Plasmacytoma and Amyloid Lymphadenopathy, FDG, and Fluorocholine.

ABSTRACT: A 56-year-old man with thoracal mass suspected of solitary plasmacytoma was referred for 18 F-FDG PET-CT scan. His PET-CT revealed FDG-avid rib mass and cervical lesion at level 2. He also underwent 18 F-fluorocholine (FCH) PET-CT to evaluate possible metastatic spread of the disease. FCH PET-CT showed increased uptake at the rib mass, while the cervical lesion was not FCH-avid. Biopsies confirmed rib lesion was a solitary plasmacytoma; however, the cervical lesion was an amyloid deposited lymph node. This case showed FCH PET-CT is a valuable companion of FDG scan for the evaluation of plasma cell dyscrasias with a better specificity.

Diagnostic Performance of 99mTc-Sestamibi SPECT/CT and 18F-Choline PET/CT in Locating Hyperfunctioning Parathyroid Glands in Patients with Primary Hyperparathyroidism.

OBJECTIVE: This study aimed to assess the diagnostic performance of 99mTc-sestamibi SPECT/CT and 18F-choline PET/CT in detecting hyperfunctioning parathyroid glands in patients undergoing surgery for primary hyperparathyroidism (PHPT). METHODS: A retrospective analysis was conducted on patients who underwent PHPT-related surgery between April 2019 and May 2022. The study focused on patients undergoing either 99mTc-sestamibi SPECT/CT (81 patients) or 18F-choline PET/CT (33 patients) scans before surgery to pinpoint hyperfunctioning parathyroid gland(s). In the majority of patients, 18F-choline PET/CT was performed after negative or inconclusive findings on 99mTc-sestamibi SPECT/CT. Pathohistological reports were utilized as the reference standard for evaluating the accuracy of the imaging findings. RESULTS: The study encompassed 83 patients (70 females, 84.3%) with an average age of 57.2 years (24-80 years). The pathohistological analysis identified a total of 98 glands. In a per-lesion analysis, the detection rate of 99mTc-sestamibi SPECT/CT was 57% (95% CI 45.3-68.1), while the detection rate of 18F-choline PET/CT was 90.3% (95% CI 74.3-98.0). CONCLUSION: The results of our study showed the significant usefulness of 18F-choline PET/CT in patients with negative or inconclusive results of 99mTc-sestamibi SPECT/CT in accurately locating hyperfunctioning parathyroid glands in PHPT patients.

Performance of [18F]fluorocholine PET/CT in MEN1-related primary hyperparathyroidism before initial surgery or for persistent/recurrent disease.

PURPOSE: The aims of the study were to evaluate the performance and robustness of [18F]fluorocholine PET/CT in detecting hyperfunctioning parathyroid glands in MEN1-related primary hyperparathyroidism (pHPT) at different stages of their disease. METHODS: Retrospective French multicenter study including patients with MEN1 pHPT who underwent [18F]fluorocholine PET/CT at initial diagnosis or for evaluation of persistent/recurrent disease. PET/CT were independently reviewed by two readers in a blinded manner. The assessment of PET/CT on a per-patient basis was assessed using a comprehensive set of criteria that considered pathological findings or agreement with alternative diagnostic methods in non-operated patients. The secondary objectives included the analysis of the performance of PET/CT at a per-lesion level, with reference to a pathological Gold Standard, and examining its interobserver reproducibility. RESULTS: A total of 71 MEN1 patients were included (73 PET/CT) in the study. At the per-patient level (entire cohort), [18F]fluorocholine PET/CT sensitivity ranged from 98.5 to 100% among the different readers. An average of 1.77 glands per PET was described, with 2.35 glands at the initial diagnosis (n = 23) and 1.5 in previously operated cases (n = 50). PET/CT detected more lesions than conventional imaging work-up (neck ultrasound and/or scintigraphy). At the per-lesion level (41 operated patients), sensitivity ranged across different readers from 84.4 to 87%, and specificity ranged from 94.7 to 98.8%. At initial diagnosis, all patients that exhibited 3 or more abnormal glands on PET underwent subtotal parathyroidectomy while 7 out of 13 patients with 1 or 2 gland abnormalities on PET underwent less than subtotal parathyroidectomy. Finally, the degree of inter-observer agreement was high. CONCLUSION: [18F]fluorocholine PET/CT is a reliable and robust imaging modality for the evaluation of MEN1-related pHPT and could guide surgeons in achieving the optimal benefit-risk ratio. This study gives a great impetus for its adoption as a primary diagnostic tool in this context.

The value of baseline 18F-sodium fluoride and 18F-choline PET activity for identifying responders to radium-223 treatment in castration-resistant prostate cancer bone metastases.

OBJECTIVES: To investigate whether baseline 18F-sodium fluoride (NaF) and 18F-choline PET activity is associated with metastatic castration-resistant prostate cancer (mCRPC) global and individual bone metastases' DWI MR imaging response to radium-223 treatment. METHODS: Thirty-six bone-only mCRPC patients were prospectively recruited from three centers. Whole-body (WB)-MRI with DWI and 18F-NaF and 18F-choline PET/CT were performed at therapy baseline and 8-week intervals. In each patient, bone disease median global (g)ADC change between baseline and follow-up was calculated. Additionally, up to five bone target lesions per patient were delineated and individual median ADC change recorded. An ADC increase > 30% defined response per-patient and per-lesion. For the same targets, baseline 18F-NaF and 18F-choline PET SUVmax were recorded. Mean SUVmax across patient targets was correlated with gADC change and lesion SUVmax with per-lesion ADC change. RESULTS: A total of 133 lesions in 36 patients (14 responders) were analyzed. 18F-NaF PET per-patient mean SUVmax was significantly higher in responders (median = 56.0 versus 38.7 in non-responders; p = 0.008), with positive correlation between SUVmax and gADC increase (rho = 0.42; p = 0.015). A 48.7 SUVmax threshold identified responders with 77% sensitivity and 75% specificity. Baseline 18F-NaF PET per-lesion SUVmax was higher in responding metastases (median = 51.6 versus 31.8 in non-responding metastases; p = 0.001), with positive correlation between baseline lesion SUVmax and ADC increase (rho = 0.39; p < 0.001). A 36.8 SUVmax threshold yielded 72% sensitivity and 63% specificity. No significant association was found between baseline 18F-choline PET SUVmax and ADC response on a per-patient (p = 0.164) or per-lesion basis (p = 0.921). CONCLUSION: 18F-NaF PET baseline SUVmax of target mCRPC bone disease showed significant association with response to radium-223 defined by ADC change. CLINICAL RELEVANCE STATEMENT: 18F-sodium fluoride PET/CT baseline maximum SUV of castration-resistant prostate cancer bone metastases could be used as a predictive biomarker for response to radium-223 therapy. KEY POINTS: • 18F-sodium fluoride PET baseline SUVmax of castration-resistant prostate cancer bone metastases showed significant association with response to radium-223. • Baseline 18F-sodium fluoride PET can improve patient selection for radium-223 therapy. • Change in whole-body DWI parameters can be used for response correlation with baseline 18F-sodium fluoride PET SUVmax in castration-resistant prostate cancer bone metastases.

Multiple brown tumors: a bone complication due to long-term untreated pseudohypoparathyroidism.

Bone lytic lesions are a possible complication of pseudohypoparathyroidism type 1B, in undertreated adult patients. Whole body [18F] F-fluorocholine PET/CT is a useful imaging tool to assess brown tumor progression in this context. We describe the case of a 33-year-old woman, referred for the diagnostic evaluation of lytic bone lesions of the lower limbs, in the context of asymptomatic pseudohypoparathyroidism. She had been treated with alfacalcidol and calcium during her childhood. Treatment was discontinued at the age of 18 years old because of the lack of symptoms. A femur biopsy revealed a lesion rich in giant cells, without malignancy, consistent with a brown tumor. Laboratory tests showed a parathyroid level at 1387 pg/ml (14-50). Whole-body Fluorocholine PET/CT revealed hypermetabolism of bone lesions. The final diagnosis was brown tumors related to hyperparathyroidism complicating an untreated pseudohypoparathyroidism. Genetic testing confirmed PHP type 1B. Pseudohypoparathyroidism with radiographic evidence of hyperparathyroid bone disease, is a very rare condition due to parathyroid hormone resistance in target organs, i.e., kidney resistance, but with conserved bone cell sensitivity. It has been reported in only a few cases of pseudohypoparathyroidism type Ib. Long-term vitamin D treatment was required to correct bone hyperparathyroidism. With this rationale, the patient was treated with calcium, alfacalcidol, and cholecalciferol. One-year follow-up showed complete resolution of pain, improvement in serum calcium, and regression of bone lesions on [18F]F-fluorocholine PET/CT. This case illustrates the usefulness of [18F]F-fluorocholine PET/CT for the imaging of brown tumors in pseudohypoparathyroidism type 1B, and emphasizes the importance of calcium and vitamin D treatment in adult patients, to avoid the deleterious effects of high parathyroid hormone on skeletal integrity.

Cost analysis of next-generation imaging in high-risk prostate cancer staging.

INTRODUCTION AND OBJECTIVE: Next-generation imaging (NGI) tests, such as choline PET/CT and PSMA PET, have shown to increase sensitivity in the detection of nodal and metastatic disease in prostate cancer. However, their use implies an increase in diagnostic costs compared to conventional imaging (CI) tests such as CT and bone scan. The aim of our study was to determine which diagnostic pathway is more cost-effective in high-risk prostate cancer. MATERIAL AND METHOD: Cost-effectiveness analysis of the available imaging tests (CI, Choline/PSMA PET) for the staging of high-risk prostate cancer. Sensitivity and specificity were estimated based on published evidence, and costs were collected from the Management Department. In order to carry out a cost-effectiveness analysis, five diagnostic pathways were proposed estimating the accurate diagnoses. RESULTS: PSMA PET was the most accurate diagnostic option. The CI diagnostic workup was the most economical and CI+PSMA the most expensive. Analyzing the diagnostic cost-effectiveness ratio, CI+PSMA proved to be the most expensive (€5627.30 per correct diagnosis) followed by PET PSMA (€4987.11), choline (€4599.84) and CI (€4444.22). CONCLUSIONS: PSMA PET is the most accurate strategy in staging distant disease in patients with high-risk prostate cancer. Radiotracer uptake tests such as CI have been shown to be the most cost-effective option, followed by choline and PSMA.

Quantitative CT Evaluation of Bone Mineral Density in the Thoracic Spine on 18F-Fluorocholine PET/CT Imaging in Patients With Primary Hyperparathyroidism.

INTRODUCTION: Measurement of bone mineral density (BMD) with quantitative CT (QCT) carries several advantages over other densitometric techniques, including superior assessment of the spine. As most QCT studies evaluated the lumbar spine, measurements of the thoracic spine are limited. We performed QCT analysis of the thoracic spine in a cohort of patients with primary hyperparathyroidism. MATERIALS AND METHODS: This study was a retrospective QCT analysis of the thoracic spine on 18F-fluorocholine PET/CT scans in patients with primary hyperparathyroidism patients between March 2018 and December 2022. Correlations between QCT-derived BMD or Hounsfield units (HU) and demographic data, laboratory parameters, results from histopathological examination after parathyroidectomy and results of DXA imaging were analyzed, when available. RESULTS: In 189 patients, mean QCT-derived BMD at the thoracic spine was 85.6 mg/cm3. Results from recent DXA were available in 122 patients. Mean thoracic QCT-derived BMD and HU were significantly correlated with DXA-derived BMD in lumbar spine, total hip and femoral neck and with the lowest T-score at DXA imaging. Only weak correlations were found with BMI or 18F-fluorocholine uptake, while no significant correlations were found with adenoma weight, PTH or calcium levels. CONCLUSION: Our study confirms correlation between QCT-derived BMD in the thoracic spine with age and DXA-derived BMD measurements within a population of patients with primary hyperparathyroidism. Establishment of reference BMD values for individual thoracic vertebrae, may allow direct osteoporosis classification on thoracic CT imaging.

18F-Fluoroethylcholine PET/CT Radiomic Analysis for Newly Diagnosed Prostate Cancer Patients: A Monocentric Study.

AIM: The aim of this study is to assess whether there are some correlations between radiomics and baseline clinical-biological data of prostate cancer (PC) patients using Fluorine-18 Fluoroethylcholine (18F-FECh) PET/CT. METHODS: Digital rectal examination results (DRE), Prostate-Specific Antigen (PSA) serum levels, and bioptical-Gleason Score (GS) were retrospectively collected in newly diagnosed PC patients and considered as outcomes of PC. Thereafter, Volumes of interest (VOI) encompassing the prostate of each patient were drawn to extract conventional and radiomic PET features. Radiomic bivariate models were set up using the most statistically relevant features and then trained/tested with a cross-fold validation test. The best bivariate models were expressed by mean and standard deviation to the normal area under the receiver operating characteristic curves (mAUC, sdAUC). RESULTS: Semiquantitative and radiomic analyses were performed on 67 consecutive patients. tSUVmean and tSkewness were significant DRE predictors at univariate analysis (OR 1.52 [1.01; 2.29], p = 0.047; OR 0.21 [0.07; 0.65], p = 0.007, respectively); moreover, tKurtosis was an independent DRE predictor at multivariate analysis (OR 0.64 [0.42; 0.96], p = 0.03) Among the most relevant bivariate models, szm_2.5D.z.entr + cm.clust.tend was a predictor of PSA levels (mAUC 0.83 ± 0.19); stat.kurt + stat.entropy predicted DRE (mAUC 0.79 ± 0.10); cm.info.corr.1 + szm_2.5D.szhge predicted GS (mAUC 0.78 ± 0.16). CONCLUSIONS: tSUVmean, tSkewness, and tKurtosis were predictors of DRE results only, while none of the PET parameters predicted PSA or GS significantly; 18F-FECh PET/CT radiomic models should be tested in larger cohort studies of newly diagnosed PC patients.

Early Recurrence Detection of Glioma Using 18 F-Fluorocholine PET/CT : GliReDe Pilot Study.

OBJECTIVE: The aim of this study was to analyze the usefulness of 18 F-fluorocholine PET/CT in the early diagnosis of tumor recurrence, increasing the diagnosis confidence of MRI. METHODS: Patients with a previous gross total resection of glioma and the first suspicious or doubtful for recurrence MRI were prospectively included and subjected to 18 F-fluorocholine PET/CT. An independent and combined assessment of 18 F-fluorocholine PET/CT and multimodal MRI was performed classifying the studies as positive or negative for tumor recurrence. Final diagnosis (recurrence or not) was obtained by histological confirmation or clinical and imaging follow-up. The relation of SUV max and tumor-to-background ratio with progression, the diagnostic performance of imaging techniques, and their concordance (κ Cohen) were analyzed. RESULTS: Twenty-four studies on 21 patients were assessed. Recurrence was diagnosed in 20 cases. PET/CT was positive in 23 cases (3 false positive), whereas MRI was positive in 15 cases (1 false positive). MRI was false negative in 6 cases. There was no false negative on 18 F-fluorocholine PET/CT. Accuracy of PET/CT versus MRI was 87.5% and 70.8%, respectively. The combined evaluation of both techniques did not show any advantage with respect to PET/CT results alone. The concordance between both imaging techniques was low (κ = 0.135; P = 0.375). SUV max and tumor-to-background ratio were related to recurrence (areas under the curve of 0.844 [ P = 0.033] and 0.869 [ P = 0.022], respectively). CONCLUSIONS: 18 F-fluorocholine PET/CT was helpful for increasing the diagnostic confidence in the cases of MRI doubtful for recurrence in order to avoid a delayed diagnosis.

Synchronous Metastatic Medullary Thyroid Carcinoma and Paraesophageal Parathyroid Adenoma Detected on 18 F-Ethylcholine PET/US Fusion Imaging.

ABSTRACT: An 80-year-old woman with osteoporosis without fractures was referred with asymptomatic primary hyperparathyroidism and elevated calcitonin level. Ultrasound, 99m Tc-pertechnetate scintigraphy, 99m Tc-MIBI scintigraphy, and CT revealed a suspicious thyroid nodule and enlarged submandibular lymph nodes. However, no parathyroid adenoma was depictable. 18 F-choline PET/CT showed increased uptake of the proximal esophagus, but neither CT nor US revealed a parathyroid lesion, and only 18 F-choline PET/US fusion imaging confirmed a paraesophageal parathyroid adenoma. Resection of both medullary thyroid carcinoma and ectopic parathyroid adenoma through a single cervicotomy was conducted (thyroidectomy, neck dissection, extirpation of parathyroid adenoma); parathyroid hormone and calcitonin dropped to normal. Multiple endocrine neoplasia IIa syndrome was suspected.

Detection of lymph node metastases in patients with prostate cancer: Comparing conventional and digital [18 F]-fluorocholine PET-CT using histopathology as a reference.

BACKGROUND: Positron emission tomography-computed tomography (PET-CT) with [18 F]-fluorocholine (FCH) is used to detect and stage metastatic lymph nodes in patients with prostate cancer. Improvements to hardware and software have recently been made. We compared the capability of detecting regional lymph node metastases using conventional and digital silicon photomultiplier (SiPM)-based PET-CT technology for FCH. Extended pelvic lymph node dissection (ePLND) histopathology was used as a reference method. METHODS: The study retrospectively examined 177 patients with intermediate or high-risk prostate cancer who had undergone staging with FCH PET-CT before ePLND. Images were obtained with either the conventional Philips Gemini PET-CT (n = 93) or the digital SiPM-based GE Discovery MI PET-CT (n = 84) and compared. RESULTS: Images that were obtained using the Philips Gemini PET-CT system showed 19 patients (20%) with suspected lymph node metastases, whereas the GE Discovery MI PET-CT revealed 36 such patients (43%). The sensitivity, specificity, and positive and negative predictive values were 0.3, 0.84, 0.47, and 0.72 for the Philips Gemini, while they were 0.58, 0.62, 0.31, and 0.83 for the GE Discovery MI, respectively. The areas under the curves in a receiver operating characteristic curve analysis were similar between the two PET-CT systems (0.57 for Philips Gemini and 0.58 for GE Discovery MI, p = 0.89). CONCLUSIONS: Marked differences in sensitivity and specificity were found for the different PET-CT systems, although the overall diagnostic performance was similar. These differences are probably due to differences in both hardware and software, including reconstruction algorithms, and should be considered when new technology is introduced.

Vaccine-Related Lymph Nodes: The Emerging Pitfalls of 18F-Fluorocholine and 68Ga-PSMA-11 PET/CT in the Era of COVID-19 Vaccination.

PURPOSE: Vaccination against coronavirus disease 2019 (COVID-19) is currently under worldwide deployment. The consequences of this vaccination can be seen in radiology and nuclear medicine explorations with visualization of axillary lymph nodes (LNs), as observed on ultrasonography, MRI, or 18F-FDG PET/CT.We aimed to evaluate on PET/CT the incidence of vaccine-related LNs and their characteristics after COVID-19 vaccination, using several radiopharmaceuticals different from 18F-FDG. PATIENTS AND METHODS: Between February and July 2021, all consecutive patients undergoing a whole-body PET/CT for any indication using a different radiopharmaceutical from 18F-FDG were eligible for inclusion if they had received at least 1 dose of the COVID-19 vaccine. The radiopharmaceutical administered and vaccine type were recorded for each patient. The incidence of positive vaccine-related axillary and supraclavicular LNs on PET/CT was our primary finding, along with the nodes characteristics. Statistical analyses were performed for patients with prostate cancer (PCa) to determine certain interaction factors that were associated with the detection of vaccine-related LNs. RESULTS: Of the 226 patients in our cohort study, 120 patients underwent an 18F-fluorocholine PET/CT, 79 a 68Ga-PSMA-11 PET/CT, 6 an 18F-FDOPA PET/CT, and 21 a 68Ga-DOTATOC PET/CT. A total of 67.3% of patients (152/226) received BNT162b2mRNA (Pfizer-BioNTech), 26.5% (60/226) ChAdOx1-S (AstraZeneca), 4.9% (11/226) mRNA-1273 (Moderna), and 1.3% (3/226) Ad26.COV2.S (Janssen). The incidence of positive vaccine-related axillary and supraclavicular LNs was 42.5% (51/120 patients) on PET/CT using 18F-fluorocholine and 12.7% (10/79 patients) with 68Ga-PSMA-11. None of our patients undergoing 18F-FDOPA or 68Ga-DOTATOC PET/CT presented any vaccine-related lymphadenopathy. Vaccine-related LNs were statistically associated with the nature of the radiopharmaceutical (P < 10-4), with the number of vaccine doses received (P = 0.041), with a short delay between vaccination and PET/CT realization (P < 10-5), and with a higher prostate-specific antigen level for patients with PCa (P = 0.032), but not with age or vaccine type. The vaccine-related nodes appeared in 85% of the cases, in the 30 days after vaccine injection, were limited in size and uptake, and were most often limited to the axilla level 1 area. CONCLUSIONS: Detecting positive LNs after COVID-19 vaccination is not an exclusive 18F-FDG PET/CT pattern but is common on 18F-fluorocholine and possible on 68Ga-PSMA-11 PET/CT. Confronting PET/CT findings with clinical data (such as date and site of injection) seems essential in the current pandemic context, just as it does for the radiopharmaceuticals used in PCa to avoid PET/CT misinterpretation and incorrect patient treatment. For 18F-FDOPA or 68Ga-DOTATOC PET/CT, this seems to have a lesser impact.

Multiple and Diffuse Gliomas by 18F-Fluorocholine PET/CT: Two Sides of the Same Coin.

ABSTRACT: Gliomas are characterized by an inherent diffuse and irregular morphology that prevents defining a boundary between tumor and healthy tissue, both in imaging assessment and surgical field. The effective identification of the extent of the disease in diffuse and multiple gliomas is crucial for their management but doing so by radiological means can be challenging. We present a broad spectrum of diffuse and multiple gliomas using 18F-fluorocholine PET/CT, demonstrating the potential of metabolic imaging in the evaluation of these gliomas, with implications in patient clinical management and outcome.

Prognostic Potential of Postoperative 18F-Fluorocholine PET/CT in Patients With High-Grade Glioma. Clinical Validation of FuMeGA Postoperative PET Criteria.

OBJECTIVE: The aim of this study was to assess the prognostic performance of postoperative 18F-fluorocholine PET/CT in patients with high-grade glioma (HGG). METHODS: Patients with HGG who underwent preoperative and postoperative 18F-fluorocholine PET/CT were prospectively enrolled in the study. Postoperative MRI was classified as complete versus incomplete resection. Postoperative 18F-fluorocholine PET/CT was classified as negative (complete) or positive for metabolic residual tumor (incomplete resection) using a 5-point score system. The correlation of positive locations on PET/CT with the sites of subsequent tumor recurrence was evaluated. The concordance of postoperative imaging techniques (Cohen κ) and their relation with progression-free survival and overall survival were assessed using Kaplan-Meier method and Cox regression analysis. RESULTS: Fifty-one studies, belonging to 47 patients, were assessed. Four patients underwent 2 postoperative 18F-fluorocholine PET/CT scans as they needed a second tumor resection for recurrence. In the follow-up, 42 patients progressed, and 37 died. Concordance between postoperative PET/CT and MRI assessment was poor. Resection grade on MRI did not show any significant association with prognosis. In multivariate analysis, only age and postoperative PET/CT showed significant association with progression-free survival (hazard ratio [HR], 1.03 [1.01-1.06, P = 0.006] and 1.88 [0.96-3.71, P = 0.067], respectively) and overall survival (HR, 1.04 [1.01-1.07, P = 0.004] and 2.63 [1.22-5.68, P = 0.014], respectively). Postoperative positive 18F-fluorocholine PET/CT locations correlated with the sites of subsequent tumor recurrence in 81.82% of cases. CONCLUSION: Postoperative 18F-fluorocholine PET/CT seems superior to postoperative MRI in the outcome prediction of patients with HGG, outperforming it in the identification of the most probable location of tumor recurrence.

Sinapine induced ferroptosis in non-small cell lung cancer cells by upregulating transferrin/transferrin receptor and downregulating SLC7A11.

Sinapine (SI) is a naturally occurring product with biological properties, but its activity against non-small cell lung cancer (NSCLC) remains unclear. This research examined the anti-tumour effects of SI in NSCLC cells and the underlying mechanisms of any effects. SI induced ferroptosis, a novel form of cell death, by increasing intracellular ferrous iron, lipid peroxidation, and reactive oxygen species (ROS) in NSCLC cells. SI treatment resulted in transferrin and transferrin receptor upregulation, and inhibition of transferrin or the transferrin receptor reduced the ferroptosis caused by SI. SI treatment also resulted in a p-53 dependent downregulation of SLC7A11. Finally, we evaluated the effects of SI in vivo and it was found that SI also successfully inhibited the growth of NSCLC in vivo. In summary, our data demonstrated that SI triggered ferroptosis in NSCLC cells and may be a promising therapeutic agent for this condition.