27 June 2017

Policymakers must take action immediately to mitigate the risk of severe disruption at certain ports, maritime straits, and inland transport routes, which could have devastating knock-on effects for global food security.

• Trade chokepoints – maritime, coastal and inland – pose an underexplored and growing risk to global food security.
• Maritime chokepoints will become increasingly integral to meeting global food supply as population growth, shifting dietary preferences, bioenergy expansion and slowing improvements in crop yields drive up demand for imported grain.
• Rising trade volumes, increasing dependence on imports among food-deficit countries, underinvestment, weak governance, climate change and emerging disruptive hazards together make chokepoint disruptions – both small-scale and large-scale – increasingly likely.
• Climate change will have a compounding effect on chokepoint risk, increasing the probability of both isolated and multiple concurrent weather-induced disturbances.
• Investment in infrastructure lags demand growth: critical networks in major crop-producing regions are weak and ageing, and extra capacity is urgently needed. 

The D-backs signed veteran free-agent reliever Greg Holland to a one-year contract on Thursday.

With Greg Holland now signed, will he be the closer or is that still going to be Archie Bradley? Beat reporter Steve Gilbert answers this question and more from fans as Spring Training approaches.

Intravenous access is difficult in some patients referred for ¹⁸F-FDG PET imaging. Extravasation at the injection site and accumulation in central catheters can lead to limited tumor ¹⁸F-FDG uptake, erroneous quantitation, and significant image artifacts. In this study, we compared the human biodistribution and dosimetry for ¹⁸F-FDG after oral and intravenous administrations sequentially in the same subjects to ascertain the dosimetry and potential suitability of orally administered ¹⁸F-FDG as an alternative to intravenous administration. We also compared our detailed intravenous ¹⁸F-FDG dosimetry with older dosimetry data. Methods: Nine healthy volunteers (6 male and 3 female; aged 19–32 y) underwent PET/CT imaging after oral and intravenous administration of ¹⁸F-FDG. Identical preparation and imaging protocols (except administration route) were used for oral and intravenous studies. During each imaging session, 9 whole-body PET scans were obtained at 5, 10, 20, 30, 40, 50, 60, 120, and 240 min after ¹⁸F-FDG administration (370 ± 16 MBq). Source organ contours drawn using CT were overlaid onto registered PET images to extract time–activity curves. Time-integrated activity coefficients derived from time–activity curves were given as input to OLINDA/EXM for dose calculations. Results: Blood uptake after orally administered ¹⁸F-FDG peaked at 45–50 min after ingestion. The oral-to-intravenous ratios of ¹⁸F-FDG uptake for major organs at 45 min were 1.07 ± 0.24 for blood, 0.94 ± 0.39 for heart wall, 0.47 ± 0.12 for brain, 1.25 ± 0.18 for liver, and 0.84 ± 0.24 for kidneys. The highest organ-absorbed doses (μGy/MBq) after oral ¹⁸F-FDG administration were observed for urinary bladder (75.9 ± 17.2), stomach (48.4 ± 14.3), and brain (29.4 ± 5.1), and the effective dose was significantly higher (20%) than after intravenous administration (P = 0.002). Conclusion: ¹⁸F-FDG has excellent bioavailability after oral administration, but peak organ activities occur later than after intravenous injection. These data suggest PET at 2 h after oral ¹⁸F-FDG administration should yield images that are comparable in biodistribution to conventional clinical images acquired 1 h after injection. Oral ¹⁸F-FDG is a palatable alternative to intravenous ¹⁸F-FDG when venous access is problematic.

Neuroinflammation is important in amyotrophic lateral sclerosis (ALS). The P2X7 receptor (P2X7R) is a promising target for neuroinflammation. The objective of this study was to compare ¹⁸F-DPA714, a second-generation translocator protein tracer, with ¹¹C-JNJ717, a novel P2X7R tracer, in vitro and in vivo in ALS. Methods: For the in vitro portion of the study, autoradiography with ¹⁸F-DPA714 and ¹¹C-JNJ717 was performed on human ALS brain sections in comparison to immunofluorescence with Iba1 and GFAP. For the in vivo portion, 3 male patients with early-stage ALS (59.3 ± 7.2 y old) and 6 healthy volunteers (48.2 ± 16.5 y old, 2 men and 4 women) underwent dynamic PET/MR scanning with ¹⁸F-DPA714 and ¹¹C-JNJ717. Volume-of-distribution images were calculated using Logan plots and analyzed on a volume-of-interest basis. Results: Autoradiography showed no difference in ¹¹C-JNJ717 binding but did show increased ¹⁸F-DPA714 binding in the motor cortex correlating with Iba1 expression (glial cells). Similar findings were observed in vivo, with a 13% increase in ¹⁸F-DPA714 binding in the motor cortex. Conclusion: In symptomatic ALS patients, ¹⁸F-DPA714 showed increased signal whereas ¹¹C-JNJ717 was not elevated.

The present study examined the predictive values of amyloid PET, ¹⁸F-FDG PET, and nonimaging predictors (alone and in combination) for development of Alzheimer dementia (AD) in a large population of patients with mild cognitive impairment (MCI). Methods: The study included 319 patients with MCI from the Alzheimer Disease Neuroimaging Initiative database. In a derivation dataset (n = 159), the following Cox proportional-hazards models were constructed, each adjusted for age and sex: amyloid PET using ¹⁸F-florbetapir (pattern expression score of an amyloid-β AD conversion–related pattern, constructed by principle-components analysis); ¹⁸F-FDG PET (pattern expression score of a previously defined ¹⁸F-FDG–based AD conversion–related pattern, constructed by principle-components analysis); nonimaging (functional activities questionnaire, apolipoprotein E, and mini-mental state examination score); ¹⁸F-FDG PET + amyloid PET; amyloid PET + nonimaging; ¹⁸F-FDG PET + nonimaging; and amyloid PET + ¹⁸F-FDG PET + nonimaging. In a second step, the results of Cox regressions were applied to a validation dataset (n = 160) to stratify subjects according to the predicted conversion risk. Results: On the basis of the independent validation dataset, the ¹⁸F-FDG PET model yielded a significantly higher predictive value than the amyloid PET model. However, both were inferior to the nonimaging model and were significantly improved by the addition of nonimaging variables. The best prediction accuracy was reached by combining ¹⁸F-FDG PET, amyloid PET, and nonimaging variables. The combined model yielded 5-y free-of-conversion rates of 100%, 64%, and 24% for the low-, medium- and high-risk groups, respectively. Conclusion: ¹⁸F-FDG PET, amyloid PET, and nonimaging variables represent complementary predictors of conversion from MCI to AD. Especially in combination, they enable an accurate stratification of patients according to their conversion risks, which is of great interest for patient care and clinical trials.

Inflammation contributes to ventricular remodeling after myocardial ischemia, but its role in nonischemic heart failure is poorly understood. Local tissue inflammation is difficult to assess serially during pathogenesis. Although ¹⁸F-FDG accumulates in inflammatory leukocytes and thus may identify inflammation in the myocardial microenvironment, it remains unclear whether this imaging technique can isolate diffuse leukocytes in pressure-overload heart failure. We aimed to evaluate whether inflammation with ¹⁸F-FDG can be serially imaged in the early stages of pressure-overload–induced heart failure and to compare the time course with functional impairment assessed by cardiac MRI. Methods: C57Bl6/N mice underwent transverse aortic constriction (TAC) (n = 22), sham surgery (n = 12), or coronary ligation as an inflammation-positive control (n = 5). MRI assessed ventricular geometry and contractile function at 2 and 8 d after TAC. Immunostaining identified the extent of inflammatory leukocyte infiltration early in pressure overload. ¹⁸F-FDG PET scans were acquired at 3 and 7 d after TAC, under ketamine-xylazine anesthesia to suppress cardiomyocyte glucose uptake. Results: Pressure overload evoked rapid left ventricular dilation compared with sham (end-systolic volume, day 2: 40.6 ± 10.2 μL vs. 23.8 ± 1.7 μL, P < 0.001). Contractile function was similarly impaired (ejection fraction, day 2: 40.9% ± 9.7% vs. 59.2% ± 4.4%, P < 0.001). The severity of contractile impairment was proportional to histology-defined myocardial macrophage density on day 8 (r = –0.669, P = 0.010). PET imaging identified significantly higher left ventricular ¹⁸F-FDG accumulation in TAC mice than in sham mice on day 3 (10.5 ± 4.1 percentage injected dose [%ID]/g vs. 3.8 ± 0.9 %ID/g, P < 0.001) and on day 7 (7.8 ± 3.7 %ID/g vs. 3.0 ± 0.8 %ID/g, P = 0.006), though the efficiency of cardiomyocyte suppression was variable among TAC mice. The ¹⁸F-FDG signal correlated with ejection fraction (r = –0.75, P = 0.01) and ventricular volume (r = 0.75, P < 0.01). Western immunoblotting demonstrated a 60% elevation of myocardial glucose transporter 4 expression in the left ventricle at 8 d after TAC, indicating altered glucose metabolism. Conclusion: TAC induces rapid changes in left ventricular geometry and contractile function, with a parallel modest infiltration of inflammatory macrophages. Metabolic remodeling overshadows inflammatory leukocyte signal using ¹⁸F-FDG PET imaging. More selective inflammatory tracers are requisite to identify the diffuse local inflammation in pressure overload.

We aimed to assess the value of ¹¹C-choline PET in patients with primary hyperparathyroidism and negative or discordant results on ^99mTc-sestamibi imaging and neck ultrasound. Methods: Eighty-seven such patients were assessed and subsequently underwent parathyroidectomy. PET/CT image data were analyzed semiquantitatively using SUV_max and SUV ratios (target to contralateral thyroid gland and carotid artery). A positive PET/CT result was defined as focal uptake significantly higher than regular thyroid tissue. Ectopic foci were also considered positive. Inconclusive PET/CT cases were defined as a lesion with uptake equal to normal thyroid tissue. If no prominent or ectopic uptake was detectable, the PET/CT result was considered negative. Results: When dichotomizing the ¹¹C-choline PET/CT imaging results by defining lesions with both positive and inconclusive uptake as positive, we found 84 of 92 lesions (91.3%) to have true-positive uptake whereas 8 lesions (8.7%) had false-positive uptake. One lesion showed false-negative uptake; the sensitivity was 98.8%. The corresponding positive predictive value for lesions was 91.3%. The mean SUV_max was 6.15 ± 4.92 in 72 lesions with positive uptake (70 patients) and 2.96 ± 2.32 in 20 lesions with inconclusive uptake (18 patients). Conclusion: These results in a large group of patients indicate that ¹¹C-choline PET/CT is a promising tool for parathyroid adenoma localization when ultrasound and ^99mTc-sestamibi imaging yield negative or discordant results.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, definitive treatment usually requiring surgical removal of the offending parathyroid glands. To perform focused surgical approaches, it is necessary to localize all hyperfunctioning glands. The aim of the study was to compare the efficiency of established conventional scintigraphic imaging modalities with emerging ¹⁸F-fluorocholine PET/CT imaging in preoperative localization of hyperfunctioning parathyroid glands in a larger series of PHPT patients. Methods: In total, 103 patients with PHPT were imaged preoperatively with ¹⁸F-fluorocholine PET/CT and conventional scintigraphic imaging methods, consisting of ^99mTc-sestamibi SPECT/CT, ^99mTc-sestamibi/pertechnetate subtraction imaging, and ^99mTc-sestamibi dual-phase imaging. The results of histologic analysis, as well as intact parathyroid hormone and serum calcium values obtained 1 d after surgery and on follow-up, served as the standard of truth for evaluation of imaging results. Results: Diagnostic performance of ¹⁸F-fluorocholine PET/CT surpassed conventional scintigraphic methods (separately or combined), with calculated sensitivity of 92% for PET/CT and 39%–56% for conventional imaging (65% for conventional methods combined) in the entire patient group. Subgroup analysis, differentiating single and multiple hyperfunctioning parathyroid glands, showed PET/CT to be most valuable in the group with multiple hyperfunctioning glands, with sensitivity of 88%, whereas conventional imaging was significantly inferior, with sensitivity of 22%–34% (44% combined). Conclusion: ¹⁸F-fluorocholine PET/CT is a diagnostic modality superior to conventional imaging methods in patients with PHPT, allowing for accurate preoperative localization.

Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D₂ and D₃ receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (¹¹C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14–30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20–30 min; spleen as reference region) demonstrated a statistically significant reduction (–36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20–30 min) (R² = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20–30 min) (R² = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20–30 min) (R² = 0.57, P = 0.05), nor did mean baseline proinsulin (R² = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D₃ receptor and dopamine D₂ receptor in HCs. No colocalization of the dopamine D₃ receptor or dopamine D₂ receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D₃ receptor, dopamine D₂ receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D₃ receptor and dopamine D₂ receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for ¹¹C-(+)-PHNO, a dopamine D₃ receptor–preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, ⁶⁴Cu (half-life, 12.7 h) and ²²⁵Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of ⁶⁴Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of ⁶⁸Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, ²²⁵Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of ⁶⁴Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of ⁶⁴Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for ⁶⁴Cu-FAPI-04 than for ⁶⁸Ga-FAPI-04, except in the heart, and excretion in the urine was higher for ⁶⁸Ga-FAPI-04 than for ⁶⁴Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. ²²⁵Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that ⁶⁴Cu-FAPI-04 and ²²⁵Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

¹⁸F-DCFPyL (2-(3-{1-carboxy-5-[(6-¹⁸F-fluoropyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) is a promising PET radiopharmaceutical targeting prostate-specific membrane antigen (PSMA). We present our experience with this single-academic-center prospective study evaluating the positivity rate of ¹⁸F-DCFPyL PET/CT in patients with biochemical recurrence (BCR) of prostate cancer (PC). Methods: We prospectively enrolled 72 men (52–91 y old; mean ± SD, 71.5 ± 7.2) with BCR after primary definitive treatment with prostatectomy (n = 42) or radiotherapy (n = 30). The presence of lesions compatible with PC was evaluated by 2 independent readers. Fifty-nine patients had scans concurrent with at least one other conventional scan: bone scanning (24), CT (21), MR (20), ¹⁸F-fluciclovine PET/CT (18), or ¹⁸F-NaF PET (14). Findings from ¹⁸F-DCFPyL PET/CT were compared with those from other modalities. Impact on patient management based on ¹⁸F-DCFPyL PET/CT was recorded from clinical chart review. Results: ¹⁸F-DCFPyL PET/CT had an overall positivity rate of 85%, which increased with higher prostate-specific antigen (PSA) levels (ng/mL): 50% (PSA < 0.5), 69% (0.5 ≤ PSA < 1), 100% (1 ≤ PSA < 2), 91% (2 ≤ PSA < 5), and 96% (PSA ≥ 5). ¹⁸F-DCFPyL PET detected more lesions than conventional imaging. For anatomic imaging, 20 of 41 (49%) CT or MRI scans had findings congruent with ¹⁸F-DCFPyL, whereas ¹⁸F-DCFPyL PET was positive in 17 of 41 (41%) cases with negative CT or MRI findings. For bone imaging, 26 of 38 (68%) bone or ¹⁸F-NaF PET scans were congruent with ¹⁸F-DCFPyL PET, whereas ¹⁸F-DCFPyL PET localized bone lesions in 8 of 38 (21%) patients with negative results on bone or ¹⁸F-NaF PET scans. In 8 of 18 (44%) patients, ¹⁸F-fluciclovine PET had located the same lesions as did ¹⁸F-DCFPyL PET, whereas 5 of 18 (28%) patients with negative ¹⁸F-fluciclovine findings had positive ¹⁸F-DCFPyL PET findings and 1 of 18 (6%) patients with negative ¹⁸F-DCFPyL findings had uptake in the prostate bed on ¹⁸F-fluciclovine PET. In the remaining 4 of 18 (22%) patients, ¹⁸F-DCFPyL and ¹⁸F-fluciclovine scans showed different lesions. Lastly, 43 of 72 (60%) patients had treatment changes after ¹⁸F-DCFPyL PET and, most noticeably, 17 of these patients (24% total) had lesion localization only on ¹⁸F-DCFPyL PET, despite negative results on conventional imaging. Conclusion: ¹⁸F-DCFPyL PET/CT is a promising diagnostic tool in the work-up of biochemically recurrent PC, given the high positivity rate as compared with Food and Drug Administration–approved currently available imaging modalities and its impact on clinical management in 60% of patients.

PET using radiolabeled prostate-specific membrane antigen (PSMA) is now being more widely adopted as a valuable tool to evaluate patients with prostate cancer (PC). Recently, 3 different criteria for interpretation of PSMA PET were published: the European Association of Nuclear Medicine (EANM) criteria, the Prostate Cancer Molecular Imaging Standardized Evaluation criteria, and the PSMA Reporting and Data System. We compared these 3 criteria in terms of interreader, intrareader, and intercriteria agreement. Methods: Data from 104 patients prospectively enrolled in research protocols at our institution were retrospectively reviewed. The cohort consisted of 2 groups: 47 patients (mean age, 64.2 y old) who underwent Glu-NH-CO-NH-Lys-(Ahx)-[⁶⁸Ga(HBED-CC)] (⁶⁸Ga-PSMA11) PET/MRI for initial staging of biopsy-proven intermediate- or high-risk PC, and 57 patients (mean age, 70.5 y old) who underwent ⁶⁸Ga-PSMA11 PET/CT because of biochemically recurrent PC. Three nuclear medicine physicians independently evaluated all ⁶⁸Ga-PSMA11 PET/MRI and PET/CT studies according to the 3 interpretation criteria. Two of them reevaluated all studies 6 mo later in the same manner and masked to the initial reading. The Gwet agreement coefficient was calculated to evaluate interreader, intrareader, and intercriteria agreement based on the following sites: local lesion (primary tumor or prostate bed after radical prostatectomy), lymph node metastases, and other metastases. Results: In the PET/MRI group, interreader, intrareader, and intercriteria agreement ranged from substantial to almost perfect for any site according to all 3 criteria. In the PET/CT group, interreader agreement ranged from substantial to almost perfect except for judgment of distant metastases based on the PSMA Reporting and Data System (Gwet agreement coefficient, 0.57; moderate agreement), in which the most frequent cause of disagreement was lung nodules. Intrareader agreement ranged from substantial to almost perfect for any site according to all 3 criteria. Intercriteria agreement for each site was also substantial to almost perfect. Conclusion: Although the 3 published criteria have good interreader and intrareader reproducibility in evaluating ⁶⁸Ga-PSMA11 PET, there are some factors causing interreader disagreement. Further work is needed to address this issue.

¹⁸F-PSMA-1007 is a novel prostate-specific membrane antigen (PSMA)–based radiopharmaceutical for imaging prostate cancer (PCa). The aim of this study was to compare the diagnostic accuracy of ¹⁸F-PSMA-1007 with ⁶⁸Ga-PSMA-11 PET/CT in the same patients presenting with newly diagnosed intermediate- or high-risk PCa. Methods: Sixteen patients with intermediate- or high-risk PCa underwent ¹⁸F-PSMA-1007 and ⁶⁸Ga-PSMA-11 PET/CT within 15 d. PET findings were compared between the 2 radiotracers and with reference-standard pathologic specimens obtained from radical prostatectomy. The Cohen -coefficient was used to assess the concordance between ¹⁸F-PSMA-1007 and ⁶⁸Ga-PSMA-11 for detection of intraprostatic lesions. The McNemar test was used to assess agreement between intraprostatic PET/CT findings and histopathologic findings. Sensitivity, specificity, positive predictive value, and negative predictive value were reported for each radiotracer. SUV_max was measured for all lesions, and tumor-to-background activity was calculated. Areas under receiver-operating-characteristic curves were calculated for discriminating diseased from nondiseased prostate segments, and optimal SUV cutoffs were calculated using the Youden index for each radiotracer. Results: PSMA-avid lesions in the prostate were identified in all 16 patients with an almost perfect concordance between the 2 tracers ( ranged from 0.871 to 1). Aside from the dominant intraprostatic lesion, similarly detected by both radiotracers, a second less intense positive focus was detected in 4 patients only with ¹⁸F-PSMA-1007. Three of these secondary foci were confirmed as Gleason grade 3 lesions, whereas the fourth was shown on pathologic examination to represent chronic prostatitis. Conclusion: This pilot study showed that both ¹⁸F-PSMA-1007 and ⁶⁸Ga-PSMA-11 identify all dominant prostatic lesions in patients with intermediate- or high-risk PCa at staging. ¹⁸F-PSMA-1007, however, may detect additional low-grade lesions of limited clinical relevance.

Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of ⁸⁹Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of ⁸⁹Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1–2, 6–8, 24, 48, and 96–144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results: ⁸⁹Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time–activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24–48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most ⁸⁹Zr-IAB22M2C–positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion: ⁸⁹Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell–rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.

Posttreatment high-grade gliomas are usually monitored with contrast-enhanced MRI, but its diagnostic accuracy is limited as it cannot adequately distinguish between true tumor progression and treatment-related changes. According to recent Response Assessment in Neuro-Oncology recommendations, PET overcomes this limitation. However, it is currently unknown which tracer yields the best results. Therefore, a systematic review and metaanalysis were performed to compare the diagnostic accuracy of the different PET tracers in differentiating tumor progression from treatment-related changes in high-grade glioma patients. Methods: PubMed, Web of Science, and Embase were searched systematically. Study selection, data extraction, and quality assessment were performed independently by 2 authors. Metaanalysis was performed using a bivariate random-effects model when at least 5 studies were included. Results: The systematic review included 39 studies (11 tracers). ¹⁸F-FDG (12 studies, 171 lesions) showed a pooled sensitivity and specificity of 84% (95% confidence interval, 72%–92%) and 84% (95% confidence interval, 69%–93%), respectively. O-(2-¹⁸F-fluoroethyl)-l-tyrosine (¹⁸F-FET) (7 studies, 172 lesions) demonstrated a sensitivity of 90% (95% confidence interval, 81%–95%) and specificity of 85% (95% confidence interval, 71%–93%). For S-¹¹C-methyl)-l-methionine (¹¹C-MET) (8 studies, 151 lesions), sensitivity was 93% (95% confidence interval, 80%–98%) and specificity was 82% (95% confidence interval, 68%–91%). The numbers of included studies for the other tracers were too low to combine, but sensitivity and specificity ranged between 93%–100% and 0%–100%, respectively, for ¹⁸F-FLT; 85%–100% and 72%–100%, respectively, for 3,4-dihydroxy-6-¹⁸F-fluoro-l-phenylalanine (¹⁸F-FDOPA); and 100% and 70%–88%, respectively, for ¹¹C-choline. Conclusion: ¹⁸F-FET and ¹¹C-MET, both amino-acid tracers, showed a comparably higher sensitivity than ¹⁸F-FDG in the differentiation between tumor progression and treatment-related changes in high-grade glioma patients. The evidence for other tracers is limited; thus, ¹⁸F-FET and ¹¹C-MET are preferred when available. Our results support the incorporation of amino-acid PET tracers for the treatment evaluation of high-grade gliomas.

The University of Iowa recently completed a 4-y expedition into the uncharted waters of the Food and Drug Administration (FDA) new-drug application (NDA) process that ultimately resulted in approval of ⁶⁸Ga-DOTATOC in August 2019. The journey was enlightening, revealing a highly structured, arcane, but rigorous regulatory approval process. The FDA proved to be an efficient, reasonable, and communicative regulatory body that achieved balance between support of the initiative and its mission-bound, process-bound duty to ensure that the application met the expected safety and efficacy standards of the agency. With several clinically valuable PET radiopharmaceuticals without intellectual property residing in regulatory limbo, without industry champions to bring them to marketing approval, there may be justification for a more concerted effort from the molecular imaging community into generating better understanding, support, and perhaps even infrastructure for the academic NDA. As a first step, this article briefly describes the start-to-finish story for ⁶⁸Ga-DOTATOC, including a description of the clinical trials, a broad overview of the structured content of the NDA document, and the distilled experiences associated with the ⁶⁸Ga-DOTATOC NDA process. It is anticipated that with sustained free sharing of information relating to the FDA drug registration process, it will prove less daunting and more efficient in future academically sponsored NDA filings for PET imaging agents.

Type 1 diabetes is an autoimmune-mediated disease that culminates in the targeted destruction of insulin-producing β-cells. CD4 responses in NOD mice are dominated by insulin epitope B:9-23 (InsB_9-23) specificity, and mutation of the key T-cell receptor (TCR) contact residue within the epitope prevents diabetes development. However, it is not clear how insulin self-antigen controls the selection of autoimmune and regulatory T cells (Tregs). Here we demonstrate that mutation of insulin epitope results in escape of highly pathogenic T cells. We observe an increase in antigen reactivity, clonality, and pathogenicity of insulin-specific T cells that develop in the absence of cognate antigen. Using a single TCR system, we demonstrate that Treg development is greatly diminished in mice with the Y16A mutant epitope. Collectively, these results suggest that the tyrosine residue at position 16 is necessary to constrain TCR reactivity for InsB_9-23 by both limiting the development of pathogenic T cells and supporting the selection of Tregs.

OP-CONTRIBUTION: EMPLOYMENT CONTRACTS The COVID-19 pandemic is hitting businesses and the economy in a manner perhaps not seen since the Second World War. This, of course, has affected the ability of employers to pay their employees. The COVID-19...

FOUR MORE applicants are vying to provide mobile payment services in various formats, including one applicant seeking to use phone credit as a cash equivalent, but successful applicants will fall under a new framework the regulator calls its “...

The Jamaica Stock Exchange (JSE) Combined Index continued its mild rally on Thursday with an advance/decline ratio of 38/27 The index advanced marginally 2,427.05 points or 0.67 per cent to close at 364,908.47. The JSE Main Market Index was up 2,...

Members Event

Event participants

Rory Stewart, Member of Parliament for Penrith and The Border (2010-19); Secretary of State for International Development (2019)

Chair: Daniel Bruce, Chief Executive, Transparency International UK

Members Event

Event participants

Katrín Jakobsdóttir, Prime Minister, Iceland
Chair: Professor Tim Benton, Director, Energy Environment and Resources Department, Chatham House
 

Invitation Only Research Event

Event participants

Professor Philippe Sands QC, Professor of Law, UCL 
Richard Burt, Managing Partner, McLarty Associates
Chair: Dr Leslie Vinjamuri, Director, US and Americas Programme; Dean, Queen Elizabeth II Academy, Chatham House