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Mutations in the transcription factors encoded by PHOX2B or LBX1 correlate with congenital central hypoventilation disorders. These conditions are typically characterized by pronounced hypoventilation, central apnea, and diminished chemoreflexes, particularly to abnormally high levels of arterial PCO 2 . The dysfunctional neurons causing these respiratory disorders are largely unknown. Here, we show that distinct, and previously undescribed, sets of medullary neurons coexpressing both transcription factors (dB2 neurons) account for specific respiratory functions and phenotypes seen in congenital hypoventilation. By combining intersectional chemogenetics, intersectional labeling, lineage tracing, and conditional mutagenesis, we uncovered subgroups of dB2 neurons with key functions in (i) respiratory tidal volumes, (ii) the hypercarbic reflex, (iii) neonatal respiratory stability, and (iv) neonatal survival. These data provide functional evidence for the critical role of distinct medullary dB2 neurons in neonatal respiratory physiology. In summary, our work identifies distinct subgroups of dB2 neurons regulating breathing homeostasis, dysfunction of which causes respiratory phenotypes associated with congenital hypoventilation.

Pulmonary arterial hypertension (PAH) is driven by pathologies associated with increased metabolism such as pulmonary revascularization, vasoconstriction and smooth muscle cell proliferation in pulmonary artery wall. 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) is an imaging technique sensitive to glucose metabolism and might be considered as a non-invasive method for diagnosis due to significant role of inflammation in idiopathic pulmonary artery hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The present study aimed to investigate the role of PET/CT imaging of patients with IPAH and CTEPH as an alternative diagnosis method. Demographic characteristics, FDG uptake in lungs, pulmonary artery and right ventricle (RV) of 17 patients (10 IPAH, 7 CTEPH), and 30 controls were evaluated. PET scanning, 6-min walk test, pro-BNP level, right heart catheterization of patients were performed both at the onsert and after 6-month PAH specific treatment. IPAH and CTEPH patients had significantly higher left lung FDG ( p  = 0.006), right lung FDG ( p  = 0.004), right atrial (RA) FDG ( p  < 0.001) and RV FDG ( p  < 0.001) uptakes than controls. Positive correlation was detected between the RV FDG uptake and the mean pulmonary artery pressure (mPAP) ( r  = 0.7, p  = 0.012) and between the RA FDG uptake and the right atrial pressure (RAP) ( r  = 0.5, p  = 0.02). Increased RV FDG and RA FDG uptakes predicts the presence of pulmonary hypertension and correlates with mPAP and RAP, respectively, which are important indicators in the prognosis of PAH. Further studies are required whether FDG PET imaging can be used to diagnose or predict the prognosis of pulmonary hypertension., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background and Aim: Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Circulating cell-free DNA (cfDNA) methylation of tumor suppressor genes are emerging potential biomarkers in HCC. We aimed to evaluate the cfDNA methylation status of RASSF1 and CDKN2AIP genes in patients with liver cirrhosis (LC) with or without HCC caused by HBV., Materials and Methods: A total of 47 patients with HBV cirrhosis were included in the study. Patients were divided into two groups: HCC and LC (HCC+LC, n=22) and HBV cirrhosis only (LC, n=25). cfDNA was isolated from the plasma samples of the patients. Methylation analysis was performed for RASSF1 and CDKN2AIP genes., Results: Mean methylation percentage of CDKN2AIP gene was 0.001±0.004% in the HCC+LC group and 0.008±0.004 % in the LC only group. The mean methylation percentage of RASSF1 gene was 5.1±16.1% in the HCC+LC group and 9.7±25.9% in the LC only group. The methylation rate of CDKN2AIP was significantly lower in the HCC+LC group (p=0.027). A positive correlation was found with the absence of cfDNA methylation of CDKN2AIP gene in the presence of HCC (R=0.667, p=0.018)., Conclusion: cfDNA methylation of CDKN2AIP and RASSF1 genes may provide important diagnostic information regarding the development of HCC in the setting of HBV cirrhosis., Competing Interests: The authors have no conflict of interest to declare., (© Copyright 2022 by Hepatology Forum.)

Purpose: This study investigates the prognostic value of 68 Ga-Pentixafor PET/CT using PET-derived quantitative in multiple myeloma (MM) patients with suspected recurrence in comparison to 18 F-FDG PET/CT and clinical data., Methods: Twenty-four MM patients with suspicion for relapse who underwent 68 Ga-Pentixafor and 18 F-FDG PET/CT were retrospectively evaluated. Total bone marrow glycolysis for 18 F-FDG (TBM FDG ) and total bone marrow uptake for 68 Ga-Pentixafor PET/CT (TBM CXCR4 ) were calculated using whole-body metabolic tumor burden obtained by dedicated software (MIM 7.0.6). The patients were followed for 19-24 months, and the association of PET-derived quantitative data with overall survival (OS) was analyzed., Results: 68 Ga-Pentixafor PET/CT was positive in 17 patients, of which 13 were also positive on 18 F-FDG PET/CT, whereas 7 patients were negative on both scans. The positive rate of 68 Ga-Pentixafor and 18 F-FDG PET/CT on a patient-based approach was 70.8% and 54.1%, respectively. 68 Ga-Pentixafor positivity was significantly associated with OS (p = 0.009), and 18 F-FDG positivity was at the margin of statistical significance (p = 0.056). TBM CXCR4 and TBM FDG were negatively correlated with OS (r = -0.457, p = 0.025 and r = -0.617, p = 0.001, respectively). The OS was negatively correlated with beta-2-microglobulin levels (r = -0.511, p = 0.01) and CRAB score (r = -0.592, p = 0.002) as an indicator of the end-organ disease, which confirmed these results. Serum beta-2-microglobulin levels and CRAB score were also correlated with TBM CXCR4 (r = 0.442, p = 0.039 and r = 0.573, p = 0.003, respectively) and TBM FDG (r = 0.543, p = 0.009 and r = -0.424, p = 0.003, respectively)., Conclusion: 68 Ga-Pentixafor PET/CT positivity is a negative prognostic factor in the survival outcome of MM patients. Complementary 68 Ga-Pentixafor PET/CT has the potential to overcome 18 F-FDG PET/CT limitations and helps a more precise risk stratification., (© 2021. The Japanese Society of Nuclear Medicine.)

Purpose: We investigated the role of PSMA-derived tumor burden in predicting docetaxel (DTX) therapy response in metastatic castration-resistant prostate cancer (mCRPC)., Methods: Fifty-two mCRPC patients who received at least six cycles of DTX as the first-line treatment following 68 Ga-PSMA PET/CT were enrolled in this retrospective study. Total PSMA-derived tumor volume (TV-PSMA) and total lesion PSMA activity (TL-PSMA) were derived from metastatic lesions. A ≥ 50% decline in PSA was defined as a response; a ≥ 25% increase in PSA was defined as progression. Univariate/multivariate logistic and cox regression analyses were performed to predict PSA response, OS, and TTP., Results: Twelve (23%) patients had PSA progression after chemotherapy, while 40 patients (77%) achieved a PSA response. On univariate analysis, a significant association was found between TV-PSMA (p = 0.001), TL-PSMA (p = 0.001), pre-PSA (p = 0.012), LDH (p = 0.003), Hg (p = 0.035), and PSA response to DTX. High TV-PSMA (> 107 cm 3 ) (p = 0.04) and high LDH (> 234 U/L) (p = 0.017) were 8.2 times and 12.2 times more likely for DTX failure in multivariate regression analyses. The median TTP was 16 months, and the median OS was not reached. Patients with high TV-PSMA (p = 0.017), high TL-PSMA (> 1013 cm 3 ) (p = 0.042), high age (> 70 years) (p = 0.016), and high LDH (p ≤ 0.001) had significantly shorter OS, while only high TV-PSMA (p = 0.038) and high age (p = 0.006) were significantly related with shorter TTP. High TV-PSMA (p = 0.017) and high age (p = 0.01) were significant predictors for shorter OS, while only high age (p = 0.006) was a significant predictor for shorter TTP in multivariate analysis., Conclusion: Patients with high TV-PSMA had a significantly higher risk for DTX failure. PSMA-based tumor burden prior to DTX therapy seems to be a reliable predictive tool for survival in mCRPC patients.

The mature cerebellum controls motor skill precision and participates in other sophisticated brain functions that include learning, cognition, and speech. Different types of GABAergic and glutamatergic cerebellar neurons originate in temporal order from two progenitor niches, the ventricular zone and rhombic lip, which express the transcription factors Ptf1a and Atoh1, respectively. However, the molecular machinery required to specify the distinct neuronal types emanating from these progenitor zones is still unclear. Here, we uncover the transcription factor Olig3 as a major determinant in generating the earliest neuronal derivatives emanating from both progenitor zones in mice. In the rhombic lip, Olig3 regulates progenitor cell proliferation. In the ventricular zone, Olig3 safeguards Purkinje cell specification by curtailing the expression of Pax2, a transcription factor that suppresses the Purkinje cell differentiation program. Our work thus defines Olig3 as a key factor in early cerebellar development., Competing Interests: EL, AR, JS, MH, AS, EE, FB, EI, SB, SJ, VT, LH No competing interests declared, (© 2021, Lowenstein et al.)

Objective: This study sets out to evaluate patients with increased uptake in breast lesions on 68 Ga-DOTATATE PET/CT (DOTA PET) and determine the clinical significance of somatostatin receptor (SSTR) positive breast lesions., Methods: We retrospectively evaluated all patients with increased SSTR uptake in breast lesions on DOTA PET. Patients with physiological (e.g., lactation) or normal variant breast uptake (e.g., mild diffuse glandular uptake) were excluded. The maximum standard uptake value (SUVmax) was calculated using a manually drawn region of interest in the most intense uptake of breast lesions. All lesions were correlated with breast imaging, including mammography and ultrasonography. Histopathological correlation was performed if the lesion was suspicious for malignancy. Lesions were followed up radiologically (1-8 years)., Results: Out of 1573 retrospectively analyzed DOTA PET scans, the incidence of SSTR + breast lesions was measured as 1.1% (n = 18); however, 4 of 18 patients were excluded due to the lack of final diagnosis of lesions. The median age was 35 (range 14-58 years), and all patients were female. The median SUVmax of SSTR + breast lesions was 5.2 (range 1.5-12.6) for a total of 14 patients. Twelve patients had a single SSTR + breast lesion, while 2 patients had multiple SSTR + lesions on bilateral breasts. In 6 patients, single SSTR + lesions were considered as fibroadenoma; in 2 patients, multiple SSTR + lesions were considered as metastases of NET, based on correlative breast imaging. In 6 patients, histopathological confirmation was needed for the final diagnosis. Histopathologic findings confirmed fibroadenoma in 4 patients by biopsy, in 1 patient with surgical removal of the lesion. The last patient who had a history of IDC was diagnosed with a recurrence of IDC with biopsy. The median SUVmax was 5.1 (range 1.5-9.4) for malignant breast lesions and 5.4 (range 2.2-12.6) for benign breast lesions., Conclusion: SSTR + breast lesions on DOTA PET are rarely seen in clinical practice. Uptakes of breast lesions in our cases were variable and not useful for differential diagnosis of lesions. It seems that SSTR + breast lesions should be evaluated with clinical and radiological characteristics, and correlative breast imaging and/or histopathological verification should be performed for suspicious lesions to avoid misdiagnosis.

Objection: We aimed to evaluate the role of bone scintigraphy (BS) which has long been the imaging modality of choice in prostate cancer (PCa) and performed a head-to-head comparison between BS, BS + SPECT/CT and 68 Ga-PSMA-PET/CT, for the detection of bone metastasis of PCa., Methods: We evaluated 138 PCa patients who underwent BS and 68 Ga-PSMA PET/CT and SPECT/CT of 102 of 138 patients. Images were interpreted retrospectively and areas of abnormally increased tracer uptake related to PCa were documented as benign, metastatic or equivocal. Equivocal uptakes were finally diagnosed based on a consensus review of correlative imaging. Patient- and lesion-based analysis was performed. Patients with superscan images were excluded from lesion-based analysis., Results: At least one metastatic or equivocal uptake in skeleton was defined in 76 of 138 (55%) BS, in 33 of 102 (32.3%) SPECT/CT, and in 49 of 138 (35.5%) 68 Ga-PSMA PET/CT. 23 (16.7%) patients had also superscan findings on BS and 68 Ga-PSMA PET/CT. For patient-based analysis, sensitivity, specificity, accuracy, PPV, and NPV were calculated as 91.1%, 64.5%, 73.1%, 55.4% and 93.7% for BS; 95.5%, 82.7%, 86.9%, 72.8% and 96.2% for BS + SPECT/CT; 97.7%, 95.7%, 95.6%, 91.6% and 98.8% for 68 Ga-PSMA PET/CT. For lesion-based analysis, sensitivity, specificity, accuracy, PPV, and NPV were 53%, 63.9%, 60.1%, 42.8% and 71.8% for BS; 59.2%, 87.6%, 77.7%, 62.6% and 80% for BS + SPECT/CT; 96.4%, 98.1%, 97.5%, 96.4% and 98.1% for 68 Ga-PSMA PET/CT., Conclusion: This study has shown that 68 Ga-PSMA PET/CT overcomes the limitations of BS and proves superiority in detecting bone metastases, even in patients with SPECT/CT. Our findings present important implications that 68 Ga-PSMA PET/CT can replace BS in future practice.

Objective: Minimizing side effects by using response-adopted therapy strategies plays an important role in the management of pediatric Hodgkin lymphoma (HL); however, the criteria for the definition of adequate or inadequate response are controversial. The aim of this study is to compare different methods of interpretation of 18 F-FDG-PET/CT (PET) in the prediction of disease outcome in order to determine the optimum method in this regard., Methods: Baseline, interim and post-treatment PET scans of 72 children were interpreted according to revised International Harmonization Project criteria (IHP) and Deauville criteria. Cut-off values for changes in interim and post-treatment FDG uptake (ΔSUV max ) in the prediction of progression-free survival (PFS) were measured using ROC analysis. Quantitative and visual data were compared with each other in the prediction of PFS., Results: Mean interim and post-treatment ΔSUV max of the primary lesions were 77.4 ± 19.5 and 68.8 ± 30.4% and respective cut-off values were 82 and 73%. However, only post-treatment ΔSUV max yielded statistically significant results in the prediction of 3-year PFS (p = 0.043). Interim ΔSUV max was further analyzed according to the values reported in the literature (66 and 77%) yet statistically significant results were not reached (p = 0.604 and 0.431). For interim evaluation, IHP criteria was correlated to Deauville criteria (p = 0.002 and p = 0.001) and ΔSUV max (p = 0.03), whereas for post-treatment evaluation, significant correlation with ΔSUV max (p = 0.04) but marginally significant (p = 0.055 and p = 0.058) correlation with Deauville criteria were achieved. Overall, 1, 3 and 5-year PFS were 95.7 ± 0.2, 89.6 ± 0.4 and 80.8 ± 0.7%, respectively. All methods demonstrated comparable performance in the prediction of 3-year PFS; however, interim PET using Deauville criteria and post-treatment PET using IHP criteria were statistically significant. All methods demonstrated high negative-predictive value but substantially low positive-predictive value., Conclusions: Deauville criteria are superior to other methods in the prediction of pediatric HL outcome using interim PET data. On the other hand, quantitative evaluation and visual evaluation by IHP can be used reliably at the end of the treatment. In this regard, we report the optimal cut-off value of SUV max reduction as 73%.

(18)F-NaF was used as a bone-seeking PET tracer for skeletal imaging until the introduction of the widely available (99m)Tc-labeled bone agents. However, there is renewed clinical interest in (18)F-NaF since prior technical and logistic limitations to its routine use are no longer present, and, as a consequence, it is likely that uptake unrelated to bone and non-osseous findings will be encountered more frequently. As a result of tumoral necrosis, soft tissue metastases may demonstrate (18)F-NaF avidity due to dystrophic calcification. On the other hand, all non-osseous findings, whether (18)F-NaF avid or not, may provide important diagnostic information that may alter the course of the disease, including treatment options. Herein we present a patient with ductal carcinoma of the breast in whom findings unrelated to the skeletal system in (18)F-NaF PET/CT altered the treatment strategy.

Alveolar hydatid disease or alveolar echinococcosis is a disease of the parasite Echinococcus multilocularis that is potentially fatal if left untreated. It primarily involves the liver but can be disseminated to other organs like the lungs and the brain by hematogenous route. Multiorgan involvement and the aggressive appearance of lesions make alveolar hydatid disease easy to confuse with a metastatic malignancy. For this reason, histopathological confirmation is essential for definite diagnosis. We present the imaging features of this disease in two patients in order to emphasize that these lesions can be easily misdiagnosed as malignancies.