(Cell Press) In a study appearing April 30 in the journal Current Biology, scientists tell the story of three 16th century African slaves identified from a mass burial site in Mexico City. Using a combination of genetic, osteological, and isotope analyses, the scientists determined from where in Africa they were likely captured, the physical hardships they experienced as slaves, and what novel pathogens they may have carried with them across the Atlantic.

(Max Planck Institute for the Science of Human History) Three 16th-century skeletons from a mass burial in Mexico City highlight the role of the transatlantic slave trade in introducing and disseminating new pathogens to the Americas. Researchers from the Max Planck Institute for the Science of Human History and Escuela Nacional de Antropología e Historia in Mexico analyzed skeletal features, genetic data and isotopes to explore the life history of three enslaved Africans and explore the wide-ranging impacts of massive forced migration.

(University of Southern Denmark) Investing in the future: Researchers show how cannibalism among the invasive comb jelly enables adults to survive severe conditions at the edge of their ecological range with implications for the use and evolutionary origins of cannibalism.

Disposable masks can be used more than once, but it's important to make sure the mask isn't carrying coronavirus.

(Damon Runyon Cancer Research Foundation) The first class of Damon Runyon Quantitative Biology Fellowship Awardees launched their research in novel directions that may lead to the next breakthroughs in cancer research. Nine brilliant young scientists will apply their quantitative skills to design innovative experiments and interpret massive data sets that may help solve important biological and clinical problems.

A new study led by The Royal Marsden involving Imperial will use artificial intelligence (AI) to help cancer patients during the COVID-19 pandemic.

(Crime and Justice Research Alliance) A new study evaluated the effects of legalizing cannabis on police officers' law enforcement efforts in Washington. The study found that officers in that state, although not supportive of recriminalization, had a variety of concerns, from worries about the effect on youth to increases in impaired driving. The study can inform other states' efforts to address legalization.

(University of Huddersfield) A team of researchers received funding of almost £130,000 to work with a group of women in Zambia and create songs that warn against the dangers of the coronavirus -- and now New York wants to hear them.

Up-and-coming recording artiste Kaay Jones says she did not know she was becoming part of a transformational music project that would connect her to a wide cross section of talent in the Caribbean. Jones carries Jamaica's flag in a unified...

Antoniette Bryden has fond memories of her mother, Arlene Reid, 51, a healthcare worker originally from Yallahs, St Thomas, who died of COVID-19 in Brampton, Ontario, Canada, on April 27. Reid, a personal support worker (PSW) who worked part-time...

Tatjana Goebel
Apr 16, 2020; 0:RA120.001983v1-mcp.RA120.001983
Research

Webinar Research Event

Event participants

Mohammed Masbah, Director, Moroccan Institute for Policy Analysis; Associate Fellow, MENA Programme, Chatham House
Moderator: Lina Khatib, Director, MENA Programme, Chatham House

6 April 2020

29 April 2020

Objective: To investigate the lesion detection rate of ¹⁸F-DCFPyL-PET/CT, a prostate-specific membrane antigen (PSMA) targeted PET agent, in biochemical relapse prostate cancer patients after primary local therapy. Methods: This is a prospective institutional review board-approved study of 90 patients with documented biochemical recurrence (median PSA 2.5 ng/mL, range 0.21-35.5 ng/mL) with negative conventional imaging after primary local therapies, including radical prostatectomy (n = 38), radiation (n = 27) or combination (n = 25). Patients on androgen deprivation therapy were excluded. Patients underwent whole-body ¹⁸F-DCFPyL-PET/CT (299.9±15.5 MBq) at 2 h p.i. PSMA-PET lesion detection rate was correlated with PSA, PSA kinetics and original primary tumor grade. Results: Seventy patients (77.8%) showed a positive PSMA-PET scan, identifying a total of 287 lesions: 37 prostate bed foci, 208 lymph nodes, and 42 bone/organ distant sites; 11 patients had a negative scan and 9 patients showed indeterminate lesions, which were considered negative in this study. The detection rates were 47.6% (n = 10/21), 50% (n = 5/10), 88.9% (n = 8/9), and 94% (n = 47/50) for PSA >0.2 to <0.5, 0.5 to <1.0, 1 to <2.0, and ≥2.0 ng/mL, respectively. In post-surgical patients, PSA, PSAdt and PSAvel correlated with PET results but the same was not true for post-radiation patients. These parameters also correlated with the extent of disease on PET (intrapelvic vs. extrapelvic). There was no significant difference between the rate of positive scans in patients with higher grade vs lower grade primary tumors (Gleason score ≥4+3 vs <3+4). Tumor recurrence was histology confirmed in 40% (28/70) of patients. On a per-patient basis, positive predictive value was 93.3% (95% CI, 77.6-99.2%) by histopathologic validation, and 96.2% (95% CI, 86.3-99.7%) by the combination of histology and imaging/clinical follow-up. Conclusion: ¹⁸F-DCFPyL-PET/CT imaging offers high detection rates in biochemically recurrent prostate cancer patients; and is positive in about 50% of patients with PSA <0.5 ng/mL, which could substantially impact clinical management. In post-surgical patients, ¹⁸F-DCFPyL-PET/CT correlates with PSA, PSAdt and PSAvel suggesting it may have prognostic value. ¹⁸F-DCFPyL-PET/CT is highly promising for localizing sites of recurrent prostate cancer.

Rationale: Lymphatic tracers can help visualize the lymphatic drainage patterns and sentinel nodes of individual prostate cancer patients. To determine the role of nuclear medicine, in particular the positional guidance of a SPECT/CT-based 3D imaging roadmap, in this process we studied to which extend fluorescence-guidance underestimated the number of target lesions. Methods: SPECT/CT imaging was performed after intraprostatic tracer administration of either ICG-^99mTc-nanocolloid (hybrid tracer group) or ^99mTc-nanocolloid to create a roadmap that depicted all sentinel nodes (SNs). Patients who received ^99mTc-nanocolloid were injected with "free" ICG immediately prior to surgery ("free" ICG group). Before unblinding, fluorescence-guidance was used for intraoperative SN identification. This was followed by extended pelvic lymph node dissection (ePLND). Following unblinding of the SPECT/CT images, the number of missed SN’s were recorded and their resection was pursued when the anatomy allowed. Results: Preoperative SPECT/CT revealed no differences in the SN identification rate between ICG-^99mTc-nanocolloid and ^99mTc-nanocolloid. However, fluorescence-guidance only allowed intraoperative removal of all SNs in 40% of patients in the hybrid tracer group and in 20% of patients in the "free" ICG group. Overall, 75.9% of the intraoperatively resected SNs in the hybrid tracer group and 51.8% of the SNs in the "free" ICG group were removed solely under fluorescence-guidance. During ePLND 22 additional SNs were resected (7 in the hybrid tracer group and 15 in the "free" ICG group). After unblinding 18 remaining SNs were identified (6 in the hybrid group and 12 in the "free" ICG group). In the "free" ICG group, ex vivo evaluation of the excised specimens revealed that 14 SNs removed under ePLND or after unblinding contained radioactivity but no fluorescence. Conclusion: The preoperative imaging roadmap provided by SPECT/CT enhanced the detection of prostate SNs in more ectopic locations in 17 of the 25 patients and the hybrid tracer ICG-^99mTc-nanocolloid was shown to outperform "free" ICG. Overall, fluorescence-guided pelvic nodal surgery underestimated the number of SNs in 60-80% of patients.

Introduction: Aromatase inhibitors are the mainstay of hormonal therapy in estrogen receptor positive, postmenopausal breast cancer, although response rate is just over 50%. The goal of the present study was to validate and optimize positron emission tomography (PET) with ¹¹C-vorozole for measuring aromatase expression in postmenopausal breast cancer. Methods: Ten newly diagnosed, postmenopausal women with biopsy confirmed breast cancer were administered ¹¹C-vorozole intravenously and PET emission data collected between 40 – 90 minutes post-injection. Tracer injection and scanning were repeated 2 hours after ingestion of 2.5mg letrozole p.o. Mean and maximal standard uptake values and ratios to non-tumor tissue (SUVs, SUVRs) were calculated for tumor and non-tumor regions at baseline and after letrozole. Biopsy specimens from the same tumors were stained for aromatase using immunohistochemistry and evaluated for stain intensity and the percentage of immune-positive cells. Results: Seven of the 10 women (70%) demonstrated increased focal uptake of tracer (SUVR>1.1) coinciding with the mammographic location of the lesion. The other 3 women (30%) did not show increased uptake in the tumor (SUVR <1.0). All of the cases with SUVR above 1.1 had SUVs above 2.4 and there was no overlap in SUV between the two groups, with mean SUV in tumors overexpressing aromatase (SUVR>1.1) ranging from 2.47 to 13.6, while tumors not overexpressing aromatase (SUVR<1) ranged from 0.8 to 1.8. Pretreatment with letrozole reduced tracer uptake in the majority of subjects; although the %blocking varied across and within tumors. Tumors with high SUV in vivo also showed high staining intensity on IHC. Conclusion: PET with ¹¹C-vorozole is a useful technique for measuring aromatase expression in individual breast lesions, enabling a non-invasive quantitative measurement of baseline and post-treatment aromatase availability in primary tumors and metastatic lesions.

Numerous recent works highlight the limited utility of established tumor cell lines in recapitulating the heterogeneity of tumors in patients. More realistic preclinical cancer models are thought to be provided by transplantable, patient-derived tumor xenografts (PDX). Inter- and intra-tumor heterogeneity of PDX, however, present several challenges in developing optimal quantitative pipelines to assess response to therapy. The objective of this work was to develop and optimize image metrics of FDG-PET to assess response to combination docetaxel/carboplatin therapy in a co-clinical trial involving triple negative breast cancer (TNBC) PDX. We characterize the reproducibility of SUV metrics to assess response to therapy and optimize a preclinical PERCIST (µPERCIST) paradigm to complement clinical standards. Considerations in this effort included variability in tumor growth rate and tumor size; solid tumor vs. tumor heterogeneity and necrotic phenotype; and optimal selection of tumor slice versus whole tumor. A test-retest protocol was implemented to optimize the reproducibility of FDG-PET SUV thresholds, SUVpeak metrics, and µPERCIST parameters. In assessing response to therapy, FDG-PET imaging was performed at baseline and +4 days following therapy. The reproducibility, accuracy, variability, and performance of imaging metrics to assess response to therapy were determined. We defined an index—"Quantitative Response Assessment Score (QRAS)"—to integrate parameters of prediction and precision, and thus aid in selecting optimal image metrics of response to therapy. Our data suggests that a threshold value of 25% (SUV25) of SUVmax was highly reproducible (<9% variability). Concordance and reproducibility of µPERCIST were maximized at α=0.7 and β=2.8 and exhibited high correlation to SUV25 measures of tumor uptake. QRAS scores favor SUV25 followed by SUVP14 as optimal metrics of response to therapy. Additional studies are warranted to fully characterize the utility of SUV25 and µPERCIST SUVP14 as image metrics of response to therapy across a wide range of therapeutic regiments and PDX models.

Objectives: Lutetium-177 (¹⁷⁷Lu)-PSMA-617 (LuPSMA) is a radioligand with high affinity for prostate specific membrane antigen (PSMA) enabling targeted beta-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castrate-resistant prostate cancer (mCRPC). We now report their longer-term outcomes including a 20 patient extension cohort and outcomes of subsequent systemic treatments following completion of trial therapy. Methods: 50 patients with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. Endpoints included PSA response (PCWG2), toxicity (CTCAE v4.03), imaging response, patient-reported health-related quality of life (QoL), progression-free and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including LuPSMA. Results: 75 men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 months) and extensive prior treatment including prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline ≥ 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with ≥ 80% decrease. Of 27 patients with measurable soft tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to LuPSMA were self-limiting G1-2 dry mouth (66%), transient G1-2 nausea (48%), G3-4 thrombocytopenia (10%) and G3 anemia (10%). Brief pain inventory severity and interference scores decreased at all time points including at the 3 month follow-up with a decrease of -1.2 (95% CI -0.5 to -1.9, P = 0.001) and 1.0 (95% CI -0.2 to -0.18, P = 0.013), respectively. At a median follow-up of 31.4 months, median OS was 13.3 months (95% CI 10.5-18.7) with a significantly longer survival of 18.4 months (95% CI 13.8-23.8) in patients achieving a PSA decline ≥ 50%. At progression following prior response, further LuPSMA was administered to 15 (30%) patients (median 2 cycles commencing 359 days from enrolment) with PSA decline ≥ 50% in 11 patients (73%). 4 of 21 patients (19%) receiving other systemic therapies upon progression experienced PSA decline ≥ 50%. There were no unexpected adverse events with LuPSMA re-treatment. Conclusion: This expanded 50 patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity and improved QoL with LuPSMA radioligand therapy. Upon progression, re-challenge LuPSMA demonstrated higher response rates than other systemic therapies.

Purpose: To explore the value of ⁶⁸Ga-PSMA-PET/CT for detection of phosphatase and tensin homolog (PTEN) - loss prostate cancer (PCa). Methods: We retrospectively enrolled 75 patients who underwent multiparametric MRI (mpMRI) and ⁶⁸Ga-PSMA PET/CT before radical prostatectomy. Lesions were outlined on pathological images and regions of interest were drawn on matched mpMRI and PET/CT images. Imaging parameters including average apparent diffusion coefficient (ADCmean) and maximum standardized uptake value (SUV_max) were derived. Immunohistochemical staining was carried out to evaluate the PTEN status. The diagnostic performance of imaging parameters was analyzed by receiver operating characteristics (ROC) analysis. A univariate logistic regression analyses were used to evaluate the association between clinical and imaging variables and PTEN status. Results: Totally, 103 lesions from 54 patients were analyzed. Of these lesions, 34 of 103 (33.0%) showed PTEN-loss status. Our study showed a strong association between SUV_max and PTEN-loss tumors both in the per-patient analysis (P < 0.01) and per-lesion analysis (P < 0.01), yielding the sensitivity and specificity of 0.80 and 0.77 in the per-patient analysis and 0.83 and 0.74 in the per-lesion analysis. Meanwhile, higher pathological PSMA expression was found in the PTEN-deficiency tumors. However, there was no significant difference between PTEN-loss tumors and PTEN-intact tumors using parameters including ADCmean (P > 0.05) and PI-RADS score (P > 0.05). Surprisingly, SUV_max was a significant predictor for detection of PTEN-loss tumors (odds ratio: 7.56, 95% confidence interval: 2.18-26.24, per-patient analysis; odds ratio: 13.66, 95% confidence interval: 4.32-43.24, per-lesion analysis). Conclusion: ⁶⁸Ga-PSMA-PET/CT could effectively detect aggressive PTEN-loss tumors.

Purpose: The aim of this retrospective multicentric study was to develop and evaluate a prognostic FDG PET/CT radiomics signature in early-stage non-small cell lung cancer (NSCLC) patients treated with stereotactic radiotherapy (SBRT). Material and Methods: Patients from 3 different centers (n = 27, 29 and 8) were pooled to constitute the training set, whereas the patients from a fourth center (n = 23) were used as the testing set. The primary endpoint was local control (LC). The primary tumour was semi-automatically delineated in the PET images using the Fuzzy locally adaptive Bayesian algorithm, and manually in the low-dose CT images. A total of 184 IBSI-compliant radiomic features were extracted. Seven clinical and treatment parameters were included. We used ComBat to harmonize radiomic features extracted from the four institutions relying on different PET/CT scanners. In the training set, variables found significant in the univariate analysis were fed into a multivariate regression model and models were built by combining independent prognostic factors. Results: Median follow-up was 21.1 (1.7 – 63.4) and 25.5 (7.7 – 57.8) months in training and testing sets respectively. In univariate analysis, none of the clinical variables, 2 PET and 2 CT features were significantly predictive of LC. The best predictive models in the training set were obtained by combining one feature from PET, namely information correlation 2 (IC2) and one from CT (Flatness), reaching a sensitivity of 100% and a specificity of 96%. Another model combining 2 PET features (IC2 and Strength), reached sensitivity of 100% and specificity of 88%, both with an undefined hazard ratio (HR) (p<0.001). The latter model obtained an accuracy of 0.91 (sensitivity 100%, specificity 81%), with a HR undefined (P = 0.023) in the testing set, however other models relying on CT radiomics features only or the combination of PET and CT features failed to validate in the testing set. Conclusion: We showed that two radiomic features derived from FDG PET were independently associated with LC in patients with NSCLC undergoing SBRT and could be combined in an accurate predictive model. This model could provide local relapse-related information and could be helpful in clinical decision-making.

Purpose: Although the incidence of de novo neuroendocrine prostate cancer (NEPC) is rare, recent data suggests that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine (NE) hallmarks and androgen receptor (AR)-suppression in prostate cancer (PC). Previous clinical reports indicate that PCs with a phenotype similar to NE tumors can be more amenable to imaging by ¹⁸F-Fluorodeoxyglucose (FDG) rather than PSMA-targeting radioligands. In this study, we evaluated the association between NE gene signature and FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported FDG-avidity of PSMA-suppressed tumors. Methods: Data mining approaches, cell lines and patient-derived xenograft (PDX) models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes: HK1 to 3 and GCK) and PSMA (FOLH1 gene) following AR-inhibition and in correlation with NE hallmarks. Also, we characterize a NE-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no NE histopathology. We measured glucose uptake in a NE-induced in vitro model and a zebrafish model by non-radioactive imaging of glucose uptake using fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrates that a NE gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR-inhibitors, high expression of GCK and low expression of SLC2A12 correlated with NE histopathology and PSMA gene suppression. GLUT12-suppression and amplification of glucokinase was observed in NE-induced PC cell lines and PDX models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: NE gene signature in NEPC and NELPC associates with a distinct transcriptional profile of GLUTs and HKs. PSMA-suppression correlates with GLUT12-suppression and glucokinase-amplification. Alteration of FDG uptake-associated genes correlated positively with higher glucose uptake in AR and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient pre-clinical method for monitoring non-radioactive glucose uptake.

Due to their peculiar mechanism of action, the evaluation of radiological response to immune checkpoint inhibitors (ICI) presents many challenges in solid tumors. We aimed to compare the evaluation of first response to Nivolumab by means of CT-based criteria with respect to fluorodeoxyglucose positron emission tomography (FDG-PET) response criteria in non-small-cell lung cancer (NSCLC) patients. Methods: 72 patients with advanced NSCLC were recruited in a mono-institutional ancillary trial within the expanded access program (EAP; NCT02475382) for Nivolumab. Patients underwent CT scan and FDG-PET at baseline and after 4 cycles (first evaluation). In case of progressive disease (PD), an additional evaluation was performed after two further cycles in order to confirm progression. We evaluated the response to treatment with CT scan by means of response evaluation criteria in solid tumors (RECIST) 1.1 and Immuno-related Response Criteria (IrRC) and with FDG-PET by means of PERCIST and immunotherapy-modified-PERCIST (imPERCIST) criteria. The concordance between CT- and PET-based criteria and the capability of each method to predict overall survival (OS) were evaluated. Results: 48/72 patients were evaluable for first response assessment with both PET- and CT-based criteria. We observed low concordance between CT- and PET-based criteria (Kappa value of 0.346 and 0.355 and Kappa value of 0.128 and 0.198 between PERCIST and imPERCIST versus RECIST and irRC respectively). Looking at OS, IrRC were more reliable to distinguish responders from non-responders. However thanks to the prognostic value of partial metabolic response assessed by both PERCIST and Immuno-PERCIST, PET-based response maintained prognostic significant in patients classified as progressive disease on the basis of irRC. Conclusion: Even though the present study did not support the routine use of FDG-PET in the general population of NSCLC patients treated with ICI, it suggests the added prognostic value of the metabolic response assessment, potentially improving the therapeutic decision-making.

Objectives: The detection of cancer micrometastasis for early diagnosis and treatment poses a great challenge for conventional imaging techniques. The aim of study is to evaluate the performance of photoacoustic imaging (PAI) in detecting hepatic micrometastases from melanoma in a very early stage and perform tumor resection by intraoperative photoacoustic image-guidance. Methods: In vivo studies were performed by following protocols approved by the Ethical Committee for Animal Research at Xiamen University. First, a B16 melanoma hepatic metastasis mouse model (n = 10) was established to study the development of micrometastases in vivo. Next, the hepatic metastasis mice models were imaged by scalable PAI instrument, ultrasound, 9.4 T high-resolution magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT), and bioluminescence imaging. Photoacoustic images acquired with optical wavelengths spanning from 680 to 850 nm were spectrally unmixed by using a linear least-squares method to differentiate various components. Differences in the signal-to-background ratios among different modalities were determined with the two-tailed paired t test. The diagnosis results were assessed with histologic examinations. Excised liver samples from patients diagnosed with hepatic cancer were also examined to identify tumor boundary. In vivo metastatic melanoma removal in surgery was precisely guided by the portable PAI system. Results: PAI achieved as small as ~400 µm hepatic melanoma detection at a depth up to 7 mm in vivo, which could early detect small melanoma compared with ultrasound and MRI in mouse models. The signal ratio of tumor-to-liver acquired with PAI in micrometastases at 8 days (4.2 ± 0.2, n = 6) and 14 days (9.2 ± 0.4, n = 5) were significantly higher than those obtained with PET/CT (1.8 ± 0.1, n = 5 and 4.5 ± 0.2, n = 5, P <0.001 for both). Functional PAI provided dynamic oxygen saturation changes during tumor growth. The limit of detection was measured to be approximately 219 cells per microliter in vitro. We successfully performed intraoperative photoacoustic image-guided surgery in vivo using the rapid portable PAI system. Conclusion: Our findings offer a rapid and effective tool to noninvasively detect micrometastases and guide intraoperative resection as a complementary clinical imaging application.

Introduction: The aim of this study was to analyze patterns of persistent versus recurrent or new PET lesions in a selected patient cohort with PSA persistence following salvage lymph node dissection (SLND) and pre/post procedure prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET). Material and Methods: 16 patients were included in this multicenter study. Inclusion criteria were: a) PSMA-PET performed for biochemical recurrence before SLND (pre-SLND PET) and b) repeat PSMA-PET performed for persistently elevated PSA level (≥0.1 ng/mL) ≥6 weeks after SLND (post-SLND PET). Image analysis was performed by three independent nuclear medicine physicians applying the molecular imaging TNM system PROMISE. Lesions were confirmed by histopathology, presence on correlative CT/MRI/bone scan or PSA response after focal therapy. Results: post-SLND PET identified PCa-lesions in 88% (14/16) of patients with PSA persistence after SLND. Median PSA was 1.2 ng/mL (IQR, 0.6-2.8 ng/mL). Disease was confined to the pelvis in 56% of patients (9/16) and most of these men had common iliac (6/16, 38%) and internal iliac lymph node metastases (6/16, 38%). Extrapelvic disease was detected in 31% of patients (5/16). In pre- and post-SLND PET comparison, 10/16 had at least one lesion already detected at baseline (63% PET persistence); 4/16 had new lesions only (25% PET recurrence); 2 had no disease on post-SLND PET. All validated regions (11 regions in 9 patients) were true positive. 9/14 (64%) patients underwent repeat local therapies after SLND (7/14 radiotherapy, 2/14 surgery). Conclusion: SLND of pelvic nodal metastases was often not complete according to PSMA-PET. About two thirds of patients had PET positive nodal disease after SLND already seen on pre-SLND PSMA-PET. Notably, about one quarter of patients had new lesions, not detected by pre-surgical PSMA-PET.

Background: Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy as they can constitute as much as 90% of tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP-inhibitor PET tracer, ⁶⁸Ga-FAPI-04, has been previously shown to yield high tumor-to-background ratios (TBR) in patients with various cancers. Recent developments towards an improved compound for therapeutic application have identified FAPI-46 as a promising agent due to a longer tumor retention time in comparison with FAPI-04. Here we present a PET biodistribution and radiation dosimetry study of ⁶⁸Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial ⁶⁸Ga-FAPI-46 PET/CT scans at three time points following radiotracer injection: 10 minutes, 1 hour, and 3 hours. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and body remainder. OLINDA/EXM v.1.1 software was used to fit and integrate the kinetic organ activity data to yield total body and organ time-integrated activity coefficients/residence times and finally organ absorbed doses. Standardized uptake values (SUV) and TBR were generated from the contoured tumor and source organ volumes. Spherical volumes in muscle and blood pool were also obtained for TBR (Tumor SUV_max / Organ SUVmean). Results: At all timepoints, the highest organ SUV_max was observed in the liver. Tumor and organ mean SUVs decreased whereas TBRs in all organs but the uterus increased with time. The highest TBRs at 3 hours were observed with the bone marrow (31.1), muscle (22.8), heart (19.1), and spleen (19.0). Organs with the highest effective doses were the bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04mSv/MBq). The average effective total body dose was 7.80E-03 mSv/MBq. Thus for administration of 200 MBq ⁶⁸Ga-FAPI-46 the effective total body dose is 1.56 mSv ± 0.26 mSv, in addition to approximately 3.7 mSv from one low-dose CT scan done for attenuation correction. Conclusion: ⁶⁸Ga-FAPI-46 PET/CT has a favorable dosimetry profile with an estimated whole body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of ⁶⁸Ga-FAPI-46 (1.56± 0.26 mSv from the PET tracer and 3.7 mSv from one low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.

Purpose: To evaluate ¹¹C-choline PET/CT detection performance for biochemically recurrent prostate cancer (PCa) in a large non-European cohort in the context of emerging evidence for PSMA PET in this setting, and to map patterns of PCa recurrence. Methods: We retrospectively analyzed ¹¹C-choline PET/CT scans from 287 patients who were enrolled onto an imaging protocol based on rising prostate-specific antigen (PSA) levels (mean:3.43 ng/mL, median:0.94 ng/mL, range:0.15–89.91) and suspected recurrent PCa. A total of 187 patients had undergone primary radical prostatectomy (RP; 79/187 had secondary radiotherapy), 30 had undergone primary radiotherapy (RT), and 70 had persistent PSA elevation after receiving initial treatment (69 post-RP, 1 post-RT). The level of suspicion for recurrence on ¹¹C-choline PET/CT was scored (0:negative, 1:equivocal, 2:positive) by two readers. The correlation between ¹¹C-choline PET/CT positivity and initial treatment, Gleason score, NCCN stage, PSA level, PSA doubling time, PSA velocity, and time between initial treatment and PET imaging was evaluated. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were used to map ¹¹C-choline recurrence patterns. Results: Considering scores 1 and 2 as positives, consensus between the two readers deemed 66% of the ¹¹C-choline PET/CT scans as positive. When sorted by PSA level, 45% of patients with PSA<0.5 ng/mL, 56% of patients with PSA 0.5–0.99 ng/mL, 70% of patients with PSA 1.0–1.99 ng/mL, and 90% of patients with PSA ≥2.0 ng/mL scored either 1 or 2 on ¹¹C-choline PET/CT scans. When considering scores of 2 only, ¹¹C-choline PET/CT positivity was 54% (28%, 46%, 62%, and 81%, respectively, for patients with PSA <0.5 ng/mL, 0.5–0.99 ng/mL, 1.0–1.99 ng/mL, and ≥2.0 ng/mL). In multivariate analysis, only the PSA level was significantly associated with scan positivity. Pattern analysis showed that pelvic lymph nodes were the most common site of recurrence, and 28% of patients had ¹¹C-choline-positive suspected recurrences outside the initial treatment field. Conclusion: ¹¹C-choline PET/CT can detect PCa recurrence even among patients with low PSA levels when interpretation accounts for the clinical context, providing a certain pre-test probability. Until PSMA agents are fully approved for PCa, choline PET/CT may provide clinical utility.

Rationale: Despite its widespread use in oncology, the PET radiotracer ¹⁸F-FDG is ineffective for improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualisation of high-grade pancreatic intraepithelial neoplasias (PanIN-3), generally regarded as the non-invasive precursors of PDAC. The DNA damage response is known to be hyper-activated in late-stage PanINs. Therefore, we investigated whether the SPECT imaging agent, ¹¹¹In-anti-H2AX-TAT, allows visualisation of the DNA damage repair marker H2AX in PanIN-3s in an engineered mouse model of PDAC, to facilitate early detection of PDAC. Methods: Genetically engineered KPC mice (KRasLSL.G12D/+; p53LSL.R172H/+; PdxCre) were imaged with ¹⁸F-FDG and ¹¹¹In-anti-H2AX-TAT. PanIN/PDAC presence visualised by histology was compared with autoradiography and immunofluorescence. Separately, the survival of KPC mice imaged with ¹¹¹In-anti-H2AX-TAT was evaluated. Results: In KPC mouse pancreata, H2AX expression was increased in high-grade PanINs, but not in PDAC, corroborating earlier results obtained from human pancreas sections. Uptake of ¹¹¹In-anti-H2AX-TAT, but not ¹¹¹In-IgG-TAT or ¹⁸F-FDG, within the pancreas was positively correlated with the age of KPC mice, which was correlated with the number of high-grade PanINs. ¹¹¹In-anti-H2AX-TAT localises preferentially in high-grade PanIN lesions, but not in established PDAC. Younger, non-tumour-bearing KPC mice that show uptake of ¹¹¹In-anti-H2AX-TAT in the pancreas survive significantly shorter than mice with physiological ¹¹¹In-anti-H2AX-TAT uptake. Conclusion: ¹¹¹In-anti-H2AX-TAT imaging allows non-invasive detection of DNA damage repair signalling upregulation in pre-invasive PanIN lesions and is a promising new tool to aid in the early detection and staging of pancreatic cancer.

Prediction of post-operative pulmonary function in lung cancer patients before tumor resection is essential for patient selection for surgery and is conventionally done with a non-imaging segment counting method (SC) or a two-dimensional planar lung perfusion scintigraphy (PS). The purpose of this study was to compare quantitative analysis of PS to single photon emission computed tomography/computed tomography (SPECT/CT) and to estimate the accuracy of SC, PS and SPECT/CT in predicting post-operative pulmonary function in patients undergoing lobectomy. Methods: Seventy-five non-small cell lung cancer (NSCLC) patients planned for lobectomy were prospectively enrolled (68% males, average age 68.1±8 years ). All patients completed pre-operative forced expiratory volume capacity (FEV1), diffusing capacity of the lung for carbon monoxide (DLCO), Tc99m-MAA lung perfusion scintigraphy with PS and SPECT/CT quantification. A subgroup of 60 patients underwent video-assisted thoracoscopic (VATS) lobectomy and measurement of post-operative FEV1 and DLCO. Relative uptake of the lung lobes estimated by PS and SPECT/CT were compared. Predicted post-operative FEV1 and DLCO were derived from SC, PS and SPECT/CT. Prediction results were compared between the different methods and the true post-operative measurements in patients who underwent lobectomy. Results: Relative uptake measurements differed significantly between PS and SPECT/CT in right lung lobes, with a mean difference of -8.2±3.8, 18.0±5.0 and -11.5±6.1 for right upper, middle and lower lobes respectively (p<0.001). The differences between the methods in the left lung lobes were minor with a mean difference of -0.4±4.4 (p>0.05) and -2.0±4.0 (p<0.001) for left upper and lower lobes respectively. No significant difference and strong correlation (R=0.6-0.76, p<0.001) were found between predicted post-operative lung function values according to SC, PS, SPECT/CT and the actual post-operative FEV1 and DLCO. Conclusion: Although lobar quantification parameters differed significantly between PS and SPECT/CT, no significant differences were found between the predicted post-operative lung function results derived from these methods and the actual post-operative results. The additional time and effort of SPECT/CT quantification may not have an added value in patient selection for surgery. SPECT/CT may be advantageous in patients planned for right lobectomies but further research is warranted.

Triple negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer leading to the worst prognosis. Because current therapeutic approaches lack efficacy, there is a clinically unmet need for effective treatment alternatives. Herein, we demonstrate a promising strategy utilizing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with ¹⁷⁷Lu for targeted radionuclide therapy (TRT) of TNBC. In two murine syngeneic models of TNBC, we confirmed excellent tumor targeting and rapid normal tissue clearance of the PET imaging analog ⁸⁶Y-NM600. Based on longitudinal PET/CT data acquired with ⁸⁶Y-NM600, we estimated the dosimetry of therapeutic ¹⁷⁷Lu-NM600, which showed larger absorbed doses in the tumor compared to normal tissues. Administration of ¹⁷⁷Lu-NM600 resulted in significant tumor growth inhibition and prolonged overall survival in mice bearing syngeneic 4T07 and 4T1 tumors. Complete response was attained in 60% of 4T07 bearing mice, but animals carrying aggressive 4T1 tumor grafts succumbed to metastatic progression. The injected activities used for treatment (9.25 and 18.5 MBq) were well tolerated, and only mild transient cytopenia was noted. Overall, our results suggest that ¹⁷⁷Lu-NM600 TRT has potential for treatment of TNBC and merits further exploration in a clinical setting.

Introduction: A new pattern of response, so-called hyper-progressive disease (HPD), is emerging during treatment with immune checkpoint inhibitors (ICI). Our aim was to investigate the prevalence of such phenomenon and to assess its association with clinical variables and metabolic parameters by ¹⁸F-fludeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT). Methods: Data from 50 patients (34 male, 16 female, median age 73) with non-small cell lung carcinoma (NSCLC) and treated with ICI were prospectively collected. All patients underwent contrast-enhanced CT, ¹⁸F-FDG PET/CT, and complete peripheral blood sample at baseline before ICI. HPD was defined according to clinical and radiologic criteria. Because of the rapid disease progression or worsening of clinic conditions, radiologic response assessment was available for 46 patients. OS were analyzed using the Kaplan–Meier method and the log-rank test. A Cox proportional hazards regression analysis was used to evaluate factors independently associated with OS. Median follow-up was 12.4 months (9.7-15.2 months). Results: We identified the following response categories: 10 cases as complete/partial response (CR/PR), 17 cases with stable disease (SD), 5 patients with progressive disease (PD), and 14 with HPD. Among metabolic parameters we observed a statistically significant association between HPD status and tumor burden, expressed by both MTV (756.1ml for HPD vs 475.6ml for non-HPD, P = 0.011) and TLG (287.3 for HPD vs 62.1 for non-HPD, P = 0.042). Among clinical variables, 12/14 patients (85.7%) within the HPD group compared with 8/32 patients (25%) in the non-HDP group had more than two metastatic sites (p<0.001). In addition, the derived neutrophil-to-lymphocyte ratio (dNLR) and platelet counts was significantly associated with HPD status (P = 0.038, P = 0.025, respectively). Survival analysis showed a median OS of 4 months for HPD group compared with 15 months within non-HPD patients (P = 0.003). Likewise, median OS was significantly different when we considered all the response categories: CR/PR, SD, PD, and HPD (P = 0.001). Finally, Multivariate analysis identified MTV and dNLR as independent predictors for OS. Conclusion: Our results suggest that the use of ICI might represent a concern in patients with high metabolic tumor burden and inflammatory indexes at baseline. However Additional studies are needed.

Objectives: Radioactive iodine (¹³¹I) therapy may be used to treat thyroid cancer in end-stage renal disease patients who undergo hemodialysis. Because iodine predominantly utilizes renal clearance, treatment management in hemodialysis patients may be problematic, and no formal recommendations on hemodialysis currently exist. This work details our experience with treating thyroid cancer with iodine in chronic renal failure patients who require hemodialysis and details the therapeutic dosimetry results obtained during treatment to ensure that the dose to the bone marrow (BM) was acceptable. Methods: We treated 6 patients in the metabolic radiotherapy unit after thyroid stimulation. Two hemodialysis sessions in the metabolic radiotherapy unit were performed at 42 and 90 hours after radiopharmaceutical administration. BM toxicity was estimated with activity measurements from blood samples and with whole-body measurements that were regularly repeated during hospitalization and measured with a gamma counter. The patients underwent thyroid and hematologic monitoring to assess treatment efficacy and therapeutic toxicity in the short, medium and long term. Results: Whole-body activity was reduced on average by 66.7% [60.1-71.5] after the first dialysis session and by 53.3% [30.4-67.8] after the second. The mean estimated total absorbed dose to the BM was 0.992 Gy for all patients [0.431 – 2.323]. We did not observe any significant hematologic toxicity, and the clinical, biological and ultrasound test results confirmed the success of ablative treatment for the majority of patients. Conclusion: An approximately 30% reduction from the nominal dose in the amount of ¹³¹I activity for hemodialysis patients with thyroid cancer appears to strike an appropriate balance between the absence of BM toxicity and therapeutic efficacy. To avoid overirradiation, we recommend pretherapeutic dosimetry studies for metastatic patients to calculate the amount of activity to be administered as well as dosimetry monitoring during the hemodialysis sessions performed after therapeutic dose administration and under the same conditions.

Quantitative evaluation of radiolabeled Prostate-Specific Membrane Antigen (PSMA) PET scans may be used to monitor treatment response in patients with prostate cancer (PCa). To interpret longitudinal differences in PSMA uptake, the intrinsic variability of tracer uptake in PCa lesions needs to be defined. The aim of this study was to investigate the repeatability of quantitative ¹⁸F-DCFPyL (a second generation ¹⁸F-PSMA-ligand) PET/CT measurements in patients with PCa. Methods: Twelve patients with metastatic PCa were prospectively included, of which 2 were excluded from final analyses. Patients received two whole-body ¹⁸F-DCFPyL PET/CT scans (median dose 317 MBq; uptake time 120 min), within median 4 days (range 1-11 days). After semi-automatic (isocontour-based) tumor delineation, the following lesion-based metrics were derived: Tumor-to-Blood ratio (TBRmean, TBRpeak, and TBRmax), Standardized Uptake Value (SUVmean, SUVpeak, SUV_max, normalized to bodyweight), tumor volume, and total lesion tracer uptake (TLU). Additionally, patient-based Total Tumor Volume (sum of PSMA-positive tumor volumes; TTV) and Total Tumor Burden (sum of all lesion TLUs; TTB) were derived. Repeatability was analyzed using repeatability coefficients (RC) and intra-class correlations (ICC). Additionally, the effect of point spread function (PSF) image reconstruction on the repeatability of uptake metrics was evaluated. Results: In total, 36 ¹⁸F-DCFPyL PET positive lesions were analyzed (up to 5 lesions per patient). RCs of TBRmean, TBRpeak, and TBRmax were 31.8%, 31.7%, and 37.3%, respectively. For SUVmean, SUVpeak, SUV_max the RCs were 24.4%, 25.3% and 31.0%, respectively. All ICC were ≥0.97. Tumor volume delineations were well repeatable, with RC 28.1% for individual lesion volumes and RC 17.0% for TTV. TTB had a RC of 23.2% and 33.4%, when based on SUVmean and TBRmean, respectively. Small lesions (<4.2mL) had worse repeatability for volume measurements. The repeatability of SUVpeak, TLU, and all patient-level metrics were not affected by PSF-reconstruction. Conclusion: ¹⁸F-DCFPyL uptake measurements are well repeatable and can be used for clinical validation in future treatment response assessment studies. Patient-based TTV may be preferred for multicenter studies since its repeatability was both high and robust to different image reconstructions.

The impact of prostate specific membrane antigen (PSMA) PET/CT on management of prostate cancer (PCa) patients with biochemical recurrence (BCR) is well-established. However, whether and how PSMA PET/CT affects the management of patients undergoing scans for other clinical indications remains unknown. The goal of this study was to determine the impact of ⁶⁸Ga-PSMA-11 PET/CT on initial and subsequent management decisions in a cohort of PCa patients referred for various indications ("basket trial") excluding the two main classical indications: BCR and presurgical staging. Methods: This was a prospective study of 197 patients that aimed to determine the impact of ⁶⁸Ga-PSMA-11 PET/CT on PCa stage and management. Indications for PSMA PET/CT were: initial staging of non-surgical candidates (30 patients) and re-staging after definitive treatment (n = 168). The re-staging cohort comprised: patients re-staged with known advanced metastatic disease (n = 103), after androgen deprivation therapy only (n = 16), after surgery with serum PSA levels <0.2 ng/ml (n = 13), after radiation therapy (RT) not meeting the Phoenix criteria (n = 22) and after other primary local treatments [i.e. high-intensity focused ultrasound (HIFU), focal laser ablation, cryoablation, hyperthermia or irreversible electroporation] (n = 13). Patients with BCR and candidates for curative surgery were excluded. Impact on management was assessed using pre- and post-PET questionnaires completed by referring physicians, electronic chart review and/or patient telephone encounters. Results: PSMA PET/CT changed disease stage in 135/197 (69%) patients (38% up-stage, 30% down-stage and no changes in stage in 32%). Management was affected in 104/182 (57%) patients. Specifically, PSMA PET/CT impacted management of patients who were re-staged after RT without meeting the Phoenix criteria for BCR, after other definitive local treatments and with advanced metastatic disease in 13/18 (72%), 8/12 (67%) and 59/96 (61%), respectively. Conclusion: PSMA PET/CT has a profound impact on stage and management of PCa patients outside of the two main classical indications (BCR and presurgical staging) across all examined clinical scenarios.

Objective: To develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using ¹⁸F-DPA-714 translocator protein (TSPO) positron emission tomography (PET), and to explore the relationship between these maps and individual trajectories of disability worsening in patients with multiple sclerosis (MS). Methods: Patients with MS (n = 37), whose trajectories of disability worsening over the 2 years preceding study entry were calculated, and healthy controls (n = 19) underwent magnetic resonance magnetic and ¹⁸F-DPA-714 PET. A threshold of significant activation of ¹⁸F-DPA-714 binding was calculated with a voxel-wise randomized permutation-based comparison between patients and controls, and used to classify each WM voxel in patients as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were employed to calculate the extent of activation in WM regions-of-interests and to classify each WM lesion as "DPA-active", "DPA-inactive" or "unclassified". Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM, (NAWM in patients=24.9±9.7%; WM in controls=14.0±7.8%, p<0.001). In patients with MS, the percentage of DPA+ voxels showed a significant increase from NAWM, to perilesional areas, T2 hyperintense lesions and T1 hypointense lesions (38.1±13.5%, 45.0±17.9%, and 51.9±22.9%, respectively, p<0.001). Among the 1379 T2 lesions identified, 512 were defined as DPA-active and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (OR=1.13, P = 0.009), a higher percentage of DPA+ voxels in the NAWM (OR=1.16, P = 0.009) and in T1-spin-echo lesions (OR=1.06, P = 0.036), were significantly associated with a retrospective more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with an innate immune cells activation inside and around WM lesions. ¹⁸F-DPA-714 PET may provide a promising biomarker to identify patients at risk of severe clinical trajectory.

Galectins are carbohydrate-binding proteins overexpressed in bladder cancer (BCa) cells. Dendritic galactose moieties have a high affinity for galectin-expressing tumor cells. We radiolabeled a dendritic galactose carbohydrate with fluorine-18 – ¹⁸F-labeled galactodendritic unit 4 – and examined its potential in imaging urothelial malignancies. Methods: The ¹⁸F-labeled 1st generation galactodendritic unit 4 was obtained from its tosylate precursor. We conducted in vivo studies in galectin-expressing UMUC3 orthotopic BCa model to determine the ability of ¹⁸F-labeled galactodendritic unit 4 to image BCa. Results: Intravesical administration of ¹⁸F-labeled galactodendritic unit 4 allowed specific accumulation of the carbohydrate radiotracer in galectin-1 overexpressing UMUC3 orthotopic tumors when imaged with PET. The ¹⁸F-labeled galactodendritic unit 4 was not found to accumulate in non-tumor murine bladders. Conclusion: The ¹⁸F-labeled galactodendritic unit 4 and similar analogs may be clinically relevant and exploitable for PET imaging of galectin-1 overexpressing bladder tumors.

The purpose of this study was to investigate the feasibility and diagnostic efficacy of ⁶⁸Ga-PSMA positron emission tomography/computed tomography (PET/CT) combined with PET-ultrasound image-guided biopsy in the diagnosis of prostate cancer. Methods: A total of 31 patients with previously negative prostate biopsy, but persistent elevated serum prostate specific antigen (PSA), were imaged with a ⁶⁸Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT ligand prior to undergoing repeat prostate biopsy. Based on the proposed PROMISE criteria, PSMA PET/CT results were interpreted as negative (miPSMA-ES 0-1) or positive (miPSMA-ES 2-3). All patients underwent standard template systematic biopsy with up to four additional PSMA PET-ultrasound fusion image-guided biopsy cores. The sensitivity, specificity, positive and negative predictive values, and accuracy of PSMA PET/CT were determined. In addition, the correlation between miPSMA-ES and detection rate of prostate cancer was also analyzed. Univariate logistic regression models were established using PSMA PET/CT semi-quantitative analysis parameters to predict the outcome of repeat prostate biopsy. Results: The median age of patients was 65 years (range 53-81), and the median PSA level was 18.0 ng/ml (range 5.48-49.77 ng/ml). Prostate cancer was detected in 15/31 patients (48.4%) and 12/31 patients (38.7%) had clinically significant disease. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ⁶⁸Ga-PSMA PET/CT in the diagnosis of clinically significant prostate cancer were 100.0%, 68.4%, 66.7%, 100.0% and 80.6%, respectively. The detection rate of prostate cancer increased with the increase of miPSMA-ES score. The detection rate of clinically significant prostate cancer in miPSMA-ES 0-1, 2 and 3 groups were 0%, 54.5% and 85.7% respectively. Semi-quantitative analysis of ⁶⁸Ga-PSMA PET/CT images showed that predictive models based on maximum standardized uptake value (SUV_max), tumor-to-background normal prostate SUV (SUVT/BGp) and tumor-to-background normal liver SUV (SUVratio) could effectively predict clinically significant prostate cancer; area under the curves were 0.930, 0.877, and 0.956, respectively. Conclusion: This study preliminarily confirmed that ⁶⁸Ga-PSMA PET/CT imaging combined with PET-ultrasound fusion image-guided prostate biopsy can effectively detect clinically significant prostate cancer. Prebiopsy ⁶⁸Ga-PSMA PET/CT has predictive value for clinically significant cancer in the studied patient population.

Targeting tumor-expressed receptors using selective molecules for diagnostic, therapeutic or both diagnostic and therapeutic (theragnostic) purposes is a promising approach in oncological applications. Such approaches have increased significantly over the past decade. Peptides such as gastrin-releasing peptide receptors (GRPR) targeting radiopharmaceuticals are small molecules with fast blood clearance and urinary excretion. They demonstrate good tissue diffusion, low immunogenicity, and highly selective binding to their target cell-surface receptors. They are also easily produced. GRPR, part of the bombesin (BBN) family, are overexpressed in many tumors, including breast and prostate cancer, and therefore represent an attractive target for future development.

Purpose: The main objective of this prospective study was to determine the impact of multi-phasic acquisition of ⁶⁸Ga-PSMA PET/CT in the detection of recurrent prostate cancer (PCa) in the early stage of biochemical recurrence (BR) with prostate-serum-antigen (PSA) level <1ng/ml. Also, ⁶⁸Ga-PSMA PET/CT positivity was correlated with clinical parameters for the assessment of predictive markers. Methods: A prospective monocentric study was conducted on 135 PCa patients with BR and PSA<1ng/ml. All patients have undergone initial prostatectomy with additional radiation therapy in 19.3% and androgen-deprivation therapy (ADT) in 7.4% of patients. Dynamic acquisition [1–8min. post-injection (p.i.)] from the prostate bed, standard whole-body (60min. p.i.) and limited bed positions of delayed studies (120-150min. p.i.), were performed. Studies were reviewed by two board-certified nuclear medicine specialists, independently. A combination of visual and semi-quantitative analyses and correlation with morphological (e.g. MRI) and/or clinical follow-up findings was used for the final interpretation of abnormal lesions as benign or malignant. ⁶⁸Ga-PSMA PET/CT positivity was also correlated with primary clinical findings. Results: Incorporating the information of all phases, 116 lesions were detected in 49.6% of patients (22 local recurrences, 63 lymph nodes, and 31 distant metastases). The detection rates were 31.8%, 44.9%, and 71.4% for PSA<0.2ng/ml, 0.2≤PSA<0.5, and 0.5≤PSA<1, respectively. Additional dynamic and/or delayed phases resulted in better determination of equivocal lesions and a higher diagnostic performance in 25.9% of patients. Stand-alone dynamic and delayed images led to better interpretation of equivocal findings in the prostate bed (31.4%) and other (lymph node/bone) lesions (20%), respectively. Conclusion: ⁶⁸Ga-PSMA PET/CT revealed promising results for the early detection of recurrent disease in patients with PSA level of 0.5-1.0ng/ml. However, it showed limited value in cases with PSA<0.5ng/ml. Multi-phasic ⁶⁸Ga-PSMA PET/CT led to better determination of equivocal findings. Although, dynamic images may provide helpful information in assessment of the prostate bed; however, delayed acquisitions seem to have higher impact in clarifying of the equivocal findings.

Recently introduced PET systems using silicon photomultipliers with digital readout (dPET) have an improved timing and spatial resolution, aiming at a better image quality, over conventional PET (cPET) systems. We prospectively evaluated the performance of a dPET system in patients with cancer, as compared to high-resolution (HR) cPET imaging. Methods: After a single FDG-injection, 66 patients underwent dPET (Vereos, Philips Healthcare) and cPET (Ingenuity TF, Philips Healthcare) imaging in a randomized order. We used HR-reconstructions (2x2x2 mm³ voxels) for both scanners and determined SUV_max, SUVmean, lesion-to-background ratio (LBR), metabolic tumor volume (MTV) and lesion diameter in up to 5 FDG-positive lesions per patient. Furthermore, we counted the number of visible and measurable lesions on each PET scan. Two nuclear medicine specialists blindly determined the Tumor Node Metastasis (TNM) score from both image sets in 30 patients referred for initial staging. For all 66 patients, these specialists separately and blindly evaluated image quality (4-point scale) and determined the scan preference. Results: We included 238 lesions that were visible and measurable on both PET scans. We found 37 additional lesions on dPET in 27 patients (41%), which were unmeasurable (n = 14) or invisible (n = 23) on cPET. SUVmean, SUV_max, LBR and MTV on cPET were 5.2±3.9 (mean±SD), 6.9±5.6, 5.0±3.6 and 2991±13251 mm³, respectively. On dPET SUVmean, SUV_max and LBR increased 24%, 23% and 27%, respectively (p<0.001) while MTV decreased 13% (p<0.001) compared to cPET. Visual analysis showed TNM upstaging with dPET in 13% of the patients (4/30). dPET images also scored higher in image quality (P = 0.003) and were visually preferred in the majority of cases (65%). Conclusion: Digital PET improved the detection of small lesions, upstaged the disease and images were visually preferred as compared to high-resolution conventional PET. More studies are necessary to confirm the superior diagnostic performance of digital PET.

The aim of this work was to quantify the uptake of [¹⁸F]BMS-986192, a PD-L1 adnectin PET tracer, in patients with non-small-cell lung cancer (NSCLC). To this end, plasma input kinetic modeling of dynamic tumor uptake data with online arterial blood sampling was performed. In addition, the accuracy of simplified uptake metrics such as standardized uptake value (SUV) was investigated. Methods: Data from a study with [¹⁸F]BMS-986192 in patients with advanced stage NSCLC eligible for nivolumab treatment were used if a dynamic scan was available and lesions were present in the field of view of the dynamic scan. After injection of [¹⁸F]BMS-986192, a 60-minutes dynamic PET-CT scan was started, followed by a 30-min whole body PET-CT scan. Continuous arterial and discrete arterial and venous blood sampling were performed to determine a plasma input function. Tumor time activity curves were fitted by several plasma input kinetic models. Simplified uptake parameters included tumor to blood ratio as well as several SUV measures. Results: Twenty two tumors in nine patients were analyzed. The arterial plasma input single-tissue reversible compartment model with fitted blood volume fraction seems to be the most preferred model as it best fitted 11 out of 18 tumor time activity curves. The distribution volume V_T ranged from 0.4 to 4.8 mL·cm-3. Similar values were obtained with an image derived input function. From the simplified measures, SUV normalized for body weight (SUV_BW) at 50 and 67 minutes post injection correlated best with V_T, with an R² > 0.9. Conclusion: A single tissue reversible model can be used for the quantification of tumor uptake of the PD-L1 PET tracer [¹⁸F]BMS-986192. SUV_BW at 60 minutes post injection, normalized for body weight, is an accurate simplified parameter for uptake assessment of baseline studies. In order to assess its predictive value for response evaluation during PD-(L)1 immune checkpoint inhibition further validation of SUV against V_T based on an image derived input function is recommended.

The overexpression of integrin αvβ6 in pancreatic cancer makes it a promising target for noninvasive positron emission tomography (PET) imaging. However, currently, most integrin αvβ6-targeting radiotracers are based on linear peptides, which are quickly degraded in the serum by proteinases. Herein, we aimed to develop and assess a ⁶⁸Ga-labeled integrin αvβ6-targeting cyclic peptide (⁶⁸Ga-cycratide) for PET imaging of pancreatic cancer. Methods: ⁶⁸Ga-cycratide was prepared, and its PET imaging profile was compared with that of the linear peptide (⁶⁸Ga-linear-pep) in an integrin αvβ6-positive BxPC-3 human pancreatic cancer mouse model. Five healthy volunteers (two women and three men) underwent whole-body PET/CT imaging after injection of ⁶⁸Ga-cycratide, and biodistribution and dosimetry calculations were determined. PET/CT imaging of two patients was performed to investigate the potential role of ⁶⁸Ga-cycratide in pancreatic cancer diagnosis and treatment monitoring. Results: ⁶⁸Ga-cycratide exhibited significantly higher tumor uptake than did ⁶⁸Ga-linear-pep in BxPC-3 tumor-bearing mice, owing—at least in part—to markedly improved in vivo stability. ⁶⁸Ga-cycratide could sensitively detect the pancreatic cancer lesions in an orthotopic mouse model and was well tolerated in all healthy volunteers. Preliminary PET/CT imaging in patients with pancreatic cancer demonstrated that ⁶⁸Ga-cycratide was comparable to ¹⁸F-fludeoxyglucose for diagnostic imaging and post-surgery tumor relapse monitoring. Conclusion: ⁶⁸Ga-cycratide is an integrin αvβ6-specific PET radiotracer with favorable pharmacokinetics and dosimetry profile. ⁶⁸Ga-cycratide is expected to provide an effective noninvasive PET strategy for pancreatic cancer lesion detection and therapy response monitoring.

Background: Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer (mCRPC). However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes following ¹⁷⁷Lu-labelled prostate specific membrane antigen (LuPSMA) radionuclide treatment in mCRPC patients. Methods: Men who were treated under a compassionate access program with LuPSMA at our institution and had available PSA values at baseline, at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to three groups based on PSA changes: 1) response: ≥30% decline, 2) progression: ≥25% increase and 3) stable: <30% decline and <25% increase. The co-primary endpoints were overall survival and imaging-based progression-free survival. The secondary end points were PSA changes at 12 wk and PSA flare-up. Results: We identified 124 eligible patients with PSA values at 6 wk. A ≥30% decline in PSA at 6 wk was associated with longer overall survival (median 16.7 mo; 95%CI 14.4–19.0) compared with patients with stable PSA (median: 11.8 mo; 95%CI 8.6–15.1; P = 0.007) and progression (median: 6.5 mo; 95%CI 5.2–7.8; p<0.001). Patients with ≥30% decline in PSA at 6 wk also had a reduced risk of imaging-based progression compared with patients with stable PSA (HR: 0.60; 95%CI 0.38–0.94; P = 0.02), while patients with PSA progression had a higher risk of imaging-based progression compared with those showing stable PSA (HR: 3.18; 95%CI 1.95–5.21; p<0.001). The percentage changes of PSA at 6 wk and 12 wk were highly associated (r=0.90; p<0.001). 29 of 31 (94%) patients who experienced early PSA progression at 6 wk achieved biochemical progression at 12 wk. Overall, only 1 of 36 (3%) patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). Limitations of the study included its retrospective nature and the single center experience. Conclusion: PSA changes at 6 wk after LuPSMA initiation are an early indicator of long-term clinical outcome. Patients progressing by PSA after 6 wk of treatment could benefit from a very early treatment switch decision. PSA flare-up during LuPSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of LuPSMA.

Purpose: This prospective study evaluated the imaging performance of a novel immunological pretargeting positron-emission tomorgraphy (immuno-PET) method in patients with HER2-negative, carcinoembryonic antigen (CEA)-positive, metastatic breast cancer (BC), compared to computed tomography (CT), bone magnetic resonance imaging (MRI), and ¹⁸Fluorodeoxyglucose PET (FDG-PET). Patients and Methods: Twenty-three patients underwent whole-body immuno-PET after injection of 150 MBq ⁶⁸Ga-IMP288, a histamine-succinyl-glycine peptide given following initial targeting of a trivalent anti-CEA, bispecific, anti-peptide antibody. The gold standards were histology and imaging follow-up. Tumor standard uptake values (SUV_max and SUVmean) were measured, and tumor burden analyzed using Total Tumor Volume (TTV) and Total Lesion Activity (TLA). Results: Total lesion sensitivity of immuno-PET and FDG-PET was 94.7% (1116/1178) and 89.6% (1056/1178), respectively. Immuno-PET had a somewhat higher sensitivity than CT and FDG-PET in lymph nodes (92.4% vs 69.7% and 89.4%, respectively) and liver metastases (97.3% vs 92.1% and 94.8%, respectively), whereas sensitivity was lower for lung metastases (48.3% vs 100% and 75.9%, respectively). Immuno-PET showed higher sensitivity than MRI and FDG-PET for bone lesions (95.8% vs 90.7% and 89.3%, respectively). In contrast to FDG-PET, immuno-PET disclosed brain metastases. Despite equivalent tumor SUV_max, SUVmean, and TTV, TLA was significantly higher with immuno-PET compared to FDG PET (P = 0.009). Conclusion: Immuno-PET using anti-CEA/anti-IMP288 bispecific antibody, followed by ⁶⁸Ga-IMP288, is a potentially sensitive theranostic imaging method for HER2-negative, CEA-positive, metastatic BC patients, and warrants further research.

For individual treatment decisions in patients with metastatic prostate cancer (mPC), molecular diagnostics are increasingly used. Bone metastases are frequently the only source for obtaining metastatic tumor tissue. However, the success rate of computed tomography (CT)-guided bone biopsies for molecular analyses in mPC patients is only ~40%. Positron emission tomography (PET) using Gallium-68 prostate specific membrane antigen (⁶⁸Ga-PSMA) is a promising tool to improve the harvest rate of bone biopsies for molecular analyses. Aim of this study was to determine the success rate of ⁶⁸Ga-PSMA guided bone biopsies for molecular diagnostics in mPC patients. Methods: Within a prospective multicenter whole-genome sequencing trial (NCT01855477), 69 mPC patients underwent ⁶⁸Ga-PSMA PET/CT prior to bone biopsy. Primary endpoint was success rate (tumor percentage ≥30%) of ⁶⁸Ga-PSMA guided bone biopsies. At biopsy sites, ⁶⁸Ga-PSMA uptake was quantified using rigid body image registration of ⁶⁸Ga-PSMA PET/CT and interventional CT. Actionable somatic alterations were identified. Results: Success rate of ⁶⁸Ga-PSMA guided biopsies for molecular analyses was 70%. At biopsy sites categorized as positive, inconclusive, or negative for ⁶⁸Ga-PSMA uptake, 70%, 64%, and 36% of biopsies were tumor positive (≥30%), respectively (P = 0.0610). In tumor positive biopsies, ⁶⁸Ga-PSMA uptake was significantly higher (P = 0.008), whereas radiodensity was significantly lower (P = 0.006). With an area under the curve of 0.84 and 0.70, both ⁶⁸Ga-PSMA uptake (maximum standardized uptake value) and radiodensity (mean Hounsfield Units) were strong predictors for a positive biopsy. Actionable somatic alterations were detected in 73% of the sequenced biopsies. Conclusion: In patients with mPC, ⁶⁸Ga-PSMA PET/CT improves the success rate of CT-guided bone biopsies for molecular analyses, thereby identifying actionable somatic alterations in more patients. Therefore, ⁶⁸Ga-PSMA PET/CT may be considered for guidance of bone biopsies in both clinical practice and clinical trials.

Introduction: Neuroendocrine differentiation is associated with treatment failure and poor outcome in metastatic castration-resistant prostate cancer (mCRPC). We investigated the effect of circulating neuroendocrine biomarkers on the efficacy of PSMA-targeted radioligand therapy (RLT). Methods: Neuroendocrine biomarker profiles (progastrin-releasing peptide, neuron-specific enolase, and chromogranin-A) were analyzed in 50 patients commencing ¹⁷⁷Lu-PSMA-617 RLT. The primary endpoint was PSA response in relation to baseline neuroendocrine marker profiles. Additional endpoints included progression-free survival. Tumor uptake on post-therapeutic scans, a known predictive marker for response, was used as control-variable. Results: Neuroendocrine biomarker profiles were abnormal in the majority of patients. Neuroendocrine biomarker levels did not predict treatment failure or early progression (P ≥ 0.13). By contrast, intense PSMA-ligand uptake in metastases predicted both treatment response (P = 0.0030) and reduced risk of early progression (P = 0.0111). Conclusion: Neuroendocrine marker profiles do not predict adverse outcome of RLT. By contrast, high ligand uptake was confirmed to be crucial for achieving tumor-response.

Purpose: To determine the effect of smooth filter and partial volume correction (PVC) method on measured prostate-specific membrane antigen (PSMA) activity in small metastatic lesions and to determine the impact of these changes on the molecular imaging (mi) PSMA scoring. Materials & Methods: Men with biochemical recurrence of prostate cancer with negative CT and bone scintigraphy were referred for ¹⁸F-DCFPyL PET/CT. Examinations were performed on one of 2 PET/CT scanners (GE Discovery 610 or Siemens mCT40). All suspected tumor sites were manually contoured on co-registered CT and PET images, and each was assigned a miPSMA score as per the PROMISE criteria. The PVC factors were calculated for every lesion using the anatomical CT and then applied to the unsmoothed PET images. The miPSMA scores, with and without the corrections, were compared, and a simplified "rule of thumb" (RoT) correction factor (CF) was derived for lesions at various sizes (<4mm, 4-7mm, 7-9mm, 9-12mm). This was then applied to the original dataset and miPSMA scores obtained using the RoT CF were compared to those found using the actual corrections. Results: There were 75 men (median age, 69 years; median serum PSA of 3.69 ug/L) with 232 metastatic nodes < 12 mm in diameter (mean lesion volume of 313.5 ± 309.6 mm³). Mean SUV_max before and after correction was 11.0 ± 9.3 and 28.5 ± 22.8, respectively (p<0.00001). The mean CF for lesions <4mm (n = 22), 4-7mm (n = 140), 7-9mm (n = 50), 9-12 mm (n = 20) was 4 (range: 2.5-6.4), 2.8 (range: 1.6-4.9), 2.3 (range: 1.6-3.3) and 1.8 (range 1.4-2.4), respectively. Overall miPSMA scores were concordant between the corrected dataset and RoT in 205/232 lesions (88.4%). Conclusion: There is a significant effect of smooth filter and partial volume correction on measured PSMA activity in small nodal metastases, impacting the miPSMA score.

Gone are the days when medical imaging was used primarily to visualize anatomical structures. The emergence of molecular imaging, championed by radiolabeled fluorodeoxyglucose positron emission tomography (¹⁸FDG PET) has expanded the information content derived from imaging to include pathophysiological and molecular processes. Cancer imaging, in particular, has leveraged advances in molecular imaging agents and technology to improve the accuracy of tumor detection, interrogate tumor heterogeneity, monitor treatment response, focus surgical resection, and enable image-guided biopsy. Surgeons are actively latching on to the incredible opportunities provided by medical imaging for preoperative planning, intraoperative guidance, and postoperative monitoring. From label-free techniques to enabling cancer-selective imaging agents, image-guided surgery provides surgical oncologists and interventional radiologists both macroscopic and microscopic views of cancer in the operating room. This review highlights the current state of molecular imaging and sensing approaches available for surgical guidance. Salient features of nuclear, optical, and multimodal approaches will be discussed, including their strengths, limitations and clinical applications. To address the increasing complexity and diversity of methods available today, this review provides a framework to identify a contrast mechanism, suitable modality, and device. Emerging low cost, portable, and user-friendly imaging systems make the case for adopting some of these technologies as the global standard of care in surgical practice.

Bone is the most common site of distant metastatic spread in prostate adenocarcinoma. Prostate-specific membrane antigen uptake has been described in both benign and malignant bone lesions, which can lead to false-positive findings on ⁶⁸Ga-prostate-specific membrane antigen-11 positron emission tomography (⁶⁸Ga-PSMA-11 PET). The purpose of this study was to evaluate the diagnostic accuracy of ⁶⁸Ga-PSMA-11 PET for osseous prostate cancer metastases and improve bone uptake interpretation using semi-quantitative metrics. METHODS: 56 prostate cancer patients (18 pre-prostatectomy, 38 biochemical recurrence) who underwent ⁶⁸Ga-PSMA-11 PET/MRI or PET/CT examinations with osseous PSMA-ligand uptake were included in the study. Medical records were reviewed retrospectively by board-certified nuclear radiologists to determine true or false positivity based on a composite endpoint. For each avid osseous lesion, biological volume, size, PSMA-RADS rating, maximum standardized uptake value (SUV_max), and ratio of lesion SUV_max to liver, blood pool, and background bone SUV_max were measured. Differences between benign and malignant lesions were evaluated for statistical significance, and cut-off values for these parameters were determined to maximize diagnostic accuracy. RESULTS: Among 56 participants, 13 patients (22.8%) had false-positive osseous ⁶⁸Ga-PSMA-11 findings and 43 patients (76.8%) had true-positive osseous ⁶⁸Ga-PSMA-11 findings. Twenty-two patients (39%) had 1 osseous lesion, 18 (32%) had 2-4 lesions, and 16 (29%) had 5 or more lesions. Cut-off values resulting in statistically significant (p<0.005) differences between benign and malignant lesions were: PSMA-RADS ≥4, SUV_max ≥4.1, SUV_max ratio of lesion to blood pool ≥2.11, to liver ≥0.55, and to bone ≥4.4. These measurements corresponded to lesion-based ⁶⁸Ga-PSMA-11 PET lesion detection rate for malignancy of 80%, 93%, 89%, 21%, 89%, and a specificity of 73%, 73%, 73%, 93%, 60%, respectively. CONCLUSION: PSMA-RADS rating, SUV_max, and SUV_max ratio of lesion to blood pool can help differentiate benign from malignant lesions on ⁶⁸Ga-PSMA-11 PET. SUV_max ratio to blood pool above 2.2 is a reasonable parameter to support image interpretation and presented superior lesion detection rate and specificity when compared to visual interpretation by PSMA RADS. These parameters hold clinical value by improving diagnostic accuracy for metastatic prostate cancer on ⁶⁸Ga-PSMA-11 PET/MRI and PET/CT.