observed masses were tested against zero using the Wilcoxon signed-rank Test. RESULTS: Total mass DXA measurements differ little but significantly (P=0.016) from true mass, while total mass CT measurements based on literature values show non-significant (P=0.69) differences of 1.7% and 2.0%. BT mass estimates with DXA differed more from true mass (median -78.2 to -75.8%) than other tissue types (median -11.3 to -8.1%). Tissue mass estimates with CT and literature HU ranges showed small differences from true mass for every tissue type (median -10.4 to 8.8%). CONCLUSION: The most suited method for automated tissue segmentation is CT and can become a valuable tool in quantitative nuclear medicine.

Early biomarkers related to secondary primary cancer risk in radiotherapy treated prostate cancer patients: IMRT versus IMAT.

PURPOSE: To investigate whether rotational techniques (Volumetric Modulated Arc Therapy - VMAT) are associated with a higher risk for secondary primary malignancies compared to step-and-shoot Intensity Modulated Radiation Therapy (ss-IMRT). To this end, radiation therapy (RT) induced DNA double-strand-breaks and the resulting chromosomal damage were assessed in peripheral blood T-lymphocytes of prostate cancer (PCa) patients applying γH2AX foci and G0 micronucleus (MN) assays. METHODS AND MATERIALS: The study comprised 33PCa patients. A blood sample was taken before start of therapy and after the 1st and 3rd RT fraction to determine respectively the RT-induced γH2AX foci and MN. The equivalent total body dose (D(ETB)) was calculated based on treatment planning data. RESULTS: A linear dose response was obtained for γH2AX foci yields versus D(ETB) while MN showed a linear-quadratic dose response. Patients treated with large volume (LV) VMAT show a significantly higher level of induced γH2AX foci and MN compared to IMRT and small volume (SV) VMAT (p<0.01). Assuming a linear-quadratic relationship, a satisfactory correlation was found between both endpoints (R(2) 0.86). CONCLUSIONS: Biomarker responses were governed by dose and irradiated volume of normal tissues. No significant differences between IMRT and rotational therapy inherent to the technique itself were observed.

Dose-length product of scanners correlates with DNA damage in patients undergoing contrast CT.

OBJECTIVES: Computed tomography (CT) exams contribute for a large part to the population's radiation burden. This study addresses the question if dose settings of scanners expressed by dose-length product (DLP) are correlated with directly measurable biological effects in patients. METHODS: DLP, blood dose, effective dose and DNA damage were analyzed for patients undergoing a thoracic or abdominal contrast CT scan on two CT scanners with different dose settings. The DNA damage was assessed by scoring γ-H2AX foci representing DNA double-strand breaks (DSBs) in patient's lymphocytes. Blood dose was calculated using the ImPACT software. RESULTS: The CT system operating at higher dose settings represented by higher DLP values, resulted in a significantly higher number of radiation-induced γ-H2AX foci in patient's lymphocytes (DLP: 2.1 times higher; γ-H2AX foci: 2.3 times higher; p<0.05). Plotting γ-H2AX foci versus blood dose showed a systematic increase of DNA damage with dose. In vitro experiments ruled out a possible X-ray enhancement of DNA damage effect by contrast agent. CONCLUSIONS: Present study demonstrates that optimization of DLP setting of scanners results in a reduction of X-ray effects in patients.

Genetic variation in three candidate genes and nicotine dependence, withdrawal and smoking cessation in hospitalized patients.

AIMS: This study evaluates the relationship of six polymorphisms found in the CHRNA3, DRD2 and COMT genes with nicotine dependence, the ability to quit smoking and the occurrence of withdrawal symptoms after short-term use of nicotine patch in hospitalized patients. MATERIALS & METHODS: The study included 233 participants from a double-blind, placebo-controlled trial of nicotine patch substitution with a 6-month follow-up period. Nicotine dependence was assessed by the Fagerström Test for Nicotine Dependence (FTND) questionnaire, withdrawal symptoms by the Minnesota Nicotine Withdrawal Scale questionnaire and smoking cessation by self-reported abstinence at 1 week, 1 month and 6 months after treatment. RESULTS: After correcting for multiple testing, three polymorphisms in the DRD2 gene (Taq1A, Taq1B and Pro319Pro) were significantly associated with nicotine dependence (p = 0.018, p = 0.048 and p = 0.006, respectively). Using a cutoff point for the FTND score, the CHRNA3 Tyr215Tyr (rs1051730) polymorphism was also associated with nicotine dependence (p = 0.037 and p = 0.074 after correction for multiple testing). No association of any of the studied polymorphisms was observed with either smoking cessation or the occurrence of withdrawal symptoms. CONCLUSION: This study confirms the reported association of the CHRNA3 locus with nicotine dependence and shows the involvement of two independent DRD2 polymorphisms in nicotine dependence.

Dose response and repair kinetics of gamma-H2AX foci induced by in vitro irradiation of whole blood and T-lymphocytes with X- and gamma-radiation.

PURPOSE: Dose response and repair kinetics of phosphorylated histone H2A isoform X (gamma-H2AX) foci in T-lymphocytes were investigated in the low-dose range after in vitro irradiation of whole blood and T-lymphocytes with 100 kVp X-rays and (60)Co gamma-rays. MATERIALS AND METHODS: Whole blood or isolated T-lymphocytes were irradiated in vitro and gamma-H2AX foci were scored. Dose response was determined in the 0-500 mGy dose range. Foci kinetics were studied at doses of 5 and 200 mGy up to 24 h post-irradiation. RESULTS: After X-irradiation, the dose response for whole blood shows a biphasic behaviour with a low-dose hypersensitivity, which is less pronounced for isolated T-lymphocytes. In contrast, gamma-radiation shows a linear dose response for both irradiation conditions. Concerning repair kinetics, delayed repair was found after X-ray whole blood irradiation (5 and 200 mGy) with 40% of the foci persisting 24 h post-irradiation. This number of foci is reduced to 10% after irradiation of isolated T-lymphocytes with 200 mGy X-rays. On the contrary, gamma-H2AX foci are reduced to background levels 24 h post-irradiation with 200 mGy (60)Co gamma-rays. CONCLUSION: gamma-H2AX foci response and repair kinetics depend on irradiation conditions and radiation quality, possibly linked to Bystander response.

Prediction of late normal tissue complications in RT treated gynaecological cancer patients: potential of the gamma-H2AX foci assay and association with chromosomal radiosensitivity.

In the present study, the gamma-H2AX assay was investigated as a predictive test for the development of late normal tissue complications. Therefore, phosphorylated histone H2AX (gamma-H2AX) foci were scored in peripheral blood T-lymphocytes of gynaecological radiotherapy patients, irradiated in vitro with a high dose rate (HDR) and a low dose rate (LDR) protocol. The G2 chromatid break assay was used to compare chromosomal radiation sensitivity with DNA double-strand-break (DSB) repair capacity. Late normal tissue reactions were scored according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 scale. In our analyses, no differences in foci kinetics were found between the non to mild and moderate to severe patient groups after HDR irradiation. Furthermore, no relation was observed between the level of residual gamma-H2AX foci and CTC score after LDR irradiation. On the contrary, the number of chromatid breaks was associated with late clinical radiation sensitivity. Comparison of G2 chromatid break assay data with the residual number of radiation-induced foci after LDR irradiation and repair times after HDR irradiation showed no relationship between the assays. From this study we can conclude that scoring of gamma-H2AX foci after in vitro irradiation of isolated T-lymphocytes of patients is not predictive for late radiotoxicity. This applies as well to the assessment of the repair kinetics after an HDR dose as to the determination of the number of residual foci after a LDR dose.

gamma-H2AX foci as a biomarker for patient X-ray exposure in pediatric cardiac catheterization: are we underestimating radiation risks?

BACKGROUND: A better knowledge of patient x-ray dose and the associated radiation risk in pediatric interventional cardiology is warranted in view of the extensive use of x-rays and the higher radiosensitivity of children. In the present study, gamma-H2AX foci were used as a biomarker for radiation-induced effects. Patient-specific dose was assessed and radiation risks were estimated according to the linear-no-threshold model, commonly used in radiation protection, and the gamma-H2AX foci data. METHODS AND RESULTS: In 49 pediatric patients (median age, 0.75 years) with congenital heart disease who underwent cardiac catheterization procedures, blood samples were taken before and shortly after the procedure. gamma-H2AX foci were determined in peripheral blood T lymphocytes. In each patient, a net increase in gamma-H2AX foci, representing DNA double-strand breaks induced by interventional x-rays, was observed. In addition, a patient-specific Monte Carlo simulation of the procedure was performed, resulting in individual blood, organ, and tissue doses. Plotting of gamma-H2AX foci versus blood dose indicated a low-dose hypersensitivity. Median effective doses calculated according to the International Commission on Radiological Protection 60 and 103 publications are 5.6 and 6.4 mSv, respectively. The lifetime-attributable risk of cancer mortality was calculated from the linear-no-threshold model and the gamma-H2AX foci data. This resulted in lifetime-attributable risk values of 1% and 4%, respectively, for the patient population under study. CONCLUSIONS: gamma-H2AX foci as a biomarker for DNA damage indicate that radiation risk estimates according to the linear-no-threshold hypothesis are possibly underestimates. Great care should be taken to minimize and optimize patient radiation exposure.