Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): a single-arm, phase 2 trial.

BACKGROUND: Metastatic phaeochromocytomas and paragangliomas (MPPGs) are orphan diseases. Up to 50% of MPPGs are associated with germline pathogenic variants of the SDHB gene. These tumours and many non-familial MPPGs exhibit a phenotype that is characterised by abnormal angiogenesis. We aimed to assess the activity and safety of cabozantinib, an antiangiogenic multi-tyrosine kinase inhibitor, in patients with MPPGs. METHODS: The Natalie Trial is a single-arm, phase 2 clinical trial being conducted at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 18 years or older with histologically confirmed, progressive, and unresectable MPPGs, with an Eastern Cooperative Oncology Group performance status of 0-2, were treated with oral cabozantinib 60 mg/day. The primary endpoint was the investigator-assessed overall response rate per the Response Evaluation Criteria in Solid Tumours version 1.1 criteria. All outcomes were assessed in all evaluable participants who received any amount of study treatment. The trial is registered with ClinicalTrials.gov (NCT02302833) and is active but not recruiting. FINDINGS: From March 10, 2015, to May 11, 2021, 17 patients (13 male participants and four female participants) were enrolled. The median follow-up was 25 months (IQR 18-49). The overall response rate was 25·0% (95% CI 7·3-52·4; four of 16 patients). Seven grade 3 adverse events were reported in six patients, including single cases of hand-and-foot syndrome, hypertension, rectal fistula, QT prolongation, and asymptomatic hypomagnesaemia, and two cases of asymptomatic elevations of amylase and lipase. There were no grade 4 adverse events and no patient died on-study. INTERPRETATION: Cabozantinib shows promising activity in patients with MPPGs. FUNDING: Team NAT Foundation, Margaret Cazalot, and Clarence P Cazalot.

Novel alternative tools for metastatic pheochromocytomas/paragangliomas prediction.

OBJECTIVE: The existing prediction models for metastasis in pheochromocytomas/paragangliomas (PPGLs) showed high heterogeneity in different centers. Therefore, this study aimed to establish new prediction models integrating multiple variables based on different algorithms. DESIGN AND METHODS: Data of patients with PPGLs undergoing surgical resection at the Peking Union Medical College Hospital from 2007 to 2022 were collected retrospectively. Patients were randomly divided into the training and testing sets in a ratio of 7:3. Subsequently, decision trees, random forest, and logistic models were constructed for metastasis prediction with the training set and Cox models for metastasis-free survival (MFS) prediction with the total population. Additionally, Ki-67 index and tumor size were transformed into categorical variables for adjusting models. The testing set was used to assess the discrimination and calibration of models and the optimal models were visualized as nomograms. Clinical characteristics and MFS were compared between patients with and without risk factors. RESULTS: A total of 198 patients with 59 cases of metastasis were included and classified into the training set (n = 138) and testing set (n = 60). Among all models, the logistic regression model showed the best discrimination for metastasis prediction with an AUC of 0.891 (95% CI, 0.793-0.990), integrating SDHB germline mutations [OR: 96.72 (95% CI, 16.61-940.79)], S-100 (-) [OR: 11.22 (95% CI, 3.04-58.51)], ATRX (-) [OR: 8.42 (95% CI, 2.73-29.24)] and Ki-67 ≥ 3% [OR: 7.98 (95% CI, 2.27-32.24)] evaluated through immunohistochemistry (IHC), and tumor size ≥ 5 cm [OR: 4.59 (95% CI, 1.34-19.13)]. The multivariate Cox model including the above risk factors also showed a high C-index of 0.860 (95% CI, 0.810-0.911) in predicting MFS after surgery. Furthermore, patients with the above risk factors showed a significantly poorer MFS (P ≤ 0.001). CONCLUSIONS: Models established in this study provided alternative and reliable tools for clinicians to predict PPGLs patients' metastasis and MFS. More importantly, this study revealed for the first time that IHC of ATRX could act as an independent predictor of metastasis in PPGLs.

Adrenal Metastasectomy in the Era of Immuno- and Targeted Therapy.

Adrenal metastasectomy has an increasing role in multimodality oncologic care for diverse primary cancer types. In this review, we discuss the epidemiology, evaluation, and contemporary best practices in the management of adrenal metastases from various primaries. Initial evaluation of suspected adrenal metastases should include diagnostic imaging to assess the extent of tumor involvement and determine surgical resectability, as well as biochemical evaluation for hormone secretion. Biopsy has a minimal role and should only be performed in tumors that are established to be non-hormone secreting and when the biopsy results would change clinical management. Adrenal metastasectomy is associated with survival benefit in selected patients. We suggest that adrenal metastasectomy has the greatest benefit in four clinical scenarios: (1) disease limited to the adrenal gland in which adrenalectomy renders the patient disease-free; (2) isolated progression in the adrenal gland in the setting of otherwise controlled metastatic extra-adrenal disease; (3) need for palliation of symptoms related to adrenal metastases; or (4) in the context of tissue-based clinical trials. Both minimally invasive and open adrenalectomy techniques are safe and appear to have equivalent oncologic outcomes. Minimally invasive approaches are favored when technically feasible while maintaining oncologic principles. A multidisciplinary evaluation including clinicians with expertise in the primary cancer type is essential to the successful management of adrenal metastases.

Dual Energy-Derived Metrics for Differentiating Adrenal Adenomas From Nonadenomas on Single-Phase Contrast-Enhanced CT.

BACKGROUND. Adrenal masses are often indeterminate on single-phase postcontrast CT. Dual-energy CT (DECT) with three-material decomposition algorithms may aid characterization. OBJECTIVE. The purpose of this study was to compare the diagnostic performance of metrics derived from portal venous phase DECT, including virtual noncontrast (VNC) attenuation, fat fraction, iodine density, and relative enhancement ratio, for characterizing adrenal masses. METHODS. This retrospective study included 128 patients (82 women, 46 men; mean age, 64.6 ± 12.7 [SD] years) who between January 2016 and December 2019 underwent portal venous phase abdominopelvic DECT that showed a total of 139 adrenal lesions with an available reference standard based on all imaging, clinical, and pathologic records (87 adenomas, 52 nonadenomas [48 metastases, two adrenal cortical carcinomas, one ganglioneuroma, one hematoma]). Two radiologists placed ROIs to determine the following characteristics of the masses: VNC attenuation, fat fraction, iodine density normalized to portal vein, and for masses with VNC greater than 10 HU, relative enhancement ratio (ratio of portal venous phase attenuation to VNC attenuation). Readers' mean measurements were used for ROC analyses, and clinically optimal thresholds were derived as thresholds yielding the highest sensitivity at 100% specificity. RESULTS. Adenomas and nonadenomas were significantly different (all p < .001) in VNC attenuation (mean ± SD, 18.5 ± 12.9 vs 34.1 ± 8.9 HU), fat fraction (mean ± SD, 24.3% ± 8.2% vs 14.2% ± 5.6%), normalized iodine density (mean ± SD, 0.34 ± 0.15 vs 0.17 ± 0.17), and relative enhancement ratio (mean ± SD, 186% ± 96% vs 58% ± 59%). AUCs for all metrics ranged from 0.81 through 0.91. The metric with highest sensitivity for adenoma at the clinically optimal threshold (i.e., 100% specificity) was fat fraction (threshold, ≥ 23.8%; sensitivity, 59% [95% CI, 48-69%]) followed by VNC attenuation (≤ 15.2 HU; sensitivity, 39% [95% CI, 29-50%]), relative enhancement ratio (≥ 214%; sensitivity, 37% [95% CI, 25-50%]), and normalized iodine density (≥ 0.90; sensitivity, 1% (95% CI, 0-60%]). VNC attenuation at the traditional true noncontrast attenuation threshold of 10 HU or lower had sensitivity of 28% (95% CI, 19-38%) and 100% specificity. Presence of fat fraction 23.8% or greater or relative enhancement ratio 214% or greater yielded sensitivity of 68% (95% CI, 57-77%) with 100% specificity. CONCLUSION. For adrenal lesions evaluated with single-phase DECT, fat fraction had higher sensitivity than VNC attenuation at both the clinically optimal threshold and the traditional threshold of 10 HU or lower. CLINICAL IMPACT. By helping to definitively diagnose adenomas, DECT-derived metrics can help avoid downstream imaging for incidental adrenal lesions.

[A Case of Sigmoid Colon Cancer with Simultaneous Solitary Adrenal Metastasis Refractory to Preoperative Diagnosis].

A 72-year-old man was referred to our urology department due to a giant adrenal tumor detected by computed tomography( CT). Endocrine screening showed that cortisol, renin, aldosterone, adrenaline, and noradrenaline levels were all normal, and there was no evidence of adrenal hyperfunction. The adrenal tumor was so large that we suspected malignancy. Contrast-enhanced CT of the abdomen was performed for qualitative diagnostic purposes, and showed wall thickening of the sigmoid colon extending for approximately 6 cm. Lower gastrointestinal endoscopy was performed and revealed a full circumferential type 2 tumor in the sigmoid colon. Biopsy results showed intermediate differentiated ductal adenocarcinoma. Tumor markers were as follows: CEA 23.1 ng/mL, CA19-9 962 U/mL. The adrenal tumor was suspected of being malignant due to its size, but imaging examinations did not lead to a diagnosis of primary or metastatic disease. There were no tumors other than those in the sigmoid colon and adrenal glands. Since complete resection was deemed possible, sigmoid colon resection and combined left adrenalectomy were performed for both a diagnosis and treatment. A histopathological examination revealed that the histology of the adrenal tumor resembled that of colorectal cancer, leading to a diagnosis of left adrenal metastasis from sigmoid colon cancer.

Stereotactic body radiotherapy of adrenal metastases-A dose-finding study.

Optimal doses for the treatment of adrenal metastases with stereotactic radiotherapy (SBRT) are unknown. We aimed to identify dose-volume cut-points associated with decreased local recurrence rates (LRR). A multicenter database of patients with adrenal metastases of any histology treated with SBRT (biologically effective dose, BED10 ≥50 Gy, ≤12 fractions) was analyzed. Details on dose-volume parameters were required (planning target volume: PTV-D98%, PTV-D50%, PTV-D2%; gross tumor volume: GTV-D50%, GTV-mean). Cut-points for LRR were optimized using the R maxstat package. One hundred and ninety-six patients with 218 lesions were included, the largest histopathological subgroup was adenocarcinoma (n = 101). Cut-point optimization resulted in significant cut-points for PTV-D50% (BED10: 73.2 Gy; P = .003), GTV-D50% (BED10: 74.2 Gy; P = .006), GTV-mean (BED10: 73.0 Gy; P = .007), and PTV-D2% (BED10: 78.0 Gy; P = .02) but not for the PTV-D98% (P = .06). Differences in LRR were clinically relevant (LRR ≥ doubled for cut-points that were not achieved). Further dose-escalation was not associated with further improved LRR. PTV-D50%, GTV-D50%, and GTV-mean cut-points were also associated with significantly improved LRR in the adenocarcinoma subgroup. Separate dose optimizations indicated a lower cut-point for the PTV-D50% (BED10: 69.1 Gy) in adenocarcinoma lesions, other values were similar (<2% difference). Associations of cut-points with overall survival (OS) and progression-free survival were not significant but durable freedom from local recurrence was associated with OS in a landmark model (P < .001). To achieve a significant improvement of LRR for adrenal SBRT, a moderate escalation of PTV-D50% BED10 >73.2 Gy (adenocarcinoma: 69.1 Gy) should be considered.

Can radiomic feature analysis differentiate adrenal metastases from lipid-poor adenomas on single-phase contrast-enhanced CT abdomen?

AIM: To assess if radiomic feature analysis could help to differentiate between the lipid-poor adenomas and metastases to the adrenal glands. MATERIALS AND METHODS: Eighty-six patients (women:men 42:44; mean age 66 years) with biopsy-proven adrenal metastases and 55 patients (women:men 39:16; mean age 67 years) with lipid-poor adenomas who underwent contrast-enhanced, portal-venous phase CT of the abdomen. Radiomic features were extracted using the PyRadiomics extension for 3D Slicer. Following elastic net regularisation, seven of 1,132 extracted radiomic features were selected to build a radiomic signature. This was combined with patient demographics to create a predictive nomogram. The calibration curves in both the training and validation cohorts were assessed using a Hosmer-Lemeshow test. RESULTS: The radiomic signature alone yielded an area under the curve of 91.7% in the training cohort (n=93) and 87.1% in the validation cohort (n=48). The predictive nomogram, which combined age, a previous history of malignancy, and the radiomic signature, had an AUC of 97.2% in the training cohort and 90.4% in the validation cohort. CONCLUSION: The present nomogram has the potential to differentiate between a lipid-poor adrenal adenoma and adrenal metastasis on portal-venous CT.

Stereotactic or conformal radiotherapy for adrenal metastases: Patient characteristics and outcomes in a multicenter analysis.

To report outcome (freedom from local progression [FFLP], overall survival [OS] and toxicity) after stereotactic, palliative or highly conformal fractionated (>12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤12 fractions, biologically effective dose [BED10] ≥ 50 Gy), 3DCRT/IMRT (>12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 < 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). Three hundred twenty-six patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT and Pall-RT in 260, 27 and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%) and melanoma (6.7%). Unadjusted FFLP was higher after SBRT vs Pall-RT (P = .026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4% and 27.7%). OS was longer after SBRT vs other groups (P < .05) and increased in patients with locally controlled metastases in a landmark analysis (P < .0001). Toxicity was mostly mild; notably, four cases of adrenal insufficiency occurred, two of which were likely caused by immunotherapy or tumor progression. Radiotherapy for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. One-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway.

Adrenalectomy for Secondary Malignancy: Patients, Outcomes, and Indications.

OBJECTIVE: The goal of this study was to examine a multi-institutional experience with adrenal metastases to describe survival outcomes and identify subpopulations who benefit from adrenal metastasectomy. BACKGROUND: Adrenalectomy for metastatic disease is well-described, although indications and outcomes are incompletely defined. METHODS: A retrospective cohort study was performed of patients undergoing adrenalectomy for secondary malignancy (2002-2015) at 6 institutions. The primary outcomes were disease free survival (DFS) and overall survival (OS). Analysis methods included Kaplan-Meier and Cox proportional hazards. RESULTS: Of 269 patients, mean age was 60.1 years; 50% were male. The most common primary malignancies were lung (n = 125, 47%), renal cell (n = 38, 14%), melanoma (n = 33, 12%), sarcoma (n = 18, 7%), and colorectal (n = 12, 5%). The median time to detection of adrenal metastasis after initial diagnosis of the primary tumor was 17 months (interquartile range: 6-41). Post-adrenalectomy, the median DFS was 18 months (1-year DFS: 54%, 5-year DFS: 31%). On multivariable analysis, lung primary was associated with longer DFS [hazard ratio (HR): 0.49, P = 0.008). Extra-adrenal oligometastatic disease at initial presentation (HR: 1.84, P = 0.016), larger tumor size (HR: 1.07, P = 0.013), chemotherapy as treatment of the primary tumor (HR: 2.07 P = 0.027) and adjuvant chemotherapy (HR: 1.95, P = 0.009) were associated with shorter DFS. Median OS was 53 months (1-year OS: 83%, 5-year OS: 43%). On multivariable analysis, extra-adrenal oligometastatic disease at adrenalectomy (HR: 1.74, P = 0.031), and incomplete resection of adrenal metastasis (R1 margins; HR: 1.62, P = 0.034; R2 margins; HR: 5.45, P = 0.002) were associated with shorter OS. CONCLUSIONS: Durable survival is observed in patients undergoing adrenal metastasectomy and should be considered for subjects with isolated adrenal metastases.

Image-Guided Percutaneous Ablation of Adrenal Metastases: A Meta-Analysis of Efficacy and Safety.

PURPOSE: To evaluate the efficacy and safety of percutaneous ablation of adrenal metastases through a meta-analysis of various image-guided percutaneous ablation techniques. MATERIALS AND METHODS: A comprehensive literature search of PubMed and Embase databases was performed for studies evaluating the efficacy and/or safety of image-guided percutaneous ablation of adrenal metastases. A total of 37 studies published between 2009 and 2020 were analyzed, comprising a sample size of 959 patients. Proportion estimates of overall survival, local control, and toxicity were analyzed in a pooled meta-analysis. The pooled prevalence of adverse events after ablation was calculated based on common terminology criteria for adverse events (CTCAE) grading. RESULTS: Of the 959 included patients, 320 (33.3%) underwent radiofrequency ablation, 72 (7.5%) microwave ablation, 95 (9.9%) cryoablation, and 46 (4.8%) ethanol injections for treatment of adrenal metastases. The remaining 426 (44.4%) patients were from studies involving a mixture of the 4 listed percutaneous ablation techniques. The pooled 1-year local control rate was 80% (95% confidence interval [CI], 76%-83%). The pooled 1-year overall survival rate was 77% (95% CI, 70%-83%). The overall rate of severe adverse events after ablation (CTCAE grade 3 or higher) was 16.1%. The overall rate of low-grade adverse events after ablation (CTCAE grade 2 or lower) was 32.6%. Approximately 21.9% (n = 203) of patients experienced intraprocedural hypertensive crises, the majority of which were reversed with antihypertensive medications. CONCLUSIONS: This study demonstrates that image-guided percutaneous ablation can be effective in achieving acceptable short- to mid-term local tumor control and overall survival with a moderate safety profile.

Adrenal metastases: early biphasic contrast-enhanced CT findings with emphasis on differentiation from lipid-poor adrenal adenomas.

AIM: To evaluate the accuracy of unenhanced attenuation and early biphasic contrast-enhanced computed tomography (CT) in differentiating adrenal metastases (AMs) from lipid-poor adrenal adenomas (AAs). MATERIALS AND METHODS: This retrospective study included 37 patients with 50 AMs and 86 patients with 89 lipid-poor AAs. Quantitative data including the longest diameter (LD), the shortest diameter (SD), LD/SD ratio, CT attenuation values (CTu, CTa, CTv), degree of enhancement (DEAP, DEPP, DEpeak, APW, RPW), and peak enhanced/unenhanced (PE/U) CT attenuation ratio were obtained. Qualitative data including enhancement pattern, location, shape, the presence of calcification or haemorrhage, and intra-lesion necrosis were analysed. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were also calculated. RESULTS: The PE/U ratio (≤1.25), CTu (≥32.2 HU), DEpeak (≤43.15 HU), DEPP (≤37.65 HU), presence of intralesional necrosis, location (bilateral adrenal glands), and irregular shape were significant variables for differentiating AMs from lipid-poor AAs (p<0.05). Among them, PE/U ratio (≤1.25) was of greater value in differentiating the two adrenal diseases, with sensitivity, specificity, area under the receiver operating curve (ROC) curve (AUC) of 92%, 84%, 0.933, respectively. When at least any three of above criteria were combined, the sensitivity, specificity, PPV, and NPV for diagnosing AMs were 88%, 93%, 88%, and 88%, respectively. CONCLUSIONS: These seven CT criteria are conducive to differentiate AMs from lipid-poor AAs. Early biphasic contrast-enhanced CT is a high-efficient and practical imaging tool in differentiating them.

Virtual Noncontrast Images From Portal Venous Phase Spectral-Detector CT Acquisitions for Adrenal Lesion Characterization.

OBJECTIVE: The aim of this study was to investigate if Hounsfield unit (HU) values from virtual noncontrast (VNC) images derived from portal venous phase spectral-detector computed tomography can help to differentiate adrenal adenomas and metastases. METHODS: Spectral-detector computed tomography datasets of 33 patients with presence of adrenal lesions and standard of reference for lesion origin by follow-up/prior examinations or dedicated magnetic resonance imaging were included. Conventional and VNC images were reconstructed from the same scan. Region of interest-based image analysis was performed in adrenal lesions and contralateral healthy adrenal tissue. RESULTS: The 33 lesions consisted of 23 adenomas and 10 metastases. Hounsfield unit values of all lesions in VNC images were significantly lower compared with conventional images (18.2 ± 12.6 HU vs 59.6 ± 21.7 HU, P < 0.001). Hounsfield unit values in adenomas were significantly lower in VNC images (11.3 ± 6.5 HU vs 34.1 ± 9.1 HU, P < 0.001). CONCLUSIONS: Virtual noncontrast HU values differed significantly between adrenal adenomas and metastases and can therefore be used for improved characterization of incidental adrenal lesions and definition of adrenal adenomas.

Management and outcome of metastatic pheochromocytomas/paragangliomas: an overview.

BACKGROUND: Metastatic pheochromocytomas and paragangliomas (PPGLs) occur in about 5-26% of cases and are characterized by a heterogeneous prognosis. Metastases can be synchronous at the initial diagnosis, but they can occur also many years after surgery for the primary tumor. To date, the treatment of patients affected by metastatic PPGLs represents a clinical challenge because of the lack of guidelines. AIM: The aim of this article is to review the available management options and their impact on the outcomes of patients with metastatic PPGLs. RESULTS: Generally, treatments are not curative. Surgery, when possible, can be used to reduce hormonal symptoms and cardiovascular morbidity. Chemotherapy plays a role in patients with high burden tumor and rapid disease progression. Tyrosine kinases inhibitors (TKIs) might be considered for their ability to block the angiogenesis and cell growth. Radiation therapy and interventional radiology techniques can help in the management of local metastases to control symptoms and avoid tumor progression. On the other hand, peptide receptor radionuclide therapy (PRRT), using 90Y or 177Lu-DOTATATE, could be a promising therapy. In addition, high specific 131I-MIBG was approved by the Food and Drug Administration (FDA) in the US for the treatment of patients affected by metastatic and unresectable 131I-MIBG positive PPGLs. Considering the different pathways involved in the pathogenesis of PPGLs, several target therapies have been proposed and are under evaluation in clinical trials. CONCLUSIONS: The choice of the appropriate treatment should be based on multidisciplinary and personalized approach taking into account the rarity and the variability of these tumors.

Carcinoma of unknown primary origin with isolated adrenal metastasis: a report of two cases.

The adrenal glands are one of the most common sites of malignant tumor metastasis. However, metastatic adrenal carcinoma of unknown primary origin with localized adrenal gland involvement is an extremely rare condition. Herein, we reported two cases of carcinoma of unknown primary origin with isolated adrenal metastasis. In the first case, back pain was the trigger; while in the second case, the triggers were low fever and weight loss. Metabolic abnormalities such as hypertension and obesity were not detected in either case. Neither patient had relevant previous medical histories, including malignancy. However, both had a long-term history of smoking. Systemic imaging studies revealed only adrenal tumors and surrounding lesions. Primary adrenocortical carcinoma was initially suspected, and chemotherapy including mitotane was considered. However, due to difficulty in complete resection of the tumor, core needle tumor biopsies were performed. Histopathological examination of biopsy specimens led to the diagnosis of carcinoma of unknown primary origin with isolated adrenal metastasis. In both cases, additional laboratory testing showed high levels of serum squamous cell carcinoma-related antigen and serum cytokeratin fragment. Malignant lesions confined to the adrenal glands are rare. As in our cases, it could be occasionally difficult to differentiate non-functioning primary adrenocortical carcinoma from metastatic adrenal carcinoma of unknown primary origin localized to the adrenal gland. If the lesion is unresectable and there are elevated levels of several tumor markers with no apparent hormonal excess, core needle tumor biopsy should be considered to differentiate the primary tumor from the metastatic tumor.

Immune checkpoint inhibitor toxicity: A new indication for therapeutic plasma exchange?

Novel immune-modulating anticancer drugs are being used with increasing frequency. With increased use, there are more frequent cases of toxicities caused by these drugs, termed immune-related adverse events (irAEs). We present a case in which we successfully treated a case of severe, steroid-refractory, nivolumab-induced myocarditis with therapeutic plasma exchange (TPE). Nivolumab is an immune checkpoint inhibitor (ICI) which blocks programmed death receptor-1 (PD-1). This blockade allows for enhanced T-cell function and increased anti-tumor response. The patient presented with signs and symptoms of heart failure and was found to have a significantly depressed cardiac ejection fraction. Over the course of her five TPE procedures, she improved clinically and was discharged home with improved left ventricular ejection function. This case suggests an emerging role of TPE in the management of severe ICI-induced toxicity, such as myocarditis.

Aggressive surgical approach in patients with adrenal-only metastases from hepatocellular carcinoma enables higher survival rates than standard systemic therapy.

BACKGROUND: Although guidelines recommend systemic therapy even in patients with limited extrahepatic metastases from hepatocellular carcinoma (HCC), a few recent studies suggested a potential benefit for resection of extrahepatic metastases. However, the benefit of adrenal resection (AR) for adrenal-only metastases (AOM) from HCC was not proved yet. This is the first study to compare long-term outcomes of AR to those of sorafenib in patients with AOM from HCC. METHODS: The patients with adrenal metastases (AM) from HCC were identified from the electronic records of the institution between January 2002 and December 2018. Those who presented AM and other sites of extrahepatic disease were excluded. Furthermore, the patients with AOM who received other therapies than AR or sorafenib were excluded. RESULTS: A total of 34 patients with AM from HCC were treated. Out of these, 22 patients had AOM, 6 receiving other treatment than AR or sorafenib. Eventually, 8 patients with AOM underwent AR (AR group), while 8 patients were treated with sorafenib (SOR group). The baseline characteristics of the two groups were not significantly different in terms of age, sex, number and size of the primary tumor, timing of AM diagnosis, Child-Pugh and ECOG status. After a median follow-up of 15.5 months, in the AR group, the 1-, 3-, and 5-year overall survival rates (85.7%, 42.9%, and 0%, respectively) were significantly higher than those achieved in the SOR group (62.5%, 0% and 0% at 1-, 3- and 5-year, respectively) (P = 0.009). The median progression-free survival after AR (14 months) was significantly longer than that after sorafenib therapy (6 months, P = 0.002). CONCLUSIONS: In patients with AOM from HCC, AR was associated with significantly higher overall and progression-free survival rates than systemic therapy with sorafenib. These results could represent a starting-point for future phase II/III clinical trials.

Adrenal Adenomas versus Metastases: Diagnostic Performance of Dual-Energy Spectral CT Virtual Noncontrast Imaging and Iodine Maps.

Background Dual-energy CT allows virtual noncontrast (VNC) attenuation and iodine density measurements from contrast material-enhanced examination, potentially enabling adrenal lesion characterization. However, data regarding diagnostic performance remain limited, and combined diagnostic values have never been investigated. Purpose To determine whether VNC attenuation, iodine density, and combination of the two allow reliable differentiation between adrenal adenomas and metastases. Materials and Methods This retrospective study included patients with adrenal lesions who underwent unenhanced and portal venous phase dual-energy CT between January 2017 and December 2018. Unenhanced, contrast-enhanced, and VNC attenuation, as well as iodine density, were measured for each lesion. Agreement between unenhanced and VNC attenuation was assessed by using Wilcoxon rank-sum test, Pearson correlation coefficient, and Bland-Altman plot. The ratio of iodine density to VNC attenuation was calculated for lesions with positive VNC attenuation. Each parameter was compared between adenomas and metastases; diagnostic performance was evaluated by using the area under the receiver operating characteristic curve (AUC) with sensitivity and specificity. Results A total of 149 patients (mean age, 65 years ± 13 [standard deviation]; 89 men; 98 patients with 104 adenomas; 51 patients with 56 metastases) were evaluated. VNC attenuation showed strong positive correlation with unenhanced attenuation (r = 0.92) but resulted in overestimates of adenoma attenuation (mean bias, +11 HU; P < .001) and was less sensitive (P = .03) in the diagnosis of adenomas compared with unenhanced attenuation (sensitivity of 79% [81 of 102] [95% confidence interval {CI}: 70%, 87%] and specificity of 95% [53 of 56] [95% CI: 85%, 99%] versus sensitivity of 85% [87 of 102] [95% CI: 77%, 92%] and specificity of 96% [54 of 56] [95% CI: 88%, 100%], with thresholds of ≤29 HU and ≤22 HU, respectively). Contrast-enhanced attenuation had no discriminatory ability (AUC, 0.54; 95% CI: 0.45, 0.62). Iodine density yielded moderate performance (sensitivity of 78% [80 of 102] [95% CI: 69%, 86%] and specificity of 71% [40 of 56] [95% CI: 58%, 83%], with a threshold of ≥1.82 mg/mL). The iodine-to-VNC ratio was higher in adenomas than in metastases (mean, 14.5 vs 4.6; P < .001), with sensitivity of 95% (97 of 102; 95% CI: 89%, 98%) and specificity of 95% (53 of 56; 95% CI: 85%, 99%), with a threshold of 6.7 or greater. Conclusion Contrast-enhanced dual-energy CT during the portal venous phase enabled accurate differentiation between adrenal adenomas and metastases by combining virtual noncontrast attenuation and iodine density. Virtual noncontrast imaging alone led to overestimates of adenoma attenuation, and iodine density alone had limited discriminatory utility. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Hindman and Megibow in this issue.

Single-institutional outcome-analysis of low-dose stereotactic body radiation therapy (SBRT) of adrenal gland metastases.

BACKGROUND: Adrenal gland metastases are a common diagnostic finding in various tumor diseases. Due to the increased use of imaging methods, they are diagnosed more frequently, especially in asymptomatic patients. SBRT has emerged as a new, alternative treatment option in the field of radiation oncology. In the past, it was often used for treating inoperable lung, liver, prostate, and brain tumors. Meanwhile, it is also an established keystone in the treatment of oligometastatic diseases. This retrospective study aims to evaluate the effect of low-dose SBRT in patients with adrenal metastases. METHODS: We analyzed a group of 31 patients with 34 adrenal gland lesions treated with low-dose SBRT between July 2006 and July 2019. Treatment-planning was performed through contrast-enhanced CT, followed by image-guided stereotactic radiotherapy using cone-beam CT. The applied cumulative median dose was 35 Gy; the median single dose was 7 Gy. We focused on local control (LC), progression-free survival (PFS), overall survival (OS), as well as acute and late toxicity. RESULTS: Seven adrenal gland metastases (20.6%) experienced local failure, 80.6% of the patients faced a distant progression. Fourteen patients were still alive. Median follow-up for all patients was 9.8 months and for patients alive 14.4 months. No treatment-related side-effects >grade 2 occurred. Of all, 48.4% suffered from acute gastrointestinal disorders; 32.3% reported acute fatigue, throbbing pain in the renal area, and mild adrenal insufficiency. Altogether, 19.4% of the patients faced late-toxicities, which were as follows: Grade 1: 12.9% gastrointestinal disorders, 3.2% fatigue, Grade 2: 9.7% fatigue, 6.5% headache, 3.2% loss of weight. The 1-year OS and probability of LF were 64 and 25.9%, respectively. CONCLUSION: Low-dose SBRT has proven as an effective and safe method with promising outcomes for treating adrenal metastases. There appeared no high-grade toxicities >grade 2, and 79.4% of treated metastases were progression-free. Thus, SBRT should be considered as a therapy option for adrenal metastases as an individual therapeutic concept in the interdisciplinary discussion as an alternative to surgical or systemic treatment.

Imaging features and prognostic value of 18F-FDG PET/CT detection of soft-tissue metastasis from lung cancer: a retrospective study.

BACKGROUND: Soft-tissue metastasis (STM) is a relatively rare, but not exceptional, manifestation of lung cancer. The purpose of this study was to evaluate the imaging features of STM from lung cancer using fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), and assess the impact of STM detected at baseline PET/CT on patient survival. METHODS: Out of 4543 patients with lung cancer who underwent 18F-FDG PET/CT in our hospital between January 2013 and September 2018, 85 were diagnosed with STM (78 at baseline PET/CT and 7 at restaging PET/CT) and included in the imaging study. We conducted a comparative survival analysis between patients with stage 4 lung cancer with and without STM at baseline PET/CT (n = 78 in each group) and performed univariate and multivariate analyses to investigate the factors affecting the prognosis of lung cancer. RESULTS: A total of 219 lesions were identified by 18F-FDG PET/CT: 215 were detected by PET and 139 by CT. Muscle STM were primarily found in the hip and upper limb muscle, whereas subcutaneous STM were mainly distributed in the chest, abdomen, and back. In 68 patients, STM were found incidentally during routine 18F-FDG PET/CT staging. Isolated STM were detected in 6 patients, whose tumor staging and treatment were affected by PET/CT findings. There were no significant differences in the 1-, 3-, and 5-year survival rates between patients with and without STM at baseline PET/CT. Brain and adrenal metastases, but not STM, were associated with poor prognosis of stage 4 lung cancer. CONCLUSIONS: We described the PET/CT imaging characteristics of STM from lung cancer, and confirmed that PET/CT can detect unsuspected STM to change the staging and treatment of some patients. Our analysis indicates that STM is not a useful prognostic indicator for patients with advanced lung cancer, while brain and adrenal metastases portend a poor prognosis.

Restaging Patients with Rectal Cancer Following Neoadjuvant Chemoradiation: A Systematic Review.

BACKGROUND: In the USA, most patients with clinical stage II/III rectal cancer receive neoadjuvant chemoradiation (chemo/XRT) over 5-6 weeks followed by a 6-10-week break before proctectomy. As chemotherapy is delivered at radio-sensitizing doses, there is essentially a 3-month window during which potential systemic disease is untreated. Evidence regarding the utility of restaging patients prior to proctectomy is limited. METHODS: PubMed, Scopus, Web of Science, and the Cochrane Library were searched for studies evaluating the utility of restaging patients with rectal cancer after completion of long-course chemo/XRT, and reporting associated changes in management. Studies that were non-English, included <50 patients, or examining the diagnostic accuracy of imaging modalities were excluded. Study quality was evaluated using the modified Newcastle Ottawa Scale. RESULTS: Eight studies were identified including a total of 1251 patients restaged between completion of chemo/XRT and proctectomy. All studies were retrospective. Restaging identified new metastatic disease in 72 (6.0%) patients, with 4 studies reporting specific sites: liver (n = 28), lung (n = 8), adrenal (n = 1), bone (n = 1), and multiple sites (n = 7). Overall progression (distant or local) was detected in 88 (7.0%) patients and resulted in a change in management in 77 (87.5%) of these patients. Tumor-related prognostic characteristics were inconsistently reported among studies, precluding meta-analysis. CONCLUSIONS: Although restaging between completion of neoadjuvant chemo/XRT and proctectomy detects disease progression in only a small percentage of patients, findings alter the treatment plan in the vast majority of these patients. Multi-institutional collaboration with analysis of well-defined prognostic variables may better identify patients most likely to benefit from restaging.