Clinical trial links oncolytic immunoactivation to survival in glioblastoma.

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).

Computational drug discovery for castration-resistant prostate cancers through in vitro drug response modeling.

Prostate cancer (PC) is the most frequently diagnosed malignancy and a leading cause of cancer deaths in US men. Many PC cases metastasize and develop resistance to systemic hormonal therapy, a stage known as castration-resistant prostate cancer (CRPC). Therefore, there is an urgent need to develop effective therapeutic strategies for CRPC. Traditional drug discovery pipelines require significant time and capital input, which highlights a need for novel methods to evaluate the repositioning potential of existing drugs. Here, we present a computational framework to predict drug sensitivities of clinical CRPC tumors to various existing compounds and identify treatment options with high potential for clinical impact. We applied this method to a CRPC patient cohort and nominated drugs to combat resistance to hormonal therapies including abiraterone and enzalutamide. The utility of this method was demonstrated by nomination of multiple drugs that are currently undergoing clinical trials for CRPC. Additionally, this method identified the tetracycline derivative COL-3, for which we validated higher efficacy in an isogenic cell line model of enzalutamide-resistant vs. enzalutamide-sensitive CRPC. In enzalutamide-resistant CRPC cells, COL-3 displayed higher activity for inhibiting cell growth and migration, and for inducing G1-phase cell cycle arrest and apoptosis. Collectively, these findings demonstrate the utility of a computational framework for independent validation of drugs being tested in CRPC clinical trials, and for nominating drugs with enhanced biological activity in models of enzalutamide-resistant CRPC. The efficiency of this method relative to traditional drug development approaches indicates a high potential for accelerating drug development for CRPC.

Prevalence of lung cysts in adolescents and adults with a germline DICER1 pathogenic/likely pathogenic variant: a report from the National Institutes of Health and International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

Demonstration of a low loss, highly stable and re-useable edge coupler for high heralding efficiency and low g(2)(0) SOI correlated photon pair sources.

We report a stable, low loss method for coupling light from silicon-on-insulator (SOI) photonic chips into optical fibers. The technique is realized using an on-chip tapered waveguide and a cleaved small core optical fiber. The on-chip taper is monolithic and does not require a patterned cladding, thus simplifying the chip fabrication process. The optical fiber segment is composed of a centimeter-long small core fiber (UHNA7) which is spliced to SMF-28 fiber with less than -0.1 dB loss. We observe an overall coupling loss of -0.64 dB with this design. The chip edge and fiber tip can be butt coupled without damaging the on-chip taper or fiber. Friction between the surfaces maintains alignment leading to an observation of ±0.1 dB coupling fluctuation during a ten-day continuous measurement without use of any adhesive. This technique minimizes the potential for generating Raman noise in the fiber, and has good stability compared to coupling strategies based on longer UHNA fibers or fragile lensed fibers. We also applied the edge coupler on a correlated photon pair source and observed a raw coincidence count rate of 1.21 million cps and raw heralding efficiency of 21.3%. We achieved an auto correlation function g H(2)(0) as low as 0.0004 at the low pump power regime.

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.

Testicular Sertoli cell tumour and potentially testicular Leydig cell tumour are features of DICER1 syndrome.

DICER1 syndrome is a rare paediatric autosomal dominant inherited disorder predisposing to various benign and malignant tumours. It is caused by a germline pathogenic variant in DICER1, and the second hit for tumour development is usually a missense hotspot pathogenic variant in the DICER1 ribonuclease IIIb domain. While DICER1 predisposing variants account for about 60% of ovarian Sertoli-Leydig cell tumours, no DICER1-related testicular stromal tumours have been described. Here we report the first two cases of testicular stromal tumours in children carrying a DICER1 germline pathogenic variant: a case of Sertoli cell tumour and a case of Leydig cell tumour diagnosed at 2 and 12 years of age, respectively. A somatic DICER1 hotspot pathogenic variant was detected in the Sertoli cell tumour. This report extends the spectrum of DICER1-related tumours to include testicular Sertoli cell tumour and potentially testicular Leydig cell tumour. Diagnosis of a testicular Sertoli cell tumour should prompt DICER1 genetic testing so that patients with a DICER1 germline pathogenic variant can benefit from established surveillance guidelines. DICER1 genetic evaluation may be considered for testicular Leydig cell tumour. Our findings suggest that miRNA dysregulation underlies the aetiology of some testicular stromal tumours.

Shear wave elastography: How well does it perform in chronic hepatitis D virus infection?

Hepatitis delta virus (HDV) infection is associated with accelerated progression of liver disease to cirrhosis. Shear wave elastography (SWE) is a non-invasive evaluation method of liver fibrosis. Its performance in accurately characterizing HDV fibrosis compared to other noninvasive markers remains unknown. We assessed the performance of SWE in patients with chronic HDV, Hepatitis B (HBV) and Hepatitis C (HCV) infection. Cirrhosis was determined by histology or clinical data. Area under receiver operator characteristics (AUROC) was used to assess diagnostic performance in identifying cirrhosis by SWE in comparison with Fibroscan® (VCTE) and serologic tests of fibrosis. 158 patients with chronic hepatitis (HDV:44%, HBV: 46% and HCV: 29%) were evaluated. Cirrhosis was diagnosed in 28 (17.7%) patients. Mean noninvasive fibrosis measurements for the HBV/HCV and HDV groups, respectively, were as follows: APRI: 0.73 ± 1.08 and 1.3 ± 1.38; FIB-4: 1.90 ± 2.24 and 2.33 ± 2.24; VCTE: 8.9 ± 6.7 kPa vs 10.4 ± 5.3 kPa; SWE: 1.5 ± 0.2 m/s and 1.6 ± 0.2 m/s. The performance of SWE in detecting HDV-induced cirrhosis (AUROC 0.84, 95% CI 0.71-0.97) was slightly lower than in HBV/HCV induced disease (AUROC 0.88, 95% CI 0.81-0.96). For HDV patients, the performance of SWE was comparable to VCTE and slightly better than APRI and FIB-4 especially in APRI and FIB-4 indeterminate zones. The overall less accurate performance of noninvasive markers in HDV in comparison with HBV and HCV may be a result of significant hepatic inflammation in HDV.

Fine-grained all-fiber nonlocal dispersion compensation in the telecommunications O-band.

Nonlocal dispersion compensation between broadband nondegenerate photon pairs propagated over fiber corresponding to the ITU-T G.652D telecommunications standard was studied extensively via fine-grained measurements of the temporal correlation between them. We demonstrated near-ideal levels of nonlocal dispersion compensation by adjusting the propagation distance of the photon pairs to preserve photon timing correlations close to the effective instrument resolution of our detection apparatus (41.0±0.1ps). Experimental data indicates that this degree of compensation can be achieved with relatively large fiber increments (1km), compatible with real-world deployment. Ultimately, photon timing correlations were preserved down to 51ps±21ps over two multi-segmented 10km spans of deployed metropolitan fiber.

Boosting topological zero modes using elastomer waveguide arrays.

We employ the Su-Schrieffer-Heeger model in elastic polymer waveguide arrays to design and realize traveling topologically protected modes. The observed delocalization of the optical field for superluminal defect velocities agrees well with theoretical descriptions. We apply mechanical strain to modulate the lattices' coupling coefficient. This work demonstrates a novel, to the best of our knowledge, platform for rapid prototyping of topological photonic devices and establishes strain-tuning as a viable design parameter for topological waveguide arrays.

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.

Gastrointestinal Computed Tomography Findings in Chronic Granulomatous Disease with Subgroup Clinicopathologic Analysis.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency which can lead to gastrointestinal (GI) complications including inflammatory bowel disease. Radiographic findings in this cohort have not been well described. AIMS: To describe the frequency and spectrum of gastrointestinal abnormalities seen on computed tomography (CT) in patients with CGD and determine whether radiography was predictive of endoscopic or histopathologic inflammatory findings. METHODS: A retrospective review was conducted on 141 consecutive CGD patients seen at the National Institutes of Health between 1988 and 2011. All corresponding CTs were reviewed for gastrointestinal abnormalities including wall thickening. Endoscopic and histopathologic findings were reviewed in subjects with documented endoscopy within 30 days of an imaging study. Findings were compared between patients with and without wall thickening on CT to determine whether bowel wall thickening was predictive of endoscopic or histologic inflammatory findings. RESULTS: Two hundred and ninety-two CTs were reviewed. GI wall thickening was present on CT in 61% of patients (n = 86). Among a subgroup of 20 patients who underwent endoscopy at the time of their imaging, there was a statistically significant correlation between radiographic gastrointestinal wall thickening and endoscopic inflammation in the same intestinal segment (p = 0.035). Additionally, there was a significant correlation between radiographic gastrointestinal wall thickening and inflammatory features on histopathology (p = 0.02). CONCLUSIONS: GI abnormalities are commonly observed on CT in CGD patients. Bowel wall thickening correlates with endoscopic and histopathologic evidence of inflammation. These findings may be used to better facilitate directed endoscopic assessment and histopathologic sampling in patients with CGD.

Fibre polarisation state compensation in entanglement-based quantum key distribution.

Quantum key distribution (QKD) using polarisation encoding can be hard to implement over deployed telecom fibres because the routing geometry and the birefringence of the fibre link can alter the polarisation states of the propagating photons. These alterations cause a basis mismatch, leading to an increased quantum bit error rate (QBER). In this work we demonstrate a technique for a dynamically compensating fibre-induced state alteration in a QKD system. This compensation scheme includes a feedback loop that minimizes the QBER using a stochastic optimization algorithm. The effectiveness of this technique is implemented and verified in a polarisation entanglement QKD system over a deployed telecom fibre.

Manipulation and measurement of quantum states with liquid crystal devices.

We present the use of liquid crystal retarders (LCR) as phase control elements in optical quantum technologies. We show that an entangled photon pair state can be actively controlled using an LCR without introducing state mixing or polarization drifts. Similarly, we demonstrate that the entanglement quality can be conveniently analyzed using liquid crystal polarization retarders.

Enhancing SPDC brightness using elliptical pump shapes.

We report on the use of elliptical pump spatial modes to increase the observed brightness of spontaneous parametric downconversion in critically phase-matched crystals. Simulations qualitatively predict this improvement, which depends on the eccentricity and orientation of the pump ellipse. We experimentally confirm a factor of two improvement in brightness when compared to the traditional circular-symmetric pump spatial modes. These results support previous theoretical work that proposes the use of elliptical pump modes to enhance the performance of parametric processes in anisotropic materials.

Satellite Quantum Communications When Man-in-the-Middle Attacks Are Excluded.

An application of quantum communications is the transmission of qubits to create shared symmetric encryption keys in a process called quantum key distribution (QKD). Contrary to public-private key encryption, symmetric encryption is considered safe from (quantum) computing attacks, i.e. it provides forward security and is thus attractive for secure communications. In this paper we argue that for free-space quantum communications, especially with satellites, if one assumes that man-in-the-middle attacks can be detected by classical channel monitoring techniques, simplified quantum communications protocols and hardware systems can be implemented that offer improved key rates. We term these protocols photon key distribution (PKD) to differentiate them from the standard QKD protocols. We identify three types of photon sources and calculate asymptotic secret key rates for PKD protocols and compare them to their QKD counterparts. PKD protocols use only one measurement basis which we show roughly doubles the key rates. Furthermore, with the relaxed security assumptions one can establish keys at very high losses, in contrast to QKD where at the same losses privacy amplification would make key generation impossible.

Impaired Bone Mineral Density in Pediatric Patients with Chronic Graft-versus-Host Disease.

Pediatric allogeneic hematopoietic stem cell transplantation (AHSCT) recipients with chronic graft-versus-host disease (cGVHD) are at high risk for endocrinopathies, particularly impaired bone mineral density (BMD). However, rates of BMD impairment in pediatric AHSCT recipients with cGVHD have not been well documented. We report 33 patients with cGVHD who were referred to the National Institutes of Health (NIH) for the Natural History of Clinical and Biological Factors Determining Outcomes in Chronic Graft-versus-Host Disease Study (NCT 0092235) and underwent formal BMD assessment via dual-energy X-ray absorptiometry (DEXA). Not surprisingly, we found much higher rates of BMD impairment than previously reported for pediatric AHSCT recipients who were not stratified by the presence or absence of cGVHD. Most of these patients (73%) had a z-score ≤-2 in at least 1 anatomic site. Although we expected the rate to be higher than that observed for pediatric AHSCT recipients in studies that did not analyze patients with cGVHD separately, this rate is nonetheless extremely high. Furthermore, the overall rate of occult vertebral compression fractures (VCFs) in our cohort was 17%, and the rate was 23% in patients with at least 1 z-score of ≤-2. The rates of BMD impairment and VCF in our pediatric cohort were significantly higher than those seen in the adult AHSCT recipients who were concurrently enrolled on the same study at the NIH and had similar cGVHD severity. We found that older age at cGVHD diagnosis and a greater number of systemic therapies were associated with occult VCF. Moreover, the intensity of current immunosuppression negatively impacted lumbar spine and total hip BMD in this cohort. Our study, although limited by small patient numbers and lack of a control AHSCT recipient group without cGVHD, indicates that children with cGVHD are at a greater risk for BMD impairment than previously appreciated. Given the rising incidence of cGVHD in AHSCT recipients and our findings, we recommend that pre-AHSCT DEXA be incorporated into routine pediatric pretransplantation screening studies. A baseline DEXA study could facilitate longitudinal monitoring of BMD in children, who may be more susceptible than adults to the negative effects of AHSCT on BMD. In addition, given the high risk of BMD impairment in pediatric AHSCT recipients with cGVHD, such patients should undergo BMD evaluation upon developing cGVHD, with continued monitoring thereafter to allow intervention before progression of the BMD impairment to its severe manifestation, VCF.

Experimental entangled photon pair generation using crystals with parallel optical axes.

We present an optical design where polarization-entangled photon pairs are generated within two ß-Barium Borate crystals whose optical axes are parallel. This design increases the spatial mode overlap of the emitted photon pairs enhancing single mode collection without the need for additional spatial walk-off compensators. The observed photon pair rate is at least 65 000 pairs/s/mW with a quantum state fidelity of 99.53 ± 0.22% when pumped with an elliptical spatial profile.

Long-term use of continuous subcutaneous hydrocortisone infusion therapy in patients with congenital adrenal hyperplasia.

BACKGROUND: In a phase 2 short-term (6 months) study of patients with congenital adrenal hyperplasia (CAH), continuous subcutaneous hydrocortisone infusion (CSHI) was found to be a safe, effective and well-tolerated method of replacing cortisol with improved disease and patient-related outcomes. OBJECTIVE: To evaluate the safety and efficacy of long-term CSHI. DESIGN: Single-centre, open-label, phase 2 extension study. PATIENTS: Five adults with classic CAH. MEASUREMENTS: Biomarkers of disease control, metabolic indices and health-related quality-of-life (HRQoL) estimates. RESULTS: Six of eight patients chose to continue on long-term CSHI therapy. Compared to baseline, eighteen months of CSHI resulted in decreased (P = 0.043) 0700-hour ACTH, 17-hydroxyprogesterone, androstenedione and progesterone; increased whole-body lean mass (P = 0.024); and improved HRQoL, especially symptoms of adrenal insufficiency (P = 0.003). Findings at six and eighteen months did not differ, and improvements achieved in androgen control, lean body mass and HRQoL after 6 months of CSHI were maintained at eighteen months. The hydrocortisone dose appeared to decrease with time [6 vs 18 months: 38.3 ± 8.8 vs 33.6 ± 12.2 mg/day (P = 0.062)], especially in women receiving oral contraceptives. Reduction of testicular adrenal rest and adrenal size observed at 6 months remained stable. In one patient, an adrenal adenoma continually decreased over time. Subjective improvement in hirsutism was reported. CONCLUSIONS: Long-term use of CSHI is a safe and well-tolerated treatment option in a select set of adults with classic CAH. Improvements observed short term in disease control and subjective health status continued long term.

Superiority of 68Ga-DOTATATE over 18F-FDG and anatomic imaging in the detection of succinate dehydrogenase mutation (SDHx )-related pheochromocytoma and paraganglioma in the pediatric population.

PURPOSE: To evaluate and compare diagnostic performance of 68Ga-DOTA(0)-Tyr(3)-octreotate (68Ga-DOTATATE) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) and anatomic imaging using computed tomography and/or magnetic resonance (CT/MR) imaging in detection of SDHx-related pheochromocytomas and paragangliomas (PPGLs) in pediatric patients. METHODS: Nine pediatric patients (5:4, girls:boys; 14.6 ± 2.0 years) with an SDHx-related mutation (SDHB:SDHA:SDHD, n = 7:1:1) were included in this retrospective study. At the time of initial diagnosis, 7/9 patients had metastatic disease. They underwent CT/MR imaging along with PET/CT using 68Ga-DOTATATE (n = 9), 18F-FDG (n = 8), and positron emission tomography-magnetic resonance imaging (PET/MR) using 18F-FDG (n = 1). In this manuscript, 18F-FDG PET/CT refers to both 18F-FDG PET/CT and 18F-FDG PET/MR. The per-lesion, per-region, and per-patient detection rates were compared and calculated for each of the imaging modalities. A composite of all functional and anatomic imaging studies served as the imaging comparator. RESULTS: Eight out of nine patients were positive for PPGLs on the imaging studies that demonstrated 107 lesions in 22 anatomic regions on the imaging comparator. The per-lesion detection rates for 68Ga-DOTATATE PET/CT, 18F-FDG PET/CT, and CT/MR imaging were 93.5% (95%CI, 87.0% to 97.3%); 79.4% (95%CI, 70.5% to 86.6%); and 73.8% (95%CI, 64.5% to 81.9%), respectively. The per-lesion detection rate for 68Ga-DOTATATE PET/CT was significantly higher than that of 18F-FDG PET/CT (p = 0.001) or CT/MR imaging (p < 0.001). In all of the anatomic regions except abdomen, the per-lesion detection rates for 68Ga-DOTATATE PET/CT was found to be equal or superior to 18F-FDG PET/CT, and CT/MR imaging. The per-region detection rate was 100% (95%CI, 84.6% to 100%) for 68Ga-DOTATATE PET/CT and 90.9% (95%CI, 70.8% to 98.9%) for both 18F-FDG PET/CT and CT/MR imaging. The per-patient detection rates for 68Ga-DOTATATE PET/CT, 18FDG PET/CT, and CT/MR imaging were all 100% (95%CI, 63.1% to 100%). CONCLUSION: Our preliminary study demonstrates the superiority of 68Ga-DOTATATE PET/CT in localization of SDHx-related PPGLs in pediatric population compared to 18F-FDG PET/CT and CT/MR imaging with the exception of abdominal (excluding adrenal and liver) lesions, and suggests that it might be considered as a first-line imaging modality in pediatric patients with SDHx-related PPGLs.