Diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body diagnostic CT and MRI in the detection of spinal bone metastases associated with pheochromocytoma and paraganglioma.

OBJECTIVE: To compare the diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body CT and MRI for the detection of pheochromocytoma/paraganglioma (PPGL)-related spinal bone metastases. MATERIALS AND METHODS: Between 2014 and 2020, PPGL participants with spinal bone metastases prospectively underwent [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the cervical-thoracolumbar spine (MRIspine), contrast-enhanced MRI of the neck and thoraco-abdominopelvic regions (MRIWB), and contrast-enhanced CT of the neck and thoraco-abdominopelvic regions (CTWB). Per-patient and per-lesion detection rates were calculated. Counting of spinal bone metastases was limited to a maximum of one lesion per vertebrae. A composite of all functional and anatomic imaging served as an imaging comparator. The McNemar test compared detection rates between the scans. Two-sided p values were reported. RESULTS: Forty-three consecutive participants (mean age, 41.7 ± 15.7 years; females, 22) with MRIspine were included who also underwent [68Ga]DOTATATE PET/CT (n = 43), [18F]FDG PET/CT (n = 43), MRIWB (n = 24), and CTWB (n = 33). Forty-one of 43 participants were positive for spinal bone metastases, with 382 lesions on the imaging comparator. [68Ga]DOTATATE PET/CT demonstrated a per-lesion detection rate of 377/382 (98.7%) which was superior compared to [18F]FDG (72.0%, 275/382, p < 0.001), MRIspine (80.6%, 308/382, p < 0.001), MRIWB (55.3%, 136/246, p < 0.001), and CTWB (44.8%, 132/295, p < 0.001). The per-patient detection rate of [68Ga]DOTATATE PET/CT was 41/41 (100%) which was higher compared to [18F]FDG PET/CT (90.2%, 37/41, p = 0.13), MRIspine (97.6%, 40/41, p = 1.00), MRIWB (95.7%, 22/23, p = 1.00), and CTWB (81.8%, 27/33, p = 0.03). CONCLUSIONS: [68Ga]DOTATATE PET/CT should be the modality of choice in PPGL-related spinal bone metastases due to its superior detection rate. CLINICAL RELEVANCE STATEMENT: In a prospective study of 43 pheochromocytoma/paraganglioma participants with spinal bone metastases, [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% (377/382), compared to [18F]FDG PET/CT (p < 0.001), MRI of the spine (p < 0.001), whole-body CT (p < 0.001), and whole-body MRI (p < 0.001). KEY POINTS: • Data regarding head-to-head comparison between functional and anatomic imaging modalities to detect spinal bone metastases in pheochromocytoma/paraganglioma are limited. • [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% in the detection of spinal bone metastases associated with pheochromocytoma/paraganglioma compared to other imaging modalities: [18]F-FDG PET/CT, MRI of the spine, whole-body CT, and whole-body MRI. • [68Ga]DOTATATE PET/CT should be the modality of choice in the evaluation of spinal bone metastases associated with pheochromocytoma/paraganglioma.

First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 3-year efficacy and safety results from the phase III CheckMate 649 trial. Patients with previously untreated advanced or metastatic gastroesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy. Primary end points were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients whose tumors expressed PD-L1 combined positive score (CPS) ≥5. With 36.2-month minimum follow-up, for patients with PD-L1 CPS ≥5, the OS hazard ratio (HR) for nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI, 0.61 to 0.81); 21% versus 10% of patients were alive at 36 months, respectively; the PFS HR was 0.70 (95% CI, 0.60 to 0.81); 36-month PFS rates were 13% versus 8%, respectively. The objective response rate (ORR) per BICR was 60% (95% CI, 55 to 65) with nivolumab plus chemotherapy versus 45% (95% CI, 40 to 50) with chemotherapy; median duration of response was 9.6 months (95% CI, 8.2 to 12.4) versus 7.0 months (95% CI, 5.6 to 7.9), respectively. Nivolumab plus chemotherapy also continued to show improvement in OS, PFS, and ORR versus chemotherapy in the overall population. Adding nivolumab to chemotherapy maintained clinically meaningful long-term survival benefit versus chemotherapy alone, with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastroesophageal adenocarcinoma.

Performance of capsule endoscopy for the detection of small intestinal neuroendocrine tumors in familial carcinoid: a prospective single-site study.

BACKGROUND AND AIMS: Small-bowel neuroendocrine tumors (NETs) are slow growing, clinically silent tumors whose prognosis depends on disease stage. Members of kindreds with a familial form of small intestinal NETs (SI-NETs) represent a high-risk population for whom early detection improves disease outcome. Our aim was to determine the utility of small-bowel capsule endoscopy (SB-CE) for screening high-risk asymptomatic relatives from kindreds with familial carcinoid. METHODS: One hundred seventy-four asymptomatic subjects with a family history (≥2 family members) of SI-NETs were screened under Protocol NCT00646022, Natural History of Familial Carcinoid Tumor at the National Institutes of Health. All patients were imaged with SB-CE and 18fluoro-dihydroxphenylalanine (18F-DOPA) positron emission tomography (PET)/CT, and results were independently analyzed. Patients with a positive imaging study underwent surgical exploration. RESULTS: Thirty-five of 174 asymptomatic subjects screened for SI-NETs were positive on either SB-CE or 18F-DOPA PET. Thirty-two of 35 patients with a positive study were confirmed at surgery. SB-CE was positive in 28 of 32 patients with confirmed tumors for a per-patient sensitivity of 87.5%. SB-CE had a specificity of 97.3% and a negative predictive value of 96.5%. The average tumor number and size were 7.7 and 5.0 mm, respectively, and 81.2% of patients had multiple tumors. 18F-DOPA PET/CT had a similar sensitivity of 84% versus surgery. CONCLUSIONS: SB-CE is a sensitive and specific method comparable with 18F-DOPA PET/CT for screening high-risk patients with familial SI-NET. (Clinical trial registration number: NCT00646022.).

The effect of exercise on blood concentrations of angiogenesis markers in older adults: A systematic review and meta-analysis.

Impaired angiogenesis is associated with cognitive decline in older adults. While exercise has been broadly associated with increased angiogenesis, the relevant mechanisms in older adults are not clear. Here, we present a systematic review and meta-analysis on the relationship between exercise and specific blood angiogenesis markers in older adults to better understand the relevant mechanisms. MEDLINE, Embase, and Cochrane CENTRAL were searched for original reports of angiogenesis markers' concentrations in blood before and after exercise in older adults (≥50 years). Heterogeneity was investigated using sub-group analyses and meta-regressions. Of the 44 articles included in the review, 38 were included in the meta-analyses for five markers: vascular endothelial growth factor (VEGF), e-selectin (CD62E), endostatin, fibroblast growth factor 2, and matrix metallopeptidase-9. VEGF levels were higher (SMD[95%CI]= 0.18[0.03, 0.34], and CD62E levels were lower (SMD[95%CI]= -0.72[-1.42, -0.03], p = 0.04) after exercise. No other markers were altered. Although more studies are needed, changes in angiogenesis markers may help explain the beneficial effects of exercise on angiogenesis in older adults.

Dex-Benchmark: datasets and code to evaluate algorithms for transcriptomics data analysis.

Many tools and algorithms are available for analyzing transcriptomics data. These include algorithms for performing sequence alignment, data normalization and imputation, clustering, identifying differentially expressed genes, and performing gene set enrichment analysis. To make the best choice about which tools to use, objective benchmarks can be developed to compare the quality of different algorithms to extract biological knowledge maximally and accurately from these data. The Dexamethasone Benchmark (Dex-Benchmark) resource aims to fill this need by providing the community with datasets and code templates for benchmarking different gene expression analysis tools and algorithms. The resource provides access to a collection of curated RNA-seq, L1000, and ChIP-seq data from dexamethasone treatment as well as genetic perturbations of its known targets. In addition, the website provides Jupyter Notebooks that use these pre-processed curated datasets to demonstrate how to benchmark the different steps in gene expression analysis. By comparing two independent data sources and data types with some expected concordance, we can assess which tools and algorithms best recover such associations. To demonstrate the usefulness of the resource for discovering novel drug targets, we applied it to optimize data processing strategies for the chemical perturbations and CRISPR single gene knockouts from the L1000 transcriptomics data from the Library of Integrated Network Cellular Signatures (LINCS) program, with a focus on understudied proteins from the Illuminating the Druggable Genome (IDG) program. Overall, the Dex-Benchmark resource can be utilized to assess the quality of transcriptomics and other related bioinformatics data analysis workflows. The resource is available from: https://maayanlab.github.io/dex-benchmark.

Endoscopic Ultrasound Guided Shear Wave Elastography Is Safe With High Feasibility and Reproducibility When Used in the Pancreas: Findings From a Prospective Cohort.

OBJECTIVES: The aim of this study was to assess the safety, feasibility, and reproducibility of endoscopic ultrasound shear wave elastography (EUS-SWE) in the pancreas. METHODS: This is a prospective registry of consecutive patients undergoing clinically indicated EUS. Ten readings of SWE velocities (Vs [distance/time, m/s]) were obtained in the head (HOP), body, and tail of pancreas to quantify tissue stiffness. Each Vs score was accompanied by a reliability measurement VsN (%) with VsN >50% considered reliable. Safety was evaluated by perioperative complications rate. Feasibility was determined by technical success of obtaining measurements. Reproducibility was evaluated using intraclass correlation coefficient analysis. RESULTS: Total of 3320 EUS-SWE measurements were performed on 117 patients without perioperative complications. Measurement success rate was 100% across all locations. Reliable measurements were more common in the HOP (953/1120 [85.1%]) followed by body (853/1130 [75.5%]) and tail of pancreas (687/1070 [64.2%]) (P < 0.001). The analysis showed good reproducibility in all locations (intraclass correlation coefficient range, 0.80-0.89). CONCLUSIONS: Endoscopic ultrasound-SWE is safe, has 100% technical success rate, and is highly reproducible when used in the pancreas. Our study suggests that SWE measurements in the HOP offer the highest reliability, likely because of large study area and less respiratory artifact.

Multimodal analgesia did not improve post-operative pain scores, reduce opioid consumption or reduce length of stay following hip arthroscopy.

PURPOSE: To determine whether different regimens of multimodal analgesia will reduce postoperative pain scores, opioid consumption, costs and hospital length-of-stay following hip arthroscopy. METHODS: From 2018 to 2021, 132 patients undergoing hip arthroscopy for femoroacetabular impingement syndrome (FAIS) were included in this prospective, single-center randomized controlled trial. Patients were randomized into four treatment groups: (1) Group 1-Control: opioid medication (oxycodone-acetaminophen 5 mg/325 mg, 1-2 tabs q6H as needed), Heterotopic ossification prophylaxis-Naprosyn 500 mg twice daily × 3 weeks); (2) Group 2-Control + postoperative sleeping aid (Zopiclone 7.5 mg nightly × 7 days); (3) Group 3-Control + preoperative and postoperative Gabapentin (600 mg orally, 1 h preoperatively; 600 mg postoperatively, 8 h following pre-op dose); (4) Group 4-Control + pre-medicate with Celecoxib (400 mg orally, 1 h preoperatively) The primary outcome was pain measured with a visual analog scale, monitored daily for the first week and every other day for 6 weeks. Secondary outcomes included opioid consumption, healthcare resource use, and hospital length of stay. RESULTS: Patient characteristics were similar between groups. There were no statistically significant differences in pain scores between groups at any timepoint after adjusting for intra-operative traction time, intra-operative opioid administration and preoperative pain scores (p > 0.05). There were also no significant differences in the number of days that opioids were taken (n.s.) and the average daily morphine milligram equivalents consumed (n.s.). Similarly, there were no statistically significant differences in length of stay in the experimental groups, compared with the control group (n.s.). Finally, there were no differences in cost between groups (n.s.). CONCLUSION: The routine use of Zopiclone, Celecoxib and Gabapentin did not improve postoperative pain control or reduce length-of-stay following hip arthroscopy. Therefore, these medications are not recommended for routine postoperative pain control following hip arthroscopy. LEVEL OF EVIDENCE: l.

Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

BACKGROUND: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive. METHODS: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors. RESULTS: Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001). DISCUSSION: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer's disease while considering the burden on the healthcare system.

Venetoclax plus azacitidine compared with intensive chemotherapy as induction for patients with acute myeloid leukemia: retrospective analysis of an electronic medical record database in the United States.

Intensive chemotherapy (IC) is commonly used to achieve remission in patients with acute myeloid leukemia (AML). Venetoclax plus azacitidine (VEN-AZA) is FDA-approved to treat patients with AML aged ≥ 75 years or who are ineligible for IC. This retrospective analysis used de-identified electronic health records from the US-based Flatiron Health database from patients diagnosed 11/21/2018 to 10/31/2021 to compare treatment outcomes with VEN-AZA vs. IC. Patients were 1:1 propensity score-matched ([Formula: see text]). Assessments included rates of complete remission (CR) and hematopoietic stem cell transplant (HSCT), overall survival (OS), and relapse-free survival (RFS). CR and HSCT rates were higher with IC than with VEN-AZA (60.9% vs. 44.2% [P = 0.006] and 18.1% vs. 8.0% [P = 0.012], respectively). Median OS was 17.7 months in patients treated with IC and 11.3 months with VEN-AZA without censoring (P = 0.278) and 13.7 vs. 10.6 months, respectively, with censoring at HSCT (P = 0.584). Median RFS was 12.0 months in patients treated with IC vs. 9.5 months with VEN-AZA without censoring (P = 0.431) and 6.4 vs. 7.4 months, respectively, with censoring at HSCT (P = 0.444). No OS or RFS differences observed between the two arms reached statistical significance. Randomized controlled trials comparing the two approaches are warranted, as are novel approaches to reduce relapse rates following CR.

The effect of exercise on blood concentrations of angiogenesis markers in older adults: a systematic review and meta-analysis.

Background: Physical exercise has positive impacts on health and can improve angiogenesis, which is impaired during aging, but the underlying mechanisms of benefit are unclear. This meta-analysis and systematic review investigated the effects of exercise on several peripheral angiogenesis markers in older adults to better understand the relationship between exercise and angiogenesis. Methods: MEDLINE, Embase, and Cochrane CENTRAL were searched for original, peer-reviewed reports of peripheral concentrations of angiogenesis markers before and after exercise interventions in older adults (> 50 years). The risk of bias was assessed with standardized criteria. Standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated from random-effects models. Publication bias was assessed with Egger's test, funnel plots, and trim-and-fill. A priori subgroup analyses and meta-regressions were performed to investigate heterogeneity where possible. Results: Of the 44 articles included in the review, 38 were included in meta-analyses for five proteins. Vascular endothelial growth factor (VEGF) was found to be higher after exercise (SMD[95%CI] = 0.18[0.03, 0.34], p = 0.02), and e-selectin (CD62E) was found to be lower after exercise (SMD[95%CI]= -0.72[-1.42, -0.03], p = 0.04). Endostatin (SMD[95%CI] = 0.28[-0.56, 1.11], p = 0.5), fibroblast growth factor 2 (SMD[95%CI] = 0.03[-0.18, 0.23], p = 0.8), and matrix metallopeptidase-9 (SMD[95%CI] = -0.26[-0.97, 0.45], p = 0.5) levels did not change after exercise. Conclusions: Of the five angiogenesis blood markers evaluated in this meta-analysis, only VEGF and CD62E changed with exercise. Although more studies are needed, changes in angiogenesis markers may explain the beneficial effects of exercise on angiogenesis and health in older adults.

Performances of Functional and Anatomic Imaging Modalities in Succinate Dehydrogenase A-Related Metastatic Pheochromocytoma and Paraganglioma.

The study identifies the importance of positron emission tomographic (PET) and anatomic imaging modalities and their individual performances in detecting succinate dehydrogenase A (SDHA)-related metastatic pheochromocytoma and paraganglioma (PPGL). The detection rates of PET modalities-68Ga-DOTATATE, 18F-FDG, and 18F-FDOPA-along with the combination of computed tomography (CT) and magnetic resonance imaging (MRI) are compared in a cohort of 11 patients with metastatic PPGL in the setting of a germline SDHA mutation. The imaging detection performances were evaluated at three levels: overall lesions, anatomic regions, and a patient-by-patient basis. 68Ga-DOTATATE PET demonstrated a lesion-based detection rate of 88.6% [95% confidence interval (CI), 84.3-92.5%], while 18F-FDG, 18F-FDOPA, and CT/MRI showed detection rates of 82.9% (CI, 78.0-87.1%), 39.8% (CI, 30.2-50.2%), and 58.2% (CI, 52.0-64.1%), respectively. The study found that 68Ga-DOTATATE best detects lesions in a subset of patients with SDHA-related metastatic PPGL. However, 18F-FDG did detect more lesions in the liver, mediastinum, and abdomen/pelvis anatomic regions, showing the importance of a combined approach using both PET modalities in evaluating SDHA-related PPGL.

Cannabis and cocaine use, drinking outcomes, and quality of life in general hospital inpatients with alcohol use disorder.

Background: While associations between cannabis and cocaine use, and heavy drinking and quality of life (QOL), are well-established in the general population, it is unclear whether they are present in hospital inpatients with alcohol use disorder (AUD). The aim of the study was to assess associations between cannabis and cocaine use and two outcomes [heavy drinking days (HDDs) and QOL] among hospital inpatients with AUD. Methods: Hospitalized patients with AUD and at least one past-month HDD participated in this cross-sectional study. Cannabis and cocaine use were assessed using the Alcohol, Smoking, and Substance Involvement Screening Test. HDDs were assessed using the Timeline Followback. QOL was assessed by the WHOQOL-BREF instrument. Multivariable regression models assessed associations. Results: Of 248 participants, 225 (91%) had severe AUD. There were no statistically significant associations between: recent cannabis use and HDDs [Incidence Rate Ratio (IRR) = 0.95; 95% Confidence Interval (95% CI): 0.80, 1.14], cocaine use and HDDs [IRR = 0.88; 95% CI: 0.66, 1.18], or both cannabis and cocaine use and HDDs [IRR = 0.87; 95%CI: 0.70, 1.09], as compared to use of neither cannabis nor cocaine. Use of cannabis, cocaine, and both, were not associated with QOL [(odds ratio (OR) = 0.98; 95% CI:0.55, 1.74), (OR = 0.76; 95% CI:0.30, 1.93), (OR = 1.00; 95%CI: 0.49, 2.03), respectively]. Conclusions: Among hospital inpatients with AUD, there were no significant associations between cannabis and cocaine use, heavy drinking, or QOL. Our findings raise questions regarding how drug use affects AUD and whether similar results would be found among those with milder AUD and in prospective studies.

Altered central and blood glutathione in Alzheimer's disease and mild cognitive impairment: a meta-analysis.

BACKGROUND: Increasing evidence implicates oxidative stress (OS) in Alzheimer disease (AD) and mild cognitive impairment (MCI). Depletion of the brain antioxidant glutathione (GSH) may be important in OS-mediated neurodegeneration, though studies of post-mortem brain GSH changes in AD have been inconclusive. Recent in vivo measurements of the brain and blood GSH may shed light on GSH changes earlier in the disease. AIM: To quantitatively review in vivo GSH in AD and MCI compared to healthy controls (HC) using meta-analyses. METHOD: Studies with in vivo brain or blood GSH levels in MCI or AD with a HC group were identified using MEDLINE, PsychInfo, and Embase (1947-June 2020). Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. Outcome measures included brain GSH (Meshcher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) versus non-MEGA-PRESS) and blood GSH (intracellular versus extracellular) in AD and MCI. The Q statistic and Egger's test were used to assess heterogeneity and risk of publication bias, respectively. RESULTS: For brain GSH, 4 AD (AD=135, HC=223) and 4 MCI (MCI=213, HC=211) studies were included. For blood GSH, 26 AD (AD=1203, HC=1135) and 7 MCI (MCI=434, HC=408) studies were included. Brain GSH overall did not differ in AD or MCI compared to HC; however, the subgroup of studies using MEGA-PRESS reported lower brain GSH in AD (SMD [95%CI] -1.45 [-1.83, -1.06], p<0.001) and MCI (-1.15 [-1.71, -0.59], z=4.0, p<0.001). AD had lower intracellular and extracellular blood GSH overall (-0.87 [-1. 30, -0.44], z=3.96, p<0.001). In a subgroup analysis, intracellular GSH was lower in MCI (-0.66 [-1.11, -0.21], p=0.025). Heterogeneity was observed throughout (I2 >85%) and not fully accounted by subgroup analysis. Egger's test indicated risk of publication bias. CONCLUSION: Blood intracellular GSH decrease is seen in MCI, while both intra- and extracellular decreases were seen in AD. Brain GSH is decreased in AD and MCI in subgroup analysis. Potential bias and heterogeneity suggest the need for measurement standardization and additional studies to explore sources of heterogeneity.

Sporadic Primary Pheochromocytoma: A Prospective Intraindividual Comparison of Six Imaging Tests (CT, MRI, and PET/CT Using 68Ga-DOTATATE, FDG, 18F-FDOPA, and 18F-FDA).

BACKGROUND. Recent professional society guidelines for radionuclide imaging of sporadic pheochromocytoma (PHEO) recommend 18F-fluorodihydroxyphenylala-nine (18F-FDOPA) as the radiotracer of choice, deeming 68Ga-DOTATATE and FDG to be second- and third-line agents, respectively. An additional agent, 18F-fluorodopamine (18F-FDA), remains experimental for PHEO detection. A paucity of research has performed head-to-head comparison among these agents. OBJECTIVE. The purpose of this study was to perform an intraindividual comparison of 68Ga-DOTATATE PET/CT, FDG PET/CT, 18F-FDOPA PET/CT, 18F-FDA PET/CT, CT, and MRI in visualization of sporadic primary PHEO. METHODS. This prospective study enrolled patients referred with clinical suspicion for sporadic PHEO. Patients were scheduled for 68Ga-DOTATATE PET/CT, FDG PET/CT, 18F-FDOPA PET/CT, 18F-FDA PET/CT, whole-body staging CT (portal venous phase), and MRI within a 3-month period. PET/CT examinations were reviewed by two nuclear medicine physicians, and CT and MRI were reviewed by two radiologists; differences were resolved by consensus. Readers scored lesions in terms of confidence in diagnosis of PHEO (1-5 scale; 4-5 considered positive for PHEO). Lesion-to-liver SUVmax was computed using both readers' measurements. Interreader agreement was assessed using intraclass correlation coefficients (ICCs) for SUVmax. Analysis included only patients with histologically confirmed PHEO on resection. RESULTS. The analysis included 14 patients (eight women, six men; mean age, 52.4 ± 16.8 [SD] years) with PHEO. Both 68Ga-DOTATATE PET/CT and FDG PET/CT were completed in all 14 patients, 18F-FDOPA PET/CT in 11, 18F-FDA PET/CT in 7, CT in 12, and MRI in 12. Mean conspicuity score for PHEO was 5.0 ± 0.0 for 18F-FDOPA PET/CT, 4.7 ± 0.5 for MRI, 4.6 ± 0.8 for 18F-FDA PET/CT, 4.4 ± 1.0 for 68Ga-DOTATATE PET/CT, 4.3 ± 1.0 for CT, and 4.1 ± 1.5 for FDG PET/CT. The positivity rate for PHEO was 100.0% (11/11) for 18F-FDOPA PET/CT, 100.0% (12/12) for MRI, 85.7% (6/7) for 18F-FDA PET/CT, 78.6% (11/14) for FDG PET/CT, 78.6% (11/14) for 68Ga-DOTATATE PET/CT, and 66.7% (8/12) for CT. Lesion-to-liver SUVmax was 10.5 for 18F-FDOPA versus 3.0-4.2 for the other tracers. Interreader agreement across modalities ranged from 85.7% to 100.0% for lesion positivity with ICCs of 0.55-1.00 for SUVmax measurements. CONCLUSION. Findings from this small intraindividual comparative study support 18F-FDOPA PET/CT as a preferred first-line imaging modality in evaluation of sporadic PHEO. CLINICAL IMPACT. This study provides data supporting current guidelines for imaging evaluation of suspected PHEO. TRIAL REGISTRATION. ClinicalTrials.gov NCT00004847.

Prognostic Value of Cardiac Axis Deviation in Systemic Sclerosis-Related Pulmonary Hypertension.

OBJECTIVE: Systemic sclerosis-related pulmonary hypertension (SSc-PH) is a common complication of SSc associated with accelerated mortality. The present study was undertaken to investigate whether cardiac axis deviation indicates abnormalities in cardiac function allowing for prognostication of disease severity and mortality. METHODS: This was a retrospective study in which electrocardiograms (ECGs) were reviewed for cardiac axis deviation and their association with echocardiography and cardiopulmonary hemodynamics on right-sided heart catheterization. The primary outcome observed was all-cause mortality from the time of PH diagnosis. RESULTS: ECG results were reviewed from 169 patients with SSc-PH. Right axis deviation (RAD) and left axis deviation (LAD) occurred in 28.4% and 30.8% of patients with SSc-PH, respectively. Compared to those without RAD, patients with RAD exhibited predominantly right-sided cardiac disease on echocardiography and increased PH severity by cardiopulmonary hemodynamics including a greater mean ± SD pulmonary artery pressure (42.0 ± 12.5 mm Hg versus 29.8 ± 7.0 mm Hg) and mean ± SD pulmonary vascular resistance (645.6 ± 443.2 dynes · seconds/cm5 versus 286.3 ± 167.7 dynes · seconds/cm5 ). LAD was associated with predominantly left-sided cardiac disease on echocardiography but was not associated with PH severity on cardiopulmonary hemodynamics. Both RAD (hazard ratio 10.36 [95% confidence interval 4.90-21.93], P < 0.001) and LAD (hazard ratio 2.94 [95% confidence interval 1.53-5.68], P = 0.001) were associated with an increased hazard for all-cause mortality. CONCLUSION: RAD and LAD reflect structural cardiac abnormalities and are associated with poor prognosis in patients with SSc-PH. These findings support the importance of electrocardiography, an inexpensive, widely available noninvasive test, in risk stratification.

A systematic literature review of disease burden and clinical efficacy for patients with relapsed or refractory acute myeloid leukemia.

Acute myeloid leukemia (AML) is a rapidly progressive hematological malignancy that is difficult to cure. The prognosis is poor and treatment options are limited in case of relapse. A comprehensive assessment of current disease burden and the clinical efficacy of non-intensive therapies in this population are lacking. We conducted two systematic literature reviews (SLRs). The first SLR (disease burden) included observational studies reporting the incidence and economic and humanistic burden of relapsed/refractory (RR) AML. The second SLR (clinical efficacy) included clinical trials (phase II or later) reporting remission rates (complete remission [CR] or CR with incomplete hematologic recovery [CRi]) and median overall survival (mOS) in patients with RR AML or patients with de novo AML who are ineligible for intensive chemotherapy. For both SLRs, MEDLINE®/Embase® were searched from January 1, 2008 to January 31, 2020. Clinical trial registries were also searched for the clinical efficacy SLR. After screening, two independent reviewers determined the eligibility for inclusion in the SLRs based on full-text articles. The disease burden SLR identified 130 observational studies. The median cumulative incidence of relapse was 29.4% after stem cell transplant and 46.8% after induction chemotherapy. Total per-patient-per-month costs were $28,148-$29,322; costs and health care resource use were typically higher for RR versus non-RR patients. Patients with RR AML had worse health-related quality of life (HRQoL) scores than patients with de novo AML across multiple instruments, and lower health utility values versus other AML health states (i.e. newly diagnosed, remission, consolidation, and maintenance therapy). The clinical efficacy SLR identified 50 trials (66 total trial arms). CR/CRi rates and mOS have remained relatively stable and low over the last 2 decades. Across all arms, the median rate of CR/CRi was 18.3% and mOS was 6.2 months. In conclusion, a substantial proportion of patients with AML will develop RR AML, which is associated with significant humanistic and economic burden. Existing treatments offer limited efficacy, highlighting the need for more effective non-intensive treatment options.

Systemic Radiopharmaceutical Therapy of Pheochromocytoma and Paraganglioma.

Whereas benign pheochromocytomas and paragangliomas are often successfully cured by surgical resection, treatment of metastatic disease can be challenging in terms of both disease control and symptom control. Fortunately, several options are available, including chemotherapy, radiation therapy, and surgical debulking. Radiolabeled metaiodobenzylguanidine (MIBG) and somatostatin receptor imaging have laid the groundwork for use of these radiopharmaceuticals as theranostic agents. 131I-MIBG therapy of neuroendocrine tumors has a long history, and the recent approval of high-specific-activity 131I-MIBG for metastatic or inoperable pheochromocytoma or paraganglioma by the U.S. Food and Drug Administration has resulted in general availability of, and renewed interest in, this treatment. Although reports of peptide receptor radionuclide therapy of pheochromocytoma and paraganglioma with 90Y- or 177Lu-DOTA conjugated somatostatin analogs have appeared in the literature, the approval of 177Lu-DOTATATE in the United States and Europe, together with National Comprehensive Cancer Network guidelines suggesting its use in patients with metastatic or inoperable pheochromocytoma and paraganglioma, has resulted in renewed interest. These agents have shown evidence of efficacy as palliative treatments in patients with metastatic or inoperable pheochromocytoma or paraganglioma. In this continuing medical education article, we discuss the therapy of pheochromocytoma and paraganglioma with 131I-MIBG and 90Y- or 177Lu-DOTA-somatostatin analogs.

Autocrine GMCSF Signaling Contributes to Growth of HER2+ Breast Leptomeningeal Carcinomatosis.

Leptomeningeal carcinomatosis (LC) occurs when tumor cells spread to the cerebrospinal fluid-containing leptomeninges surrounding the brain and spinal cord. LC is an ominous complication of cancer with a dire prognosis. Although any malignancy can spread to the leptomeninges, breast cancer, particularly the HER2+ subtype, is its most common origin. HER2+ breast LC (HER2+ LC) remains incurable, with few treatment options, and the molecular mechanisms underlying proliferation of HER2+ breast cancer cells in the acellular, protein, and cytokine-poor leptomeningeal environment remain elusive. Therefore, we sought to characterize signaling pathways that drive HER2+ LC development as well as those that restrict its growth to leptomeninges. Primary HER2+ LC patient-derived ("Lepto") cell lines in coculture with various central nervous system (CNS) cell types revealed that oligodendrocyte progenitor cells (OPC), the largest population of dividing cells in the CNS, inhibited HER2+ LC growth in vitro and in vivo, thereby limiting the spread of HER2+ LC beyond the leptomeninges. Cytokine array-based analyses identified Lepto cell-secreted GMCSF as an oncogenic autocrine driver of HER2+ LC growth. LC/MS-MS-based analyses revealed that the OPC-derived protein TPP1 proteolytically degrades GMCSF, decreasing GMCSF signaling and leading to suppression of HER2+ LC growth and limiting its spread. Finally, intrathecal delivery of neutralizing anti-GMCSF antibodies and a pan-Aurora kinase inhibitor (CCT137690) synergistically inhibited GMCSF and suppressed activity of GMCSF effectors, reducing HER2+ LC growth in vivo. Thus, OPC suppress GMCSF-driven growth of HER2+ LC in the leptomeningeal environment, providing a potential targetable axis. SIGNIFICANCE: This study characterizes molecular mechanisms that drive HER2+ leptomeningeal carcinomatosis and demonstrates the efficacy of anti-GMCSF antibodies and pan-Aurora kinase inhibitors against this disease.