Abdominopelvic CT Image Quality: Evaluation of Thin (0.5-mm) Slices Using Deep Learning Reconstruction.

BACKGROUND. Because thick-section images (typically 3-5 mm) have low image noise, radiologists typically use them to perform clinical interpretation, although they may additionally refer to thin-section images (typically 0.5-0.625 mm) for problem solving. Deep learning reconstruction (DLR) can yield thin-section images with low noise. OBJECTIVE. The purpose of this study is to compare abdominopelvic CT image quality between thin-section DLR images and thin- and thick-section hybrid iterative reconstruction (HIR) images. METHODS. This retrospective study included 50 patients (31 men and 19 women; median age, 64 years) who underwent abdominopelvic CT between June 15, 2020, and July 29, 2020. Images were reconstructed at 0.5-mm section using DLR and at 0.5-mm and 3.0-mm sections using HIR. Five radiologists independently performed pairwise comparisons (0.5-mm DLR and either 0.5-mm or 3.0-mm HIR) and recorded the preferred image for subjective image quality measures (scale, -2 to 2). The pooled scores of readers were compared with a score of 0 (denoting no preference). Image noise was quantified using the SD of ROIs on regions of homogeneous liver. RESULTS. For comparison of 0.5-mm DLR images and 0.5-mm HIR images, the median pooled score was 2 (indicating a definite preference for DLR) for noise and overall image quality and 1 (denoting a slight preference for DLR) for sharpness and natural appearance. For comparison of 0.5-mm DLR and 3.0-mm HIR, the median pooled score was 1 for the four previously mentioned measures. These assessments were all significantly different (p < .001) from 0. For artifacts, the median pooled score for both comparisons was 0, which was not significant for comparison with 3.0-mm HIR (p = .03) but was significant for comparison with 0.5-mm HIR (p < .001) due to imbalance in scores of 1 (n = 28) and -1 (slight preference for HIR, n = 1). Noise for 0.5-mm DLR was lower by mean differences of 12.8 HU compared with 0.5-mm HIR and 4.4 HU compared with 3.0-mm HIR (both p < .001). CONCLUSION. Thin-section DLR improves subjective image quality and reduces image noise compared with currently used thin- and thick-section HIR, without causing additional artifacts. CLINICAL IMPACT. Although further diagnostic performance studies are warranted, the findings suggest the possibility of replacing current use of both thin- and thick-section HIR with the use of thin-section DLR only during clinical interpretations.

Safety and technical efficacy of early minimally invasive endoscopy-guided surgery for intracerebral haemorrhage: the Dutch Intracerebral haemorrhage Surgery Trial pilot study.

BACKGROUND: Previous randomised controlled trials could not demonstrate that surgical evacuation of intracerebral haemorrhage (ICH) improves functional outcome. Increasing evidence suggests that minimally invasive surgery may be beneficial, in particular when performed early after symptom onset. The aim of this study was to investigate safety and technical efficacy of early minimally invasive endoscopy-guided surgery in patients with spontaneous supratentorial ICH. METHODS: The Dutch Intracerebral Haemorrhage Surgery Trial pilot study was a prospective intervention study with blinded outcome assessment in three neurosurgical centres in the Netherlands. We included adult patients with spontaneous supratentorial ICH ≥10mL and National Institute of Health Stroke Scale (NIHSS) score ≥2 for minimally invasive endoscopy-guided surgery within 8 h after symptom onset in addition to medical management. Primary safety outcome was death or increase in NIHSS ≥4 points at 24 h. Secondary safety outcomes were procedure-related serious adverse events (SAEs) within 7 days and death within 30 days. Primary technical efficacy outcome was ICH volume reduction (%) at 24 h. RESULTS: We included 40 patients (median age 61 years; IQR 51-67; 28 men). Median baseline NIHSS was 19.5 (IQR 13.3-22.0) and median ICH volume 47.7mL (IQR 29.4-72.0). Six patients had a primary safety outcome, of whom two already deteriorated before surgery and one died within 24 h. Sixteen other SAEs were reported within 7 days in 11 patients (of whom two patients that already had a primary safety outcome), none device related. In total, four (10%) patients died within 30 days. Median ICH volume reduction at 24 h was 78% (IQR 50-89) and median postoperative ICH volume 10.5mL (IQR 5.1-23.8). CONCLUSIONS: Minimally invasive endoscopy-guided surgery within 8 h after symptom onset for supratentorial ICH appears to be safe and can effectively reduce ICH volume. Randomised controlled trials are needed to determine whether this intervention also improves functional outcome. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03608423, August 1st, 2018.

Exploring the missing heritability in subjects with hearing loss, enlarged vestibular aqueducts, and a single or no pathogenic SLC26A4 variant.

Pathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype-phenotype correlation, a significant part of cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, we first determined the presence of the previously described EVA-associated haplotype (Caucasian EVA (CEVA)), characterized by 12 single nucleotide variants located upstream of SLC26A4. We found this haplotype and a delimited V1-CEVA haplotype to be significantly enriched in our M1 patient cohort (10/16 cases). The CEVA haplotype was also present in two M0 cases (2/12). Short- and long-read whole genome sequencing and optical genome mapping could not prioritize any of the variants present within the CEVA haplotype as the likely pathogenic defect. Short-read whole-genome sequencing of the six M1 cases without this haplotype and the two M0/CEVA cases only revealed previously overlooked or misinterpreted splice-altering SLC26A4 variants in two cases, who are now genetically explained. No deep-intronic or structural variants were identified in any of the M1 subjects. With this study, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases. For pinpointing the pathogenic effect of the CEVA haplotype, additional analyses are required addressing defect(s) at the RNA, protein, or epigenetic level.

Long-term cognitive, psychosocial, and neurovascular complications of unilateral head and neck irradiation in young to middle-aged adults.

BACKGROUND: With a growing, younger population of head and neck cancer survivors, attention to long-term side-effects of prior, often radiotherapeutic, treatment is warranted. Therefore, we studied the long-term cognitive effects in young adult patients irradiated for head and neck neoplasms (HNN). METHODS: Young to middle-aged adults with HNN (aged 18-40 years) and treated with unilateral neck irradiation ≥ 5 years before inclusion underwent cardiovascular risk and neuropsychological assessments and answered validated questionnaires regarding subjective cognitive complaints, fatigue, depression, quality of life, and cancer-specific distress. Additionally, magnetic resonance imaging (MRI) of the brain was performed to assess white matter hyperintensities (WMH), infarctions, and atrophy. RESULTS: Twenty-nine patients (aged 24-61, 13 men) median 9.2 [7.3-12.9] years post-treatment were included. HNN patients performed worse in episodic memory (Z-score = -1.16 [-1.58-0.34], p < 0.001) and reported more fatigue symptoms (Z-score = 1.75 [1.21-2.00], p < 0.001) compared to normative data. Furthermore, patients had a high level of fear of tumor recurrence (13 patients [44.8%]) and a heightened speech handicap index (13 patients [44.8%]). Only a small number of neurovascular lesions were found (3 infarctions in 2 patients and 0.11 [0.00-0.40] mL WMH), unrelated to the irradiated side. Cognitive impairment was not associated with WMH, brain atrophy, fatigue, or subjective speech problems. CONCLUSIONS: HNN patients showed impairments in episodic memory and an increased level of fatigue ≥ 5 years after radiotherapy compared to normative data. Cognitive impairments could not be explained by WMH or brain atrophy on brain MRI or psychological factors. TRIAL REGISTRATION: Clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT04257968 ).

Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants.

AIMS: Management of kaposiform haemangioendotheliomas (KHE) with Kasabach-Merritt phenomenon is challenging in young infants who are subjected to developmental pharmacokinetic changes. Sirolimus, sometimes combined with corticosteroids, can be used as an effective treatment of KHE. Simultaneously, toxicities such as interstitial pneumonitis related to the use of sirolimus may be fatal. As infants have a very low CYP3-enzyme expression at birth, which rises during ageing, we hypothesize that a reduced metabolization of sirolimus might lead to high sirolimus serum levels and low dose may be sufficient without the side effects. METHODS: A case series of 5 infants with kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon was analysed retrospectively. All infants were treated with sirolimus 0.2 mg/m2 every 24 or 48 hours according to their age. Prednisone was added to the therapy for additional effect in 4 patients. RESULTS: In all patients, low dose of sirolimus led to therapeutic sirolimus levels (4-6 ng/mL). All infants (aged 4 days-7 months) had a complete haematological response, without serious adverse events. In all patients, the Kasabach-Merritt phenomenon resolved, the coagulation profile normalized and tumour size reduction was seen. CONCLUSION: Low-dose sirolimus treatment is safe for infants with kaposiform haemangioendothelioma and Kasabach-Merritt phenomenon. It is essential to realize that during the first months of life, metabolism is still developing and enzymes necessary to metabolise drugs like sirolimus still have to mature. To avoid toxic levels, the sirolimus dosage should be based on age and the associated pharmacological developments.

Diagnosing necrotizing external otitis on CT and MRI: assessment of pattern of extension.

BACKGROUND AND PURPOSE: Necrotizing external otitis (NEO) is a serious complication of external otitis. NEO can be classified according to-anterior, medial, posterior, intracranial, and contralateral-extension patterns. Currently there is no consensus on the optimal imaging modality for the identification of disease extension. This study compares NEO extension patterns on MR and CT to evaluate diagnostic comparability. METHODS: Patients who received a CT and MR within a 3-month interval were retrospectively examined. Involvement of subsites and subsequent spreading patterns were assessed on both modalities by a radiologist in training and by a senior head and neck radiologist. The prevalence of extension patterns on CT and MR were calculated and compared. RESULTS: All 21 included NEO cases showed an anterior extension pattern on CT and MR. Contrary to MR, medial extension was not recognized on CT in two out of six patients, and intracranial extension in five out of eight patients. The posterior extension pattern was not recognized on MR. Overall, single anterior extension pattern (62%) is more prevalent than multiple extension patterns (38%). CONCLUSION: All anterior NEO extension pattern were identified on CT as well as MR. However, the medial and intracranial spreading patterns as seen on MR could only be identified on CT in a small number of patients. The posterior spreading pattern can be overlooked on MR. Thus, CT and MR are complimentary for the initial diagnosis and work-up of NEO as to correctly delineate disease extent through the skull base.

Deep learning-based reconstruction may improve non-contrast cerebral CT imaging compared to other current reconstruction algorithms.

OBJECTIVES: To evaluate image quality and reconstruction times of a commercial deep learning reconstruction algorithm (DLR) compared to hybrid-iterative reconstruction (Hybrid-IR) and model-based iterative reconstruction (MBIR) algorithms for cerebral non-contrast CT (NCCT). METHODS: Cerebral NCCT acquisitions of 50 consecutive patients were reconstructed using DLR, Hybrid-IR and MBIR with a clinical CT system. Image quality, in terms of six subjective characteristics (noise, sharpness, grey-white matter differentiation, artefacts, natural appearance and overall image quality), was scored by five observers. As objective metrics of image quality, the noise magnitude and signal-difference-to-noise ratio (SDNR) of the grey and white matter were calculated. Mean values for the image quality characteristics scored by the observers were estimated using a general linear model to account for multiple readers. The estimated means for the reconstruction methods were pairwise compared. Calculated measures were compared using paired t tests. RESULTS: For all image quality characteristics, DLR images were scored significantly higher than MBIR images. Compared to Hybrid-IR, perceived noise and grey-white matter differentiation were better with DLR, while no difference was detected for other image quality characteristics. Noise magnitude was lower for DLR compared to Hybrid-IR and MBIR (5.6, 6.4 and 6.2, respectively) and SDNR higher (2.4, 1.9 and 2.0, respectively). Reconstruction times were 27 s, 44 s and 176 s for Hybrid-IR, DLR and MBIR respectively. CONCLUSIONS: With a slight increase in reconstruction time, DLR results in lower noise and improved tissue differentiation compared to Hybrid-IR. Image quality of MBIR is significantly lower compared to DLR with much longer reconstruction times. KEY POINTS: • Deep learning reconstruction of cerebral non-contrast CT results in lower noise and improved tissue differentiation compared to hybrid-iterative reconstruction. • Deep learning reconstruction of cerebral non-contrast CT results in better image quality in all aspects evaluated compared to model-based iterative reconstruction. • Deep learning reconstruction only needs a slight increase in reconstruction time compared to hybrid-iterative reconstruction, while model-based iterative reconstruction requires considerably longer processing time.

Brain CT perfusion improves intracranial vessel occlusion detection on CT angiography.

BACKGROUND AND PURPOSE: To evaluate whether brain CT perfusion (CTP) aids in the detection of intracranial vessel occlusion on CT angiography (CTA) in acute ischemic stroke. MATERIALS AND METHODS: Medical-ethical committee approval of our hospital was obtained and informed consent was waived. Patients suspected of acute ischemic stroke who underwent non-contrast CT(NCCT), CTA and whole-brain CTP in our center in the year 2015 were included. Three observers with different levels of experience evaluated the imaging data of 110 patients for the presence or absence of intracranial arterial vessel occlusion with two strategies. In the first strategy, only NCCT and CTA were available. In the second strategy, CTP maps were provided in addition to NCCT and CTA. Receiver-operating-characteristic (ROC) analysis was used for the evaluation of diagnostic accuracy. RESULTS: Overall, a brain perfusion deficit was scored present in 87-89% of the patients with an intracranial vessel occlusion, more frequently observed in the anterior than in the posterior circulation. Performance of intracranial vessel occlusion detection on CTA was significantly improved with the availability of CTP maps as compared to the first strategy (P=0.023), due to improved detection of distal and posterior circulation vessel occlusions (P-values of 0.032 and 0.003 respectively). No added value of CTP was found for intracranial proximal vessel occlusion detection, with already high accuracy based on NCCT and CTA alone. CONCLUSION: The performance of intracranial vessel occlusion detection on CTA was improved with the availability of brain CT perfusion maps due to the improved detection of distal and posterior circulation vessel occlusions.

Genotype and Phenotype Analyses of a Novel WFS1 Variant (c.2512C>T p.(Pro838Ser)) Associated with DFNA6/14/38.

The aim of this study is to contribute to a better description of the genotypic and phenotypic spectrum of DFNA6/14/38 and aid in counseling future patients identified with this variant. Therefore, we describe the genotype and phenotype in a large Dutch-German family (W21-1472) with autosomal dominant non-syndromic, low-frequency sensorineural hearing loss (LFSNHL). Exome sequencing and targeted analysis of a hearing impairment gene panel were used to genetically screen the proband. Co-segregation of the identified variant with hearing loss was assessed by Sanger sequencing. The phenotypic evaluation consisted of anamnesis, clinical questionnaires, physical examination and examination of audiovestibular function. A novel likely pathogenic WFS1 variant (NM_006005.3:c.2512C>T p.(Pro838Ser)) was identified in the proband and found to co-segregate with LFSNHL, characteristic of DFNA6/14/38, in this family. The self-reported age of onset of hearing loss (HL) ranged from congenital to 50 years of age. In the young subjects, HL was demonstrated in early childhood. At all ages, an LFSNHL (0.25-2 kHz) of about 50-60 decibel hearing level (dB HL) was observed. HL in the higher frequencies showed inter-individual variability. The dizziness handicap inventory (DHI) was completed by eight affected subjects and indicated a moderate handicap in two of them (aged 77 and 70). Vestibular examinations (n = 4) showed abnormalities, particularly in otolith function. In conclusion, we identified a novel WFS1 variant that co-segregates with DFNA6/14/38 in this family. We found indications of mild vestibular dysfunction, although it is uncertain whether this is related to the identified WFS1 variant or is an incidental finding. We would like to emphasize that conventional neonatal hearing screening programs are not sensitive to HL in DFNA6/14/38 patients, because high-frequency hearing thresholds are initially preserved. Therefore, we suggest screening newborns in DFNA6/14/38 families with more frequency-specific methods.

Subclassification of the Koos grade 2 vestibular schwannoma into 2a and 2b for individualized patient care: A validity and reliability study.

OBJECTIVE: Vestibular schwannoma (VS) growth of ≥2 mm during serial MRI observation, irrespective of size, is the benchmark for treatment initiation in almost all centers. Although the probability of less optimal outcomes significantly increases in VS closer to the brainstem, early intervention does not improve long-term quality of life. Moving beyond the recommendation of definitive treatment for all VS after detected growth, we subclassified Koos 2 tumors based on extrameatal extension and relation to the brainstem. The aim of the current study was to evaluate the Koos 2 subclassification's validity and the inter-and intra-rater reliability of the entire Koos classification. METHODS: Six experts, including neurosurgeons, otorhinolaryngologists and radiologists from two tertiary referral centers, classified 43 VS MRI scans. Validity of the Koos 2 subclassification was evaluated by the percentage agreement against the multidisciplinary skull base tumor board management advice. Inter- and intra-rater reliability were calculated using the intraclass correlation coefficient (ICC). RESULTS: Validity was almost perfect in Koos 2a VSs with a 100% agreement and 87.5% agreement for Koos 2b. Inter-rater reliability for all Koos grades was significantly excellent (ICC 0.91; 95%CI 0.866 to 0.944, p= <0.001). Five raters had an excellent intra-rater reliability (ICC > 0.90; p= <0.01) and one rater had a good intra-rater reliability (ICC 0.88; 95% CI 0.742 to 0.949). CONCLUSIONS: Although multiple factors influence decision-making, the classification of Koos 2a and 2b with excellent inter- and intra-rater reliability, can aid in recommending treatment initiation, moving beyond detected tumor growth, aiming to optimize patient centered care.

Clinical characteristics and an evaluation of predictors for a favourable outcome of Mycobacterium abscessus otomastoiditis: a systematic review and meta-analysis of individual participant data.

BACKGROUND: Otomastoiditis caused by Mycobacterium abscessus is rare, but its incidence has increased over the past decades and its optimal treatment remains unknown. This study aims to summarise the clinical and therapeutic features and find characteristics of patients with M. abscessus otomastoiditis associated with favourable treatment outcomes. METHODS: We searched MEDLINE, Embase and Web of Science to identify studies including patients with M. abscessus otomastoiditis. A 1-stage individual patient data (IPD) meta-analysis was conducted. A 2-level mixed-effects linear regression model was provided for antimycobacterial treatment duration. RESULTS: Twenty-three studies reported a total of 85 patients. Children possess a unique clinical profile including a history of ear infections, tympanostomy tube placement and antibiotic treatment. Antimycobacterial treatment was administered for 26 (interquartile range [IQR]: 15-35) weeks. Macrolides were prescribed in 98.8% of the cases. Surgery was performed in 80.5% of the cases, of which, 47.1% required revision surgery. Otalgia was a significant predictor (ß = 9.3; P = .049) of antimycobacterial treatment duration. CONCLUSIONS: Mastoid surgery (regularly requiring revision) and a multidrug regimen for a minimum of 6 months, including a minimum of 3 active agents, are most often needed to attain cure. The presence of otalgia significantly extends the treatment duration of M. abscessus otomastoiditis.

High-Accuracy Nodal Staging of Head and Neck Cancer With USPIO-Enhanced MRI: A New Reading Algorithm Based on Node-to-Node Matched Histopathology.

OBJECTIVES: Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) is a potential diagnostic tool for lymph node assessment in patients with head and neck cancer. Validation by radiologic-pathologic correlation is essential before the method is evaluated in clinical studies. In this study, MRI signal intensity patterns of lymph nodes are correlated to their histopathology to develop a new USPIO-enhanced MRI reading algorithm that can be used for nodal assessment in head and neck cancer patients. MATERIALS AND METHODS: Ten head and neck cancer patients underwent in vivo USPIO-enhanced MRI before neck dissection. An ex vivo MRI of the neck dissection specimen was performed for precise coregistration of in vivo MRI with histopathology. Normal clinical histopathological workup was extended with meticulous matching of all lymph nodes regarded as potentially metastatic based on their in vivo MRI signal intensity pattern. On the basis of histopathology of resected nodes, in vivo MRI signal characteristics were defined separating benign from malignant lymph nodes. RESULTS: Fifteen of 34 node-to-node correlated lymph nodes with remaining signal intensity on T2*-weighted MRI were histopathologically metastatic and 19 were benign. Radiological analysis revealed that metastatic lymph nodes showed equal or higher MRI signal intensity when compared with lipid tissue on T2*-weighted MGRE sequence (15/16 lymph nodes; 94%), whereas healthy lymph nodes showed lower (17/19 lymph nodes; 89%) or complete attenuation of signal intensity (273/279; 98%) when compared with lipid tissue on T2*-weighted MGRE. Histopathology of all resected specimens identified 392 lymph nodes. Six lymph nodes with (micro)metastases were missed with in vivo MRI. Whether these 6 lymph nodes were correlated to a nonmalignant lymph node on in vivo MRI or could not be detected at all is unclear. CONCLUSIONS: We developed a new reading algorithm to differentiate benign from malignant lymph nodes in head and neck cancer patients on the basis of their appearance on high-resolution T2*-weighted USPIO-enhanced MRI. Next steps involve validation of our reading algorithm to further improve the accuracy of neck lymph node staging with USPIO-enhanced MRI in prospective clinical studies with larger number of patients.

Assessing radiation-induced carotid vasculopathy using ultrasound after unilateral irradiation: a cross-sectional study.

BACKGROUND: Increased head and neck cancer (HNC) survival requires attention to long-term treatment sequelae. Irradiated HNC survivors have a higher ischemic stroke risk. However, the pathophysiology of radiation-induced vasculopathy is unclear. Arterial stiffness could be a biomarker. This study examined alterations in intima-media thickness (IMT) and stiffness-related parameters, shear wave (SWV) and pulse wave velocity (PWV), in irradiated compared to control carotids in unilateral irradiated patients. METHODS: Twenty-six patients, median 40.5 years, 5-15 years after unilateral irradiation for head and neck neoplasms underwent a bilateral carotid ultrasound using an Aixplorer system with SL18-5 and SL10-2 probes. IMT, SWV, and PWV were assessed in the proximal, mid, and distal common (CCA) and internal carotid artery (ICA). Plaques were characterized with magnetic resonance imaging. Measurements were compared between irradiated and control sides, and radiation dose effects were explored. RESULTS: CCA-IMT was higher in irradiated than control carotids (0.54 [0.50-0.61] vs. 0.50 [0.44-0.54] mm, p = 0.001). For stiffness, only anterior mid-CCA and posterior ICA SWV were significantly higher in the irradiated side. A radiation dose-effect was only (weakly) apparent for PWV (R2: end-systolic = 0.067, begin-systolic = 0.155). Ultrasound measurements had good-excellent intra- and interobserver reproducibility. Plaques had similar characteristics but were more diffuse in the irradiated side. CONCLUSIONS: Increased CCA-IMT and SWV in some segments were seen in irradiated carotids. These alterations, even in young patients, mark the need for surveillance of radiation-induced vasculopathy. TRIAL REGISTRATION: clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT04257968 ).

Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer.

AIM: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC. PATIENTS AND METHODS: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included. RESULTS: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively. CONCLUSION: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT03729297.

Interleukin-1 receptor antagonist anakinra as treatment for paradoxical responses in HIV-negative tuberculosis patients: A case series.

BACKGROUND: Paradoxical inflammatory responses can occur during microbiologically successful antituberculous therapy. Optimal treatment is unknown, but corticosteroids are used most often. It is likely that interleukin-1 (IL-1) plays a central role in the development of these paradoxical responses, and if corticosteroids fail or are undesirable because of adverse effects, anti-IL-1 therapy may therefore be a rational choice. METHODS: We present seven HIV-negative tuberculosis patients with paradoxical responses, two with exclusively pulmonary and five with extrapulmonary tuberculosis. All had received corticosteroids, with unsatisfactory effect. Patients were treated with the IL-1 receptor antagonist anakinra and monitored for reduction of fever and inflammatory markers, imaging evidence of stabilization or regression of lesions, and respiratory improvement. FINDINGS: Six patients had anemia and four patients had lymphopenia at the start of the antituberculosis treatment. Fever was present in six patients at the moment of paradoxical response. Anakinra resulted in the decrease of fever within days, followed by resolution of symptoms and radiological improvement in five patients. Anakinra induced neutropenia, necessitating its cessation in two patients, who recovered quickly afterward. CONCLUSION: Anakinra can be considered in HIV-negative tuberculosis patients with paradoxical responses when steroids fail or are undesired. Given its favorable safety profile and reversible side effects, it is conceivable that anakinra might also be used as first-line adjuvant treatment for paradoxical responses. FUNDING: A.v.L. and R.v.C. are supported by National Institutes of Health (R01AI145781).