Hi Steve, wondering if this is a rebuild year?

Spring Training is imminent, Opening Day is within sight and the big league season isn't complete for fans without a subscription to MLB.TV. The most comprehensive streaming service in professional sports is now available for the 2019 season.

When you think of the D-backs, what players spring to mind? Luis Gonzalez, Randy Johnson, Paul Goldschmidt and Matt Williams are probably some of the names that arise. But what names are familiar to baseball fans but might have even some D-backs fans saying, "He was a Diamondback?"

The D-backs will open their 22nd Spring Training on Feb. 13 when pitchers and catchers go through their first workout. Here is all you need to know to be ready for the action.

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.

There will be a lot of attention paid to D-backs infielder Jake Lamb when Spring Training gets underway. Lamb, of course, is coming off a season that was almost entirely lost to a left shoulder injury. His healthy return would play a big part in helping the D-backs' offense overcome the departures of Paul Goldschmidt and A.J. Pollock during the offseason.

Fans and analysts spend the entire offseason speculating where the top free agents could go, but sometimes an under-the-radar pickup can end up making a world of difference. As positional competitions begin to heat up at Spring Training camps this month, MLB.com's beat writers were asked to identify one potentially overlooked acquisition for each of the 30 clubs. Here's who they came up with.

Here's an early look at how the D-backs' 25-man roster could shape up on Opening Day.

All 30 Major League teams will wear special "MLB 150" patches on their uniforms for the entire 2019 season in honor of the 150th anniversary of the 1869 Cincinnati Red Stockings, the first openly all-salaried professional baseball team.

The Arizona Diamondbacks agreed to terms with catcher Caleb Joseph on a one-year contract. To make room for Joseph on the roster, the D-backs placed right-hander Taijuan Walker on the 60-day injured list. The D-backs' 40-man roster remains at 40.

Yes, catcher Carson Kelly is new to the D-backs this spring, but this wasn't the first time he's gotten to see what the inside of Salt River Fields looks like.

Monday morning, D-backs manager Torey Lovullo will stand in front of his entire team prior to the first full-squad workout of the spring.

They've talked in small groups. They've talked in larger groups. The front office has discussed it. It's a topic that kept manager Torey Lovullo up at night at times. What in the world happened to the D-backs last September when they watched the National League West Division lead slip away during an 8-19 finish?

bmj;369/may07_6/m1803/FAF1faPhoto credit: Abbas GhazanfarOn 25 March Adil El-Tayar, a renowned organ transplantation specialist, became the first working NHS surgeon to die from covid-19 in hospital...

A rise in mortality is a price worth paying to restart the US economy, President Trump has said, as many states flout advice from scientists and reopen beaches, cinemas, or hair salons while new...

bmj;369/may07_9/m1832/FAF1faYara/ReutersThe meeting in Rome of Domenico di Massa with his granddaughter Cecilia for the first time in two months was echoed across Italy as families emerged onto the...

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.

¹⁶⁶Ho-microspheres have recently been approved for clinical use for hepatic radioembolization in the European Union. The aim of this study was to investigate the absorbed dose–response relationship and its association with overall survival for ¹⁶⁶Ho radioembolization in patients with liver metastases. Methods: Patients treated in the HEPAR I and II studies who underwent an ¹⁸F-FDG PET/CT scan at baseline, a posttreatment ¹⁶⁶Ho SPECT/CT scan, and another ¹⁸F-FDG PET/CT scan at the 3-mo follow-up were included for analysis. The posttreatment ¹⁶⁶Ho-microsphere activity distributions were estimated with quantitative SPECT/CT reconstructions using a quantitative Monte Carlo–based method. The response of each tumor was based on the change in total lesion glycolysis (TLG) between baseline and follow-up and was placed into 1 of 4 categories, according to the PERCIST criteria, ranging from complete response to progressive disease. Patient-level response was grouped according to the average change in TLG per patient. The absorbed dose–response relationship was assessed using a linear mixed model to account for correlation of tumors within patients. Median overall survival was compared between patients with and without a metabolic liver response, using a log-rank test. Results: Thirty-six patients with a total of 98 tumors were included. The relation between tumor-absorbed dose and both tumor-level and patient-level response was explored. At a tumor level, a significant difference in geometric mean absorbed dose was found between complete response (232 Gy; 95% confidence interval [CI], 178–303 Gy; n = 32) and stable disease (147 Gy; 95% CI, 113–191 Gy; n = 28) (P = 0.01) and between complete response and progressive disease (117 Gy; 95% CI, 87–159 Gy; n = 21) (P = 0.0008). This constitutes a robust absorbed dose–response relationship. At a patient level, a significant difference was found between patients with complete or partial response (210 Gy; 95% CI, 161–274 Gy; n = 13) and patients with progressive disease (116 Gy; 95% CI, 81–165 Gy; n = 9) (P = 0.01). Patients were subsequently grouped according to their average change in TLG. Patients with an objective response (complete or partial) exhibited a significantly higher overall survival than nonresponding patients (stable or progressive disease) (median, 19 mo vs. 7.5 mo; log-rank, P = 0.01). Conclusion: These results confirm a significant absorbed dose–response relationship in ¹⁶⁶Ho radioembolization. Treatment response is associated with a higher overall survival.

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.

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.

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.

Our objective was to determine the diagnostic capabilities of combined prostate-specific membrane antigen (PSMA) PET/CT and sentinel node (SN) biopsy in PSMA PET/CT–negative patients for primary lymph node (LN) staging in prostate cancer (PCa) patients. Methods: Between January 2017 and March 2019, retrospectively, all consecutive patients with diagnosed intermediate- or high-risk primary PCa who underwent preoperative PSMA PET/CT (⁶⁸Ga or ¹⁸F-DCFPyL) followed by robot-assisted radical prostatectomy and extended pelvic LN dissection (ePLND) were included. All patients without suspected LN metastases on PSMA PET/CT were considered candidates for SN biopsy with indocyanine green–^99mTc-nanocolloid or ^99mTc-nanocolloid with free indocyanine green used as tracers. The ePLND was used as a reference standard. Results: Of 53 patients, 22 had positive PSMA PET/CT results and 31 underwent subsequent SN biopsy after negative PSMA PET/CT results. In total, 23 patients (43%) were pN1, of whom 6 (26%) had negative PSMA PET/CT results and underwent subsequent SN biopsy. The combined use of SN biopsy and PSMA PET/CT identified all pN1 patients (100% sensitivity; 95% confidence interval, 86%–100%) and performed correct nodal staging in 50 of 53 patients (94% diagnostic accuracy; 95% confidence interval, 84%–99%). SN biopsy identified significantly smaller LN metastases (median diameter, 2.0 mm; interquartile range, 1.0–3.8 mm) than PSMA PET/CT (median diameter, 5.5 mm; interquartile range, 2.6–9.3 mm; P = 0.007). Conclusion: Combining both modalities led to a 94% accuracy for nodal staging in diagnosed intermediate- and high-risk primary PCa. Adding SN biopsy in patients with negative PSMA PET/CT results increased the combined sensitivity to 100% for detecting nodal metastases at ePLND. This diagnostic accuracy may provide valuable information for directing further treatment in PCa patients, such as the use of PSMA PET/CT and SN biopsy rather than ePLND as the preferred approach for staging before radiotherapy.

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.

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog ¹⁷⁷Lu-DOTA-(d-Glu)₆-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH₂ (¹⁷⁷Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (~80 μg) of ¹⁷⁷Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of ¹⁷⁷Lu-PP-F11N to assess safety. Results: In all patients, ¹⁷⁷Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85–1.04), 0.42 (IQR: 0.25–1.01), 0.11 (IQR: 0.07–0.13), and 0.028 (IQR: 0.026–0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11–14.4) without SG and 13.0 (IQR: 10.2–18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14–4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: ¹⁷⁷Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, ¹⁷⁷Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of ¹⁷⁷Lu-PP-F11N.

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.

Continuous glucose monitor (CGM) readings are delayed relative to blood glucose, and this delay is usually attributed to the latency of interstitial glucose levels. However, CGM-independent data suggest rapid equilibration of interstitial glucose. This study sought to determine the loci of CGM delays. Electrical current was measured directly from CGM electrodes to define sensor kinetics in the absence of smoothing algorithms. CGMs were implanted in mice, and sensor versus blood glucose responses were measured after an intravenous glucose challenge. Dispersion of a fluorescent glucose analog (2-NBDG) into the CGM microenvironment was observed in vivo using intravital microscopy. Tissue deposited on the sensor and nonimplanted subcutaneous adipose tissue was then collected for histological analysis. The time to half-maximum CGM response in vitro was 35 ± 2 s. In vivo, CGMs took 24 ± 7 min to reach maximum current versus 2 ± 1 min to maximum blood glucose (P = 0.0017). 2-NBDG took 21 ± 7 min to reach maximum fluorescence at the sensor versus 6 ± 6 min in adipose tissue (P = 0.0011). Collagen content was closely correlated with 2-NBDG latency (R = 0.96, P = 0.0004). Diffusion of glucose into the tissue deposited on a CGM is substantially delayed relative to interstitial fluid. A CGM that resists fibrous encapsulation would better approximate real-time deviations in blood glucose.

Optimal immune-based therapies for type 1 diabetes (T1D) should restore self-tolerance without inducing chronic immunosuppression. CD4⁺Foxp3⁺ regulatory T cells (T_regs) are a key cell population capable of facilitating durable immune tolerance. However, clinical trials with expanded T_regs in T1D and solid-organ transplant recipients are limited by poor T_reg engraftment without host manipulation. We showed that T_reg engraftment and therapeutic benefit in nonautoimmune models required ablative host conditioning. Here, we evaluated T_reg engraftment and therapeutic efficacy in the nonobese diabetic (NOD) mouse model of autoimmune diabetes using nonablative, combinatorial regimens involving the anti-CD3 (αCD3), cyclophosphamide (CyP), and IAC (IL-2/JES6–1) antibody complex. We demonstrate that αCD3 alone induced substantial T-cell depletion, impacting both conventional T cells (T_conv) and T_regs, subsequently followed by more rapid rebound of T_regs. Despite robust depletion of host T_conv and host T_regs, donor T_regs failed to engraft even with interleukin-2 (IL-2) support. A single dose of CyP after αCD3 depleted rebounding host T_regs and resulted in a 43-fold increase in donor T_reg engraftment, yet polyclonal donor T_regs failed to reverse diabetes. However, infusion of autoantigen-specific T_regs after αCD3 alone resulted in robust T_reg engraftment within the islets and induced remission in all mice. This novel combinatorial therapy promotes engraftment of autoantigen-specific donor T_regs and controls islet autoimmunity without long-term immunosuppression.

M2 macrophages play an important role in tissue repair and regeneration. They have also been found to modulate β-cell replication in mouse models of pancreatic injury and disease. We previously reported that β-cell replication is strongly increased in a subgroup of human organ donors characterized by prolonged duration of stay in an intensive care unit (ICU) and increased number of leukocytes in the pancreatic tissue. In the present study we investigated the relationship between duration of stay in the ICU, M2 macrophages, vascularization, and pancreatic cell replication. Pancreatic organs from 50 donors without diabetes with different durations of stay in the ICU were analyzed by immunostaining and digital image analysis. The number of CD68⁺CD206⁺ M2 macrophages increased three- to sixfold from ≥6 days’ duration of stay in the ICU onwards. This was accompanied by a threefold increased vascular density and a four- to ninefold increase in pancreatic cells positive for the replication marker Ki67. A strong correlation was observed between the number of M2 macrophages and β-cell replication. These results show that a prolonged duration of stay in the ICU is associated with an increased M2 macrophage number, increased vascular density, and an overall increase in replication of all pancreatic cell types. Our data show evidence of marked levels of tissue repair in the human donor pancreas.

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.

β-Cell antigen recognition by autoreactive T cells is essential in type 1 diabetes (T1D) pathogenesis. Recently, insulin hybrid peptides (HIPs) were identified as strong agonists for CD4 diabetogenic T cells. Here, using BDC2.5 transgenic and NOD mice, we investigated T-cell recognition of the HIP2.5 epitope, which is a fusion of insulin C-peptide and chromogranin A (ChgA) fragments, and compared it with the WE14 and ChgA_29–42 epitopes. We measured in situ two-dimensional affinity on individual live T cells from thymus, spleen, pancreatic lymph nodes, and islets before and after diabetes. Although preselection BDC2.5 thymocytes possess higher affinity than splenic BDC2.5 T cells for all three epitopes, peripheral splenic T cells maintained high affinity only to the HIP2.5 epitope. In polyclonal NOD mice, a high frequency (~40%) of HIP2.5-specific islet T cells were identified at both prediabetic and diabetic stages comprising two distinct high- and low-affinity populations that differed in affinity by 100-fold. This high frequency of high- and low-affinity HIP2.5 T cells in the islets potentially represents a major risk factor in diabetes pathogenesis.

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

Autoimmunity against pancreatic β-cell autoantigens is a characteristic of childhood type 1 diabetes (T1D). Autoimmunity usually appears in genetically susceptible children with the development of autoantibodies against (pro)insulin in early childhood. The offspring of mothers with T1D are protected from this process. The aim of this study was to determine whether the protection conferred by maternal T1D is associated with improved neonatal tolerance against (pro)insulin. Consistent with improved neonatal tolerance, the offspring of mothers with T1D had reduced cord blood CD4⁺ T-cell responses to proinsulin and insulin, a reduction in the inflammatory profile of their proinsulin-responsive CD4⁺ T cells, and improved regulation of CD4⁺ T cell responses to proinsulin at 9 months of age, as compared with offspring with a father or sibling with T1D. Maternal T1D was also associated with a modest reduction in CpG methylation of the INS gene in cord blood mononuclear cells from offspring with a susceptible INS genotype. Our findings support the concept that a maternal T1D environment improves neonatal immune tolerance against the autoantigen (pro)insulin.