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Idiopathic rapid eye movement sleep behaviour disorder (iRBD) has now been established as an important marker of the prodromal stage of Parkinson’s disease and related synucleinopathies. However, although dopamine transporter single photon emission computed tomography (SPECT) has been used to demonstrate the presence of nigro-striatal deficit in iRBD, quantifiable correlates of this are currently lacking. Sensitivity to rewarding stimuli is reduced in some people with Parkinson’s disease, potentially contributing to aspects of the neuropsychiatric phenotype in these individuals. Furthermore, a role for dopaminergic degeneration is suggested by the fact that reward insensitivity can be improved by dopaminergic medications. Patients with iRBD present a unique opportunity to study the relationship between reward sensitivity and early dopaminergic deficit in the unmedicated state. Here, we investigate whether a non-invasive, objective measure of reward sensitivity might be a marker of dopaminergic status in prodromal Parkinson’s disease by comparing with SPECT/CT measurement of dopaminergic loss in the basal ganglia. Striatal dopaminergic deficits in iRBD are associated with progression to Parkinsonian disorders. Therefore, identification of a clinically measurable correlate of this degenerative process might provide a basis for the development of novel risk stratification tools. Using a recently developed incentivized eye-tracking task, we quantified reward sensitivity in a cohort of 41 patients with iRBD and compared this with data from 40 patients with Parkinson’s disease and 41 healthy controls. Patients with iRBD also underwent neuroimaging with dopamine transporter SPECT/CT. Overall, reward sensitivity, indexed by pupillary response to monetary incentives, was reduced in iRBD cases compared with controls and was not significantly different to that in patients with Parkinson’s disease. However, in iRBD patients with normal dopamine transporter SPECT/CT imaging, reward sensitivity was not significantly different from healthy controls. Across all iRBD cases, a positive association was observed between reward sensitivity and dopaminergic SPECT/CT signal in the putamen. These findings demonstrate a direct relationship between dopaminergic deficit and reward sensitivity in patients with iRBD and suggest that measurement of pupillary responses could be of value in models of risk stratification and disease progression in these individuals.

The ability of nucleic acids to catalyze reactions (as well as store and transmit information) is important for both basic and applied science, the first in the context of molecular evolution and the origin of life and the second for biomedical applications. However, the catalytic power of standard nucleic acids (NAs) assembled from just four nucleotide building blocks is limited when compared with that of proteins. Here, we assess the evolutionary potential of libraries of nucleic acids with six nucleotide building blocks as reservoirs for catalysis. We compare the outcomes of in vitro selection experiments toward RNA-cleavage activity of two nucleic acid libraries: one built from the standard four independently replicable nucleotides and the other from six, with the two added nucleotides coming from an artificially expanded genetic information system (AEGIS). Results from comparative experiments suggest that DNA libraries with increased chemical diversity, higher information density, and larger searchable sequence spaces are one order of magnitude richer reservoirs of molecules that catalyze the cleavage of a phosphodiester bond in RNA than DNA libraries built from a standard four-nucleotide alphabet. Evolved AEGISzymes with nitro-carrying nucleobase Z appear to exploit a general acid–base catalytic mechanism to cleave that bond, analogous to the mechanism of the ribonuclease A family of protein enzymes and heavily modified DNAzymes. The AEGISzyme described here represents a new type of catalysts evolved from libraries built from expanded genetic alphabets.

PDF file, 36K, Number of risk allele carriers.

Background: Heritable risk for breast cancer includes an increasing number of common, low effect risk variants. We conducted a multistage genetic association study in a series of independent epidemiologic breast cancer study populations to identify novel breast cancer risk variants.Methods: We tested 1,162 SNPs of greatest nominal significance from stage I of the Cancer Genetic Markers of Susceptibility breast cancer study (CGEMS; 1,145 cases, 1,142 controls) for evidence of replicated association with breast cancer in the Nashville Breast Cohort (NBC; 599 cases, 1,161 controls), the Collaborative Breast Cancer Study (CBCS; 1,552 cases, 1,185 controls), and BioVU Breast Cancer Study (BioVU; 1,172 cases, 1,172 controls).Results: Among these SNPs, a series of validated breast cancer risk variants yielded expected associations in the study populations. In addition, we observed two previously unreported loci that were significantly associated with breast cancer risk in the CGEMS, NBC, and CBCS study populations and had a consistent, although not statistically significant, risk effect in the BioVU study population. These were rs1626678 at 10q25.3 near ENO4 and KIAA1598 (meta-analysis age-adjusted OR = 1.13 [1.07–1.20], P = 5.6 × 10−5), and rs8046508 at 16q23.1 in the eighth intron of WWOX (meta-analysis age-adjusted OR = 1.20 [1.10–1.31], P = 3.5 × 10−5).Conclusions: Our data supports the association of two novel loci, at 10q25.3 and 16q23.1, with risk of breast cancer.Impact: The expanding compendium of known breast cancer genetic risk variants holds increasing power for clinical risk prediction models of breast cancer, improving upon the Gail model. Cancer Epidemiol Biomarkers Prev; 21(9); 1565–73. ©2012 AACR.

Supplementary Table 1 from A Multistage Association Study Identifies a Breast Cancer Genetic Locus at NCOA7

Supplementary Table 2 from A Multistage Association Study Identifies a Breast Cancer Genetic Locus at NCOA7

Supplementary Table 1 from Haplotype Analysis of CYP11A1 Identifies Promoter Variants Associated with Breast Cancer Risk

Supplementary Table 2 from Haplotype Analysis of CYP11A1 Identifies Promoter Variants Associated with Breast Cancer Risk

Supplementary Figure 1 from A Multistage Association Study Identifies a Breast Cancer Genetic Locus at NCOA7

Estrogen metabolism and growth factor signaling pathway genes play key roles in breast cancer development. We evaluated associations between breast cancer and tagging single-nucleotide polymorphisms (SNP) of 107 candidate genes of these pathways using single allele- and haplotype-based tests. We first sought concordance of associations between two study populations: the Nashville Breast Cohort (NBC; 510 cases, 988 controls), and the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer study (1,145 cases, 1,142 controls). Findings across the two study populations were concordant at tagging SNPs of six genes, and at previously published SNPs of FGFR2. We sought further replication of results for EGFR, NCOA7, and FGFR2 in the independent Collaborative Breast Cancer Study (CBCS; 1,552 cases, 1,185 controls). Associations at NCOA7 and FGFR2 replicated across all three studies. The association at NCOA7 on 6q22.32, detected by a haplotype spanning the initial protein-coding exon (5′-rs9375411, rs11967627, rs549438, rs529858, rs490361, rs17708107-3′), has not been previously reported. The haplotype had a significant inverse association with breast cancer in each study [ORHet: 0.69 (NBC), 0.76 (CGEMS), 0.79 (CBCS)], and a meta-analysis ORHet of 0.75 (95% CI, 0.65–0.87, P = 1.4 × 10−4) in the combined study populations. The haplotype frequency was 0.07 among cases, and 0.09 among controls; homozygotes were infrequent and each ORHom was not significant. NCOA7 encodes a nuclear receptor coactivator that interacts with estrogen receptor α to modulate its activity. These observations provide consistent evidence that genetic variants at the NCOA7 locus may confer a reduced risk of breast cancer. Cancer Res; 71(11); 3881–8. ©2011 AACR.

The CYP11A1 gene encodes the cholesterol side chain cleavage enzyme that catalyzes the initial and rate-limiting step of steroidogenesis. A large number of epidemiologic studies have implicated the duration and degree of endogenous estrogen exposure in the development of breast cancer in women. Here, we conduct a systematic investigation of the role of genetic variation of the CYP11A1 gene in breast cancer risk in a study of 1193 breast cancer cases and 1310 matched controls from the Shanghai Breast Cancer Study. We characterize the genetic architecture of the CYP11A1 gene in a Chinese study population. We then genotype tagging polymorphisms to capture common variation at the locus for tests of association. Variants designating a haplotype encompassing the gene promoter are significantly associated with both increased expression (P = 1.6e−6) and increased breast cancer risk: heterozygote age-adjusted odds ratio (OR), 1.51 [95% confidence interval (95% CI), 1.19–1.91]; homozygote age-adjusted OR, 2.94 (95% CI, 1.22–7.12), test for trend, P = 5.0e−5. Among genes controlling endogenous estrogen metabolism, CYP11A1 harbors common variants that may influence expression to significantly modify risk of breast cancer. [Cancer Res 2007;67(12):5673–82]

Objective: CT and staging laparoscopy are routinely used to stage patients with gastric cancer, however the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with CT (PET-CT) is uncertain. This systematic review synthesised the evidence regarding the impact of baseline PET-CT staging on treatment decisions and patient outcomes. Methods: Systematic database searches were performed without date restriction. Studies reporting data in patients with gastric adenocarcinoma who underwent radiological staging were included. One reviewer screened titles and abstracts for suitability and two reviewers extracted data from included articles. Primary outcome was the reported change in management after PET-CT. Secondary outcomes were the rates of recurrence and overall survival between patients staged with and without PET-CT. Risk of bias was assessed using the ROBINS-I tool. PROSPERO registration (CRD42022304314). Results: Data from 11 studies recruiting 2101 patients between 2012 and 2021 were included. PET-CT was performed in 1422 patients. Change of management varied between 3% and 29% of cases. No studies compared recurrence or survival rates between patients staged with or without PET-CT. Adenocarcinoma of intestinal subtype tended to be more FDG-avid compared to diffuse or signet-ring subtypes. No randomised data existed, and studies were considered low quality with high risk of bias. Conclusion: Evidence for the additional value of PET-CT in the gastric cancer staging pathway is limited. All studies reported a positive impact by preventing those with undetected metastatic disease on CT undergoing futile surgery. Future national guidelines should consider routine staging PET-CT in gastric cancer. Advances in knowledge: Studies indicated that FDG PET-CT added benefit in gastric cancer staging by detecting more distant metastases, but these studies were generally of low quality and at high risk of bias. Intestinal subtype of gastric adenocarcinoma tended to be more FDG-avid and therefore more distant metastases were subsequently detected.

18F-fluorodeoxyglucose PET-CT may guide treatment decisions in patients with oesophageal adenocarcinoma (OAC). This study evaluated the added value of maximum standardised uptake value (SUVmax) to a novel DNA-damage immune response (DDIR) assay to improve pathological response prediction. The diagnostic accuracy of PET response and the prognostic significance of PET metrics for recurrence-free survival (RFS) and overall survival (OS) were assessed. This was a retrospective, single-centre study of OAC patients treated with neo-adjuvant chemotherapy from 2003 to 2014. SUVmax was recorded from baseline and repeat PET-CT after completion of pre-operative chemotherapy. Logistic regression models tested the additional predictive value of PET metrics combined with the DDIR assay for pathological response. Cox regression models tested the prognostic significance of PET metrics for RFS and OS. In total, 113 patients were included; 25 (22.1%) were DDIR positive and 88 (77.9%) were DDIR negative. 69 (61.1%) were PET responders (SUVmax reduction of 35%) and 44 (38.9%) were PET non-responders. After adding PET metrics to DDIR status, post-chemotherapy SUVmax (hazard ratio (HR) 0.75, p = 0.02), SUVmax change (HR 1.04, p = 0.003) and an optimum SUVmax reduction of 46.5% (HR 4.36, p = 0.021) showed additional value for predicting pathological response. The optimised SUVmax threshold was independently significant for RFS (HR 0.47, 95% CI 0.26–0.85, p = 0.012) and OS (HR 0.51, 95% CI 0.26–0.99, p = 0.047). This study demonstrated the additional value of PET metrics, when combined with a novel DDIR assay, to predict pathological response in OAC patients treated with neo-adjuvant chemotherapy. Furthermore, an optimised SUVmax reduction threshold for pathological response was calculated and was independently significant for RFS and OS.

We present a case of sporadic Creutzfeldt–Jakob disease with profoundly abnormal 18fluoro-deoxy-glucose positron emission tomography with computed tomography (FDG PET-CT) at an early stage, and correlate this with the clear findings at magnetic resonance imaging and also postmortem histology. Prion diseases are rare but important causes of cognitive impairment. The role of FDG PET-CT is discussed, along with other investigations such as electroencephalography and cerebro-spinal fluid analyses.

Purpose\ud\udEarly and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, 18F-Fluciclovine PET/CT in biochemicAL reCurrence Of Prostate caNcer (FALCON; NCT02578940), aimed to evaluate the effect of 18F-fluciclovine on management of men with BCR of prostate cancer.\udMethods and Materials\ud\udMen with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent 18F-fluciclovine positron emission tomography/computed tomography (PET/CT) according to standardized procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as major and changes within a modality as other. The primary outcome measure was record of a revised management plan postscan. Secondary endpoints were evaluation of optimal prostate specific antigen (PSA) threshold for detection, salvage treatment outcome assessment based on 18F-fluciclovine-involvement, and safety.\udResults\ud\ud18F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA = 0.79 ng/mL). Lesions were detected in 58 out of 104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1 out of 3 of scans were positive, and 93% scans were positive at PSA >2.0 ng/mL. Sixty-six (64%) patients had a postscan management change (80% after a positive result). Major changes (43 out of 66; 65%) were salvage or systemic therapy to watchful waiting (16 out of 66; 24%); salvage therapy to systemic therapy (16 out of 66; 24%); and alternative changes to treatment modality (11 out of 66, 17%). The remaining 23 out of 66 (35%) management changes were modifications of the prescan plan: most (22 out of 66; 33%) were adjustments to planned brachytherapy/radiation therapy to include a 18F-fluciclovine-guided boost. Where 18F-fluciclovine guided salvage therapy, the PSA response rate was higher than when 18F-fluciclovine was not involved (15 out of 17 [88%] vs 28 out of 39 [72%]).\udConclusions\ud\ud18F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating 18F-fluciclovine PET/CT into treatment planning may optimize targeting of recurrence sites and avoid futile salvage therapy.

A data-driven method for respiratory gating in PET has recently been commercially developed. We sought to compare the performance of the algorithm with an external, device-based system for oncologic 18F-FDG PET/CT imaging. Methods: In total, 144 whole-body 18F-FDG PET/CT examinations were acquired, with a respiratory gating waveform recorded by an external, device-based respiratory gating system. In each examination, 2 of the bed positions covering the liver and lung bases were acquired with a duration of 6 min. Quiescent-period gating retaining approximately 50% of coincidences was then able to produce images with an effective duration of 3 min for these 2 bed positions, matching the other bed positions. For each examination, 4 reconstructions were performed and compared: data-driven gating (DDG) (we use the term DDG-retro to distinguish that we did not use the real-time R-threshold-based application of DDG that is available within the manufacturer's product), external device-based gating (real-time position management (RPM)-gated), no gating but using only the first 3 min of data (ungated-matched), and no gating retaining all coincidences (ungated-full). Lesions in the images were quantified and image quality scored by a radiologist who was masked to the method of data processing. Results: Compared with the other reconstruction options, DDG-retro increased the SUVmax and decreased the threshold-defined lesion volume. Compared with RPM-gated, DDG-retro gave an average increase in SUVmax of 0.66 ± 0.1 g/mL (n = 87, P < 0.0005). Although the results from the masked image evaluation were most commonly equivalent, DDG-retro was preferred over RPM-gated in 13% of examinations, whereas the opposite occurred in just 2% of examinations. This was a significant preference for DDG-retro (P = 0.008, n = 121). Liver lesions were identified in 23 examinations. Considering this subset of data, DDG-retro was ranked superior to ungated-full in 6 of 23 (26%) cases. Gated reconstruction using the external device failed in 16% of examinations, whereas DDG-retro always provided a clinically acceptable image. Conclusion: In this clinical evaluation, DDG-retro provided performance superior to that of the external device-based system. For most examinations the performance was equivalent, but DDG-retro had superior performance in 13% of examinations, leading to a significant preference overall.

Objectives Rapid eye movement sleep behavior disorder (RBD) patients have a high risk of developing a Parkinsonian disorder, offering an opportunity for neuroprotective intervention. Predicting near‐term conversion, however, remains a challenge. Dopamine transporter imaging, while informative, is expensive and not widely available. Here, we investigate the utility of susceptibility‐weighted MRI (SWI) to detect abnormalities of the substantia nigra in RBD, and explore their association with striatal dopaminergic deficits. Methods SWI of the substantia nigra was performed in 46 RBD patients, 27 Parkinson’s patients, and 32 control subjects. Dorsal nigral hyperintensity (DNH) was scored by two blinded raters, and separately quantified using a semiautomated process. Forty‐two RBD patients were also imaged with 123I‐ioflupane single‐photon emission computed tomography (DaT SPECT/CT). Results Consensus visual DNH classification was possible in 87% of participants. 27.5% of RBD patients had lost DNH, compared with 7.7% of control subjects and 96% of Parkinson’s patients. RBD patients lacking DNH had significantly lower putamen dopaminergic SPECT/CT activity compared to RBD patients with DNH present (specific uptake ratios 1.89 vs. 2.33, P = 0.002). The mean quantified DNH signal intensity declined in a stepwise pattern, with RBD patients having lower intensity than controls (0.837 vs. 0.877, P = 0.01) but higher than PD patients (0.837 vs. 0.765, P

Purpose To enhance the image quality of oncology [18F]-FDG PET scans acquired in shorter times and reconstructed by faster algorithms using deep neural networks. Methods List-mode data from 277 [18F]-FDG PET/CT scans, from six centres using GE Discovery PET/CT scanners, were split into ¾-, ½- and ¼-duration scans. Full-duration datasets were reconstructed using the convergent block sequential regularised expectation maximisation (BSREM) algorithm. Short-duration datasets were reconstructed with the faster OSEM algorithm. The 277 examinations were divided into training (n = 237), validation (n = 15) and testing (n = 25) sets. Three deep learning enhancement (DLE) models were trained to map full and partial-duration OSEM images into their target full-duration BSREM images. In addition to standardised uptake value (SUV) evaluations in lesions, liver and lungs, two experienced radiologists scored the quality of testing set images and BSREM in a blinded clinical reading (175 series). Results OSEM reconstructions demonstrated up to 22% difference in lesion SUVmax, for different scan durations, compared to full-duration BSREM. Application of the DLE models reduced this difference significantly for full-, ¾- and ½-duration scans, while simultaneously reducing the noise in the liver. The clinical reading showed that the standard DLE model with full- or ¾-duration scans provided an image quality substantially comparable to full-duration scans with BSREM reconstruction, yet in a shorter reconstruction time. Conclusion Deep learning–based image enhancement models may allow a reduction in scan time (or injected activity) by up to 50%, and can decrease reconstruction time to a third, while maintaining image quality.

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Pilomatricoma, also known as calcifying epithelioma of Malherbe, is a rare skin tumor originating from the hair follicle matrix. We report a case of pilomatricoma in a 50-year-old woman, presenting as a rapidly growing pretibial mass. Malignant pilomatricoma is associated with potentially fatal metastases and are clinically and histologically indistinguishable from benign pilomatricoma. Thus, an 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) scan was requested for staging, revealing marked FDG uptake restricted to the primary lesion and no evidence of separate disease. The purpose of this report is to demonstrate the importance of PET/CT in the staging of this FDG-avid tumor; the malignancy of which is often first revealed by metastases. Our case also demonstrates that pilomatricoma should be included in the differential diagnosis of a rapidly growing peripheral soft-tissue mass; conventionally, the domain of sarcoma.

Introduction Redo parathyroidectomy for persistent/recurrent primary hyperparathyroidism is associated with a higher risk of complications and should be planned only with convincing localisation. We assessed whether 18fluorocholine positron emission tomography/computed tomography could identify parathyroid adenoma(s) in patients with persistent/recurrent primary hyperparathyroidism and negative conventional scans. Materials and methods A departmental database was used to identify patients with failed localisation attempts (sestamibi single photon emission computed tomography/computed tomography and/or computed tomography/magnetic resonance imaging and/or selective parathyroid hormone sampling) after previous unsuccessful surgery for primary hyperparathyroidism. 18Fluorocholine positron emission tomography was performed in all patients and redo surgery offered to those with positive findings. Results 18Fluorocholine positron emission tomography incorporating arterial and portal phase enhanced computed tomography was performed in 12 patients with persistent/recurrent primary hyperparathyroidism (four men and eight women). Seven patients (58%) were cured after excision of adenomas located in ectopic positions (n = 3) or in anatomical position (n = 4). Five patients (42%) had persistent hypercalcaemia and repeat 18fluorocholine scan confirmed that the area highlighted on preoperative scans was excised. The arterial phase enhancement of the computed tomography was significantly different between cured and not-cured patients (P = 0.007). All seven cured patients had either a strong or weak enhancing pattern on computed tomography. Standardised uptake value at 60 minutes in patients with successful surgery (range 2.7–15.7, median 4.05) was higher than in patients with failed surgery (range 1.8–5.8, median 3.2) but was not statistically significant (P = 0.300). Discussion 18fluorocholine scanning can identify elusive parathyroid adenomas, including those that are ectopic, and is useful in the management of patients with persistent/recurrent primary hyperparathyroidism when first-line scans are negative. The grading of the arterial phase of computed tomography can help to differentiate between true adenomas and false positive targets (lymph nodes).

Objectives We recently described metabolic nodal stage (mN) and response (mNR) of cancer of the esophagus and gastro-esophageal junction (GEJ) to neoadjuvant chemotherapy (NAC) using 18F-FDG PET-CT as new markers of disease progression, recurrence, and death. We aimed to validate our findings. Methods Our validation cohort comprised all patients consecutive to our discovery cohort, staged before and after NAC using PET-CT from 2014 to 2017. Multivariate binary logistic and Cox regression were performed. Results Fifty-one of the 200 patients had FDG-avid nodes after NAC (25.5%; i.e., lack of complete mNR), and were more likely to progress during NAC to incurable disease on PET-CT or at surgery: odds ratio 3.84 (1.46–10.1; p = 0.006). In 176 patients undergoing successful resection, patients without complete mNR had a worse prognosis: disease-free survival hazard ratio 2.46 (1.34–4.50); p = 0.004. These associations were independent of primary tumor metabolic, pathological response, and stage. In a hybrid pathological/metabolic nodal stage, avid nodal metastases conferred a worse prognosis than non-avid metastases. Lack of complete mNR predicted recurrence or death at 1 and 2 years: positive predictive values 44.4% (31.7–57.8) and 74.1% (56.6–86.3) respectively. Conclusions This study provides temporal validation for mNR as a new and independent predictive and prognostic marker of esophageal and GEJ cancer treated with NAC and surgery, although external validation is required to assess generalizability. mNR may provide surrogate information regarding the phenotype of metastatic cancer clones beyond the mere presence of nodal metastases, and might be used to better inform patients, risk stratify, and personalize management, including adjuvant therapy. Key Points • We previously described metabolic nodal response (mNR) of esophageal cancer to neoadjuvant chemotherapy using 18 F-FDG PET-CT as a predictor of unresectable disease, early recurrence, and death. • We report the first validation of these findings. In an immediately consecutive cohort, we found consistent proportions of patients with and without mNR, and associations with abandoned resection, early recurrence, and death. • This supports mNR as a new and actionable biomarker in esophageal cancer. Although external validation is required, mNR may provide surrogate information about the chemosensitivity of metastatic subclones, and the means to predict treatment success, guide personalized therapy, and follow-up. Electronic supplementary material The online version of this article (10.1007/s00330-019-06310-9) contains supplementary material, which is available to authorized users.

Background We aimed to evaluate the clinical robustness of a commercially developed data-driven respiratory gating algorithm based on principal component analysis, for use in routine PET imaging. Methods One hundred fifty-seven adult FDG PET examinations comprising a total of 1149 acquired bed positions were used for the assessment. These data are representative of FDG scans currently performed at our institution. Data were acquired for 4 min/bed position (3 min/bed for legs). The data-driven gating (DDG) algorithm was applied to each bed position, including those where minimal respiratory motion was expected. The algorithm provided a signal-to-noise measure of respiratory-like frequencies within the data, denoted as R. Qualitative evaluation was performed by visual examination of the waveforms, with each waveform scored on a 3-point scale by two readers and then averaged (score S of 0 = no respiratory signal, 1 = some respiratory-like signal but indeterminate, 2 = acceptable signal considered to be respiratory). Images were reconstructed using quiescent period gating and compared with non-gated images reconstructed with a matched number of coincidences. If present, the SUVmax of a well-defined lesion in the thorax or abdomen was measured and compared between the two reconstructions. Results There was a strong (r = 0.86) and significant correlation between R and scores S. Eighty-six percent of waveforms with R ≥ 15 were scored as acceptable for respiratory gating. On average, there were 1.2 bed positions per patient examination with R ≥ 15. Waveforms with high R and S were found to originate from bed positions corresponding to the thorax and abdomen: 90% of waveforms with R ≥ 15 had bed centres in the range 5.6 cm superior to 27 cm inferior from the dome of the liver. For regions where respiratory motion was expected to be minimal, R tended to be ≺ 6 and S tended to be 0. The use of DDG significantly increased the SUVmax of focal lesions, by an average of 11% when considering lesions in bed positions with R ≥ 15. Conclusion The majority of waveforms with high R corresponded to the part of the patient where respiratory motion was expected. The waveforms were deemed suitable for respiratory gating when assessed visually, and when used were found to increase SUVmax in focal lesions.

Purpose To enhance the image quality of oncology [18F]-FDG PET scans acquired in shorter times and reconstructed by faster algorithms using deep neural networks. Methods List-mode data from 277 [18F]-FDG PET/CT scans, from six centres using GE Discovery PET/CT scanners, were split into ¾-, ½- and ¼-duration scans. Full-duration datasets were reconstructed using the convergent block sequential regularised expectation maximisation (BSREM) algorithm. Short-duration datasets were reconstructed with the faster OSEM algorithm. The 277 examinations were divided into training (n = 237), validation (n = 15) and testing (n = 25) sets. Three deep learning enhancement (DLE) models were trained to map full and partial-duration OSEM images into their target full-duration BSREM images. In addition to standardised uptake value (SUV) evaluations in lesions, liver and lungs, two experienced radiologists scored the quality of testing set images and BSREM in a blinded clinical reading (175 series). Results OSEM reconstructions demonstrated up to 22% difference in lesion SUVmax, for different scan durations, compared to full-duration BSREM. Application of the DLE models reduced this difference significantly for full-, ¾- and ½-duration scans, while simultaneously reducing the noise in the liver. The clinical reading showed that the standard DLE model with full- or ¾-duration scans provided an image quality substantially comparable to full-duration scans with BSREM reconstruction, yet in a shorter reconstruction time. Conclusion Deep learning–based image enhancement models may allow a reduction in scan time (or injected activity) by up to 50%, and can decrease reconstruction time to a third, while maintaining image quality. Supplementary Information The online version contains supplementary material available at 10.1007/s00259-021-05478-x.

Purpose Only 25% of oesophageal adenocarcinoma (OAC) patients have a pathological response to neo-adjuvant therapy (NAT) before oesophagectomy. Early response assessment using PET imaging may help guide management of these patients. We performed a systematic review and meta-analysis to synthesise the evidence detailing response rate and diagnostic accuracy of early PET-CT assessment. Methods We systematically searched several databases including MEDLINE and Embase. Studies with mixed cohorts of histology, tumour location and a repeat PET-CT assessment after more than one cycle of NAT were excluded. Reference standard was pathological response defined by Becker or Mandard classifications. Primary outcome was metabolic response rate after one cycle of NAT defined by a reduction in maximum standardised uptake value (SUVmax) of 35%. Secondary outcome was diagnostic accuracy of treatment response prediction, defined as the sensitivity and specificity of early PET-CT using this threshold. Quality of evidence was also assessed. Random-effects meta-analysis pooled response rates and diagnostic accuracy. This study was registered with PROSPERO (CRD42019147034). Results Overall, 1341 articles were screened, and 6 studies were eligible for analysis. These studies reported data for 518 patients (aged 27-78 years; 452 [87.3%] were men) between 2005 and 2020. Pooled sensitivity of early metabolic response to predict pathological response was 77.2% (95% CI 53.2%-100%). Significant heterogeneity existed between studies (I2 = 80.6% (95% CI 38.9%-93.8%), P = .006). Pooled specificity was 75.0% (95% CI 68.2%-82.5%), however, no significant heterogeneity between studies existed (I2 = 0.0% (95% CI 0.0%-67.4%), P = .73). Conclusion High-quality evidence is lacking, and few studies met the inclusion criteria of this systematic review. The sensitivity of PET using a SUVmax reduction threshold of 35% was suboptimal and varied widely. However, specificity was consistent across studies with a pooled value of 75.0%, suggesting early PET assessment is a better predictor of treatment resistance than of pathological response. Further research is required to define optimal PET-guided treatment decisions in OAC.

Objective: Pulmonary hypertension (PH) is an underdiagnosed condition associated with poor survival and increased post-operative mortality in lung cancer. CT-based parameters of pulmonary artery enlargement are strong predictors of PH. We used these parameters to investigate pulmonary artery enlargement in lung and oesophageal cancer. Methods: Consecutive patients with lung cancer (n = 100) or oesophageal cancer (n = 100) undergoing staging 18F-fluodeoxyglucose PET/CT were retrospectively identified. The transverse diameter of the main pulmonary artery (mPA) and ascending aorta, and the pulmonary artery-to-ascending aorta (PA:A) ratio were obtained. Abnormal values were defined following the Framingham Heart Study cohort. Results: Lung cancer patients had a significantly increased mPA diameter compared to the oesophageal cancer patients (males: 27.29 ± 0.39 vs. 25.88 ± 0.24 mm, females: 26.10 ± 0.28 vs. 24.45 ± 0.18 mm). Similarly, a significantly increased proportion of these patients had an abnormal mPA diameter (males: 35.1% vs 12.5%, females: 32.6% vs 10.7%). Lung cancer patients also had a significantly higher PA:A ratio (males: 0.83 ± 0.01 vs. 0.79 ± 0.008, females: 0.85 ± 0.01 vs. 0.79 ± 0.009), with a larger proportion having an abnormal PA:A ratio (males: 24.6% vs 11.1%, females: 27.9% vs 14.3%). Conclusion: Simple measurements of mPA diameter and PA:A ratio reveal that lung cancer patients exhibit increased rates of pulmonary artery enlargement compared to oesophageal cancer patients. Advances in knowledge: This study demonstrates there is an increased prevalence of pulmonary enlargement in lung cancer, easily detected on routine staging scans, holding implications for further work-up and risk stratification.

Background Patients with potentially curable oesophageal adenocarcinoma have a staging positron emission tomography (PET) examination combined with a computed tomography (CT) to assess loco-regional and distant disease. Although only 20-30% of patients are suitable for surgical resection, the majority receive neo-adjuvant therapy (chemotherapy with or without radiotherapy) before their operation. However, less than 25% experience any clinically meaningful benefit from the neo-adjuvant therapy. A repeat PET/CT after one cycle of treatment can assess for early metabolic response but remains exploratory. Patients without an early response could be offered alternative treatment strategies. The purpose of this systematic review and meta-analysis is to estimate the early response rate defined by PET/CT, its diagnostic accuracy and explore associated factors. Methods Primary studies reporting response rates and diagnostic accuracy of PET/CT will be identified from MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov databases. Peer-reviewed randomised control trials, observational cohort, cross-sectional and case-control studies reporting original response rate data, published from 2005 onwards will be included. Studies recruiting mixed cohorts and with PET/CT repeated after more than one neo-adjuvant treatment cycle will be excluded. The reference standard will be pathological response, defined by either validated Becker or Mandard tumour regression grade (TRG) classifications. The primary outcome will be metabolic response rate after one neo-adjuvant treatment cycle, defined by a reduction in maximum standardised uptake value (SUVmax) of 35%. Secondary outcome will be the sensitivity and specificity of early metabolic response to predict pathological response at this SUVmax reduction threshold. Pooled early response rate, sensitivity and specificity will be calculated using a random effects model with data extracted from selected studies. Heterogeneity between studies, risk of bias and methodological quality will be assessed. Discussion This systematic review and meta-analysis will identify and synthesise evidence to determine early response rates to neo-adjuvant therapies and the corresponding diagnostic accuracy of PET/CT to guide future clinical trials. This strategy could identify patients that will not respond to neo-adjuvant therapy and to offer this group alternative treatment strategies. Systematic review registration: PROSPERO (registration number CRD42019147034)

This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P

Despite its widespread value to molecular biology, the polymerase chain reaction (PCR) encounters modes that unproductively consume PCR resources and prevent clean signals, especially when high sensitivity, high SNP discrimination, and high multiplexing are sought. Here, we show how “self-avoiding molecular recognition systems” (SAMRS) manage such difficulties. SAMRS nucleobases pair with complementary nucleotides with strengths comparable to the A:T pair, but do not pair with other SAMRS nucleobases. This should allow primers holding SAMRS components to avoid primer–primer interactions, preventing primer dimers, allowing more sensitive SNP detection, and supporting higher levels of multiplex PCR. The experiments here examine the PCR performances of primers containing different numbers of SAMRS components placed strategically at different positions, and put these performances in the context of estimates of SAMRS:standard pairing strengths. The impact of these variables on primer dimer formation, the overall efficiency and sensitivity of SAMRS-based PCR, and the value of SAMRS primers when detecting single nucleotide polymorphisms (SNPs) are also evaluated. With appropriately chosen polymerases, SNP discrimination can be greater than the conventional allele-specific PCR, with the further benefit of avoiding primer dimer artifacts. General rules guiding the design of SAMRS-modified primers are offered to support medical research and clinical diagnostics products.

The authors report a case of diabetes insipidus (DI) associated with a ketamine infusion. A 42-year-old Asian man underwent an exploratory laparotomy and splenectomy who was admitted to the surgical intensive care unit (ICU) for postoperative management. Pain control was attempted with escalating dose of opioids but was inadequate, prompting the addition of a ketamine infusion. Shortly after initiation, a massive rise in urine output ensued in addition to a change in his urine electrolyte studies, leading to the diagnosis of drug-induced diabetes insipidus. Ketamine was discontinued, and treatment with subcutaneous desmopressin was initiated. Treatment was continued for a total of 5 days, which resulted in a resolution of his DI. This report suggests that the patient likely experienced a medication-induced DI, which was successfully resolved through proper identification of the causative agent, removal, and subsequent treatment with desmopressin. Causality assessment between ketamine and DI was determined using the Naranjo Adverse Drug Reaction Probability Scale-a total score of 7 was achieved and thus identified the adverse drug reaction as probable. Clinicians should be aware of the possibility that ketamine may be contributory in a patient with unexplained DI.

Described here are the synthesis, enzymology and some applications of a purine nucleoside analog (H) designed to have two tautomeric forms, one complementary to thymidine (T), the other complementary to cytidine (C). The performance of H is compared by various metrics to performances of other ‘biversal’ analogs that similarly rely on tautomerism to complement both pyrimidines. These include (i) the thermodynamic stability of duplexes that pair these biversals with various standard nucleotides, (ii) the ability of the biversals to support polymerase chain reaction (PCR), (iii) the ability of primers containing biversals to equally amplify targets having polymorphisms in the primer binding site, and (iv) the ability of ligation-based assays to exploit the biversals to detect medically relevant single nucleotide polymorphisms (SNPs) in sequences flanked by medically irrelevant polymorphisms. One advantage of H over the widely used inosine ‘universal base’ and ‘mixed sequence’ probes is seen in ligation-based assays to detect SNPs. The need to detect medically relevant SNPs within ambiguous sequences is especially important when probing RNA viruses, which rapidly mutate to create drug resistance, but also suffer neutral drift, the second obstructing simple methods to detect the first. Thus, H is being developed to detect variants of viruses that are rapidly mutating.

A study was performed to compare background liver signal-to-noise ratio (SNR) and visually assessed image quality of clinical PET/CT studies from the same PET acquisition data reconstructed by Bayesian penalized likelihood (BPL) and ordered subset expectation maximization (OSEM) over a range of patient weights.The effect of a BPL PET reconstruction algorithm on liver SNR and visually assessed image quality over a range of patient weights (41-196 kg; n = 108) was retrospectively compared with standard-of-care OSEM reconstruction on the same PET acquisition data after IV administration ofBPL showed no significant change (p0.05) in liver SNR with increasing weight and body mass index (BMI), whereas OSEM showed increasing noise with increasing weight and BMI. The liver SNR was significantly higher using BPL than a standard OSEM reconstruction (p0.0002 for all BMI groups). Visually assessed image quality declined at a greater rate with increasing weight and BMI in the OSEM images than with BPL images.BPL provides a more consistent visually assessed image quality and liver background SNR than does OSEM, with the greatest benefit for the heaviest patients.

Using a think aloud protocol, the interaction between motivation to fake and personality item characteristics (social desirability and face validity) on both response processes and self-ratings were studied under three instructional sets. The first study compared respond honestly to a fake-good instructional set, and results indicated that motivation to fake and item characteristics have interactive effects on both response processes and self-ratings. The second study replicated the first study using an applicant instructional set and results indicated that applicant response processes and self-ratings were more similar to the respond honestly instructional set than fake-good instructional set from study 1. However, there were meaningful differences between the applicant and respond honestly instructional sets. Results were discussed in relation to process models of faking, importance of considering item characteristics in all faking research, and practical implications related to the predictive accuracy of personality scales and detection of faking.

Early and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study,Men with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent