MEN1/DAXX/ATRX mutations enhance progression-free survival in gastroenteropancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy.

Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response rate (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs 12.13 months; P = 0.014) than wild-type (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended toward longer PFS compared to patients without concurrent mutations (31.53 vs 17.97 months; P = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs 9.83 months; P = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs 20.47 months; P = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response.

Optimization of Metabolic Tumor Volume as a Prognostic Marker in CAR T-Cell Therapy for Aggressive Large B-cell NHL.

BACKGROUND: CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a standard of care in relapsed/refractory (R/R) aggressive large B-cell non-Hodgkin lymphomas (B-NHL) though the majority of recipients do not receive durable disease benefit, prompting the need to better define risk factors for relapse/progression. OBJECTIVES: We performed a single-center, retrospective analysis of patients treated with commercial CAR T-cell therapy to evaluate the impact of tumor burden, as measured by whole-body metabolic tumor volume (MTV) from 18F fluorodeoxyglucose PET imaging, on treatment outcomes. STUDY DESIGN: Sixty-one patients treated with CAR T-cell therapy for R/R B-NHL between May 2016 and November 2021 were included. RESULTS: Using a receiver operating characteristic curve-based MTV optimization cutoff of 450 mL, 1-year progression-free survival (PFS) was 22% for high MTV versus 54% for low MTV (P < .01), and 1-year overall survival (OS) was 37% and 73%, respectively (P = .01). In a subset of 46 patients, residual MTV of less than 106 mL at the day 30 (D30) disease assessment was associated with significantly improved outcomes (1-year OS 85% vs. 13%, P < .01). Incorporation of pretreatment MTV to the International Prognostic Index (IPI) scoring system significantly distinguished 2-year PFS and OS outcomes by 3 risk groups. CONCLUSIONS: Our findings suggest that both pretreatment and D30 MTV are predictive of outcomes among R/R B-NHL patients treated with CAR T-cell therapy. These data indicate that efforts to reduce pretreatment tumor burden may improve longitudinal clinical outcomes. Furthermore, D30 postinfusion MTV quantification may aid clinicians in optimally identifying patients at high-risk for progression, and in whom closer disease monitoring should be considered. MTV also adds prognostic value to patients with high-risk IPI and holds promise for incorporation in novel risk scoring systems which can identify patients prior to CAR T-cell therapy at highest risk of adverse outcomes.

Prevalence of newly diagnosed sarcoidosis in patients with ventricular arrhythmias: a cardiac magnetic resonance and 18F-FDG cardiac PET study.

Cardiac sarcoidosis (CS) is known to be associated with ventricular tachycardia (VT); however, most investigations to date have focused on patients with known extra-cardiac sarcoidosis. The presence of CS is typically evaluated using 18F-fluorodeoxyglucose (18F-FDG) uptake on cardiac positron emission tomography (PET) or late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR). In this study, we sought to determine the prevalence of primary CS and the relationship between myocardial 18F-FDG uptake and LGE in patients with VT without known sarcoidosis. We retrospectively identified 67 patients without known sarcoidosis or active ischemic heart disease (i.e. significant ischemic disease that had not been previously revascularized) referred for both CMR and PET for evaluation of VT. Standard cine- and LGE- CMR and cardiac PET protocols were used. Myocardial LGE was defined as signal intensity > 5 SDs above the mean signal intensity of normal myocardium. Cardiac PET images were considered positive if there was focal myocardial 18F-FDG uptake having greater activity than the left ventricular blood pool. 45 patients (67%) had LGE, while only 4 (6%) had myocardial FDG uptake. Nine percent of patients with LGE had FDG-uptake while none without LGE did, and 10% of the cohort had indeterminate FDG uptake presumably from poor dietary preparation. Of those with both FDG uptake and LGE, 3/4 ultimately received a clinical diagnosis of CS. 4.5% of patients without previously known sarcoidosis or active ischemic heart disease presenting with VT have newly diagnosed CS. Detection of CS can be increased using a CMR first approach followed by cardiac PET for patients with non-ischemic LGE.

Relationship between Overall Survival of Patients with Non-Small Cell Lung Cancer and Whole-Body Metabolic Tumor Burden Seen on Postsurgical Fluorodeoxyglucose PET Images.

PURPOSE: To test the hypothesis that whole-body metabolic tumor burden (MTBWB) on postsurgical fluorodeoxyglucose (FDG) positron emission tomographic (PET)/computed tomographic (CT) images in patients with non-small cell lung cancer (NSCLC) is associated with their overall survival (OS). MATERIALS AND METHODS: The institutional review board approved this study and waived the requirement for obtaining informed consent. One hundred forty-two patients with NSCLC (69 men, 73 women; median age, 67.7 years) who underwent postsurgical FDG PET/CT were retrospectively reviewed. The whole-body metabolic tumor volume (MTVWB), whole-body total lesion glycolysis (TLGWB), and whole-body maximum standardized uptake value (SUVWBmax) were measured. OS served as the primary end point of the study. Kaplan-Meier curves and Cox regression were used to assess the association between PET/CT markers and OS. RESULTS: The interobserver variability was low, as demonstrated with intraclass correlation coefficients higher than 0.94 for SUVWBmax, MTVWB, and TLGWB. When compared with those with negative postsurgical FDG PET/CT findings, a significant decrease of OS was found in patients with the presence of FDG-avid tumor on the basis of both a log-rank test (P = .001) and a univariate Cox model (hazard ratio = 2.805, P = .001). In patients with FDG-avid tumor, there was a significant association between OS and ln MTVWB (P < .001), ln TLGWB (P < .001), and ln SUVWBmax (P < .010) in either univariate or multivariate analysis, after adjusting for patient age, sex, TNM restage, and therapy after postsurgical PET/CT studies. The OS differences between the groups dichotomized by the median value of MTVWB (11.54 mL, P = .004), TLGWB (32.38 mL, P < .001), or SUVWBmax (4.93, P = .023) were significant. CONCLUSION: MTBWB and tumor maximum standardized uptake at postsurgical FDG PET/CT are related to the patient's OS in NSCLC, independent of age, sex, TNM restaging, and therapy after postsurgical PET/CT studies.

Evaluation of the gallbladder and cystic duct patency with gadoxetate disodium enhanced MR cholangiography: prospective comparison of patients with normal gallbladder function and acute cholecystitis.

BACKGROUND: Using hepatocyte-specific magnetic resonance imaging (MRI) contrast agents such as gadoxetate disodium, MRI can provide functional information regarding the patency of the cystic duct similar to hepatobiliary scintigraphy in addition to anatomic images. PURPOSE: To describe the gadoxetate disodium enhanced MR cholangiography (GDE-MRC) findings in patients with acute cholecystitis and to compare them with findings in patients without acute cholecystitis and with normal hepatobiliary scintigraphy. MATERIAL AND METHODS: This study was HIPAA compliant and institutional review board approved. Twenty-three patients (n = 14 diagnosed with acute calculous cholecystitis based on ultrasound [US] or computed tomography [CT]; n = 9 controls with normal hepatobiliary scintigraphy) were prospectively enrolled. All patients underwent GDE-MRC within 2 days of the US, CT, or hepatobiliary scintigraphy. GDE-MRC included axial gradient echo T1-weighted images before and 3, 10, 20, 30, and 60 min after injection of 10 mL of gadoxetate disodium. If excretion of contrast into the gallbladder was not noted at 60 min, intravenous morphine was administered (0.04 mg/kg) and images were acquired 30 min later. RESULTS: In all nine controls, gadoxetate disodium was excreted into the gallbladder within 60 min (7/9 in <30 min). Twelve out of 14 patients with acute cholecystitis completed the study. Six out of 12 (50%) patients demonstrated contrast in their gallbladder within 1 h of administration similar to the control group (2/6 in <30 min). In the remaining 6/12 patients, contrast was not present in the gallbladder within 1 h from injection. Following morphine augmentation, contrast was subsequently noted in the gallbladder in 2/6 patients. CONCLUSION: GDE-MRC can assess the patency of the cystic duct. Delayed (>60 min) or lack of filling of the gallbladder during GDE-MRC supports the diagnosis of acute cholecystitis. However, filling of the gallbladder with contrast in <60 min does not exclude the diagnosis of acute calculous cholecystitis.

Advanced neuroimaging studies in a patient with brain metastases from transitional cell carcinoma of the bladder.

BACKGROUND AND PURPOSE: The differential diagnosis in single or oligo-brain lesions in metastatic cancer patients remains broad. Advanced imaging studies can be employed to help refine the differential and potentially guide treatment. METHODS: Case report of a 52-year-old male patient with known transitional cell carcinoma of the bladder presented with headaches, cognitive symptoms, and episodic presyncope. Brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and octreotide scans were performed to evaluate the underlying etiology of his symptoms. RESULTS: MRI revealed two enhancing mass lesions in left temporal and left cerebellar locations. Both lesions were octreotide avid and MRS of the temporal lesion showed a single large lipid peak at 1.3 ppm, a small NAA peak, and a markedly increased choline:creatine ratio that was relatively characteristic for metastases. Pathology from surgical resection revealed transitional cell carcinoma of the bladder. CONCLUSIONS: Resection of both lesions revealed metastatic transitional cell carcinoma. This is the first report of octreotide scan characteristics in a patient with transitional cell carcinoma with central nervous system (CNS) metastases. The octreotide avidity of these transitional cell CNS metastases suggests the presence of somatostatin receptors that may be considered as a potential therapeutic target.

FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer.

The mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([(18)F] fluorodeoxy-glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2 weeks; serial computed tomography (CT) scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8-week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37-80). Median pre- and 2-week treatment average SUVmax were 6.6 (1-17.9) and 4.2 (1-13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (-32.7% to 35.9%) at 8 weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P = 0.01; clear cell subtype P = 0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P = 0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability.

Prognostic value of metabolic tumor burden on 18F-FDG PET in nonsurgical patients with non-small cell lung cancer.

PURPOSE: The objective of this study was to assess the prognostic value of metabolic tumor burden on 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET)/CT measured with metabolic tumor volume (MTV) and total lesion glycolysis (TLG), independent of Union Internationale Contra la Cancrum (UICC)/American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) stage, in comparison with that of standardized uptake value (SUV) in nonsurgical patients with non-small cell lung cancer (NSCLC). METHODS: This study retrospectively reviewed 169 consecutive nonsurgical patients (78 men, 91 women, median age of 68 years) with newly diagnosed NSCLC who had pretreatment (18)F-FDG PET/CT scans. The (18)F-FDG PET/CT scans were performed in accordance with National Cancer Institute guidelines. The MTV of whole-body tumor (MTV(WB)), of primary tumor (MTV(T)), of nodal metastases (MTV(N)), and of distant metastases (MTV(M)); the TLG of whole-body tumor (TLG(WB)), of primary tumor (TLG(T)), of nodal metastases (TLG(N)), and of distant metastases (TLG(M)); the SUV(max) of whole-body tumor (SUV(maxWB)), of primary tumor (SUV(maxT)), of nodal metastases (SUV(maxN)), and of distant metastases (SUV(maxM)) as well as the SUV(mean) of whole-body tumor (SUV(meanWB)), of primary tumor (SUV(meanT)), of nodal metastases (SUV(meanN)), and of distant metastases (SUV(meanM)) were measured with the PETedge tool on a MIMvista workstation with manual adjustment. The median follow-up among survivors was 35 months from the PET/CT (range 2-82 months). Statistical methods included Kaplan-Meier curves, Cox regression, and C-statistics. RESULTS: There were a total of 139 deaths during follow-up. Median overall survival (OS) was 10.9 months [95% confidence interval (CI) 9.0-13.2 months]. The MTV was statistically associated with OS. The hazard ratios (HR) for 1 unit increase of ln(MTV(WB)), √(MTV(T)), √(MTV(N)), and √(MTV(M)) before/after adjusting for stage were: 1.47/1.43 (p < 0.001/<0.001), 1.06/1.05 (p < 0.001/<0.001), 1.11/1.10 (p < 0.001/<0.001), and 1.04/1.03 (p = 0.007/0.043), respectively. TLG had statistically significant associations with OS with the HRs for 1 unit increase in ln(TLG(WB)), √(TLG(T)), √(TLG(N)), and √(TLG(M)) before/after adjusting for stage being 1.36/1.33 (p < 0.001/<0.001), 1.02/1.02 (p = 0.001/0.002), 1.05/1.04 (p < 0.001/<0.001), and 1.02/1.02 (p = 0.003/0.024), respectively. The ln(SUV(maxWB)) and √(SUV(maxN)) were statistically associated with OS with the corresponding HRs for a 1 unit increase before/after adjusting for stage being 1.46/1.43 (p = 0.013/0.024) and 1.22/1.16 (p = 0.002/0.040). The √(SUV(meanN)) was statistically associated with OS before and after adjusting for stage with HRs for a 1 unit increase of 1.32 (p < 0.001) and 1.24 (p = 0.015), respectively. The √(SUV(meanM)) and √(SUV(maxM)) were statistically associated with OS before adjusting for stage with HRs for a 1 unit increase of 1.26 (p = 0.017) and 1.18 (p = 0.007), respectively, but not after adjusting for stage (p = 0.127 and 0.056). There was no statistically significant association between OS and √(SUV(maxT)), ln(SUV(meanWB)), or √(SUV(meanT)). There was low interobserver variability among three radiologists with intraclass correlation coefficients (ICC) greater than 0.94 for SUV(maxWB), ln(MTV(WB)), and ln(TLG(WB)). Interobserver variability was higher for SUV(meanWB) with an ICC of 0.806. CONCLUSION: Baseline metabolic tumor burdens at the level of whole-body tumor, primary tumor, nodal metastasis, and distant metastasis as measured with MTV and TLG on FDG PET are prognostic measures independent of clinical stage with low inter-observer variability and may be used to further stratify nonsurgical patients with NSCLC. This study also suggests MTV and TLG are better prognostic measures than SUV(max) and SUV(mean). These results will need to be validated in larger cohorts in a prospective study.

Interobserver variability among measurements of the maximum and mean standardized uptake values on (18)F-FDG PET/CT and measurements of tumor size on diagnostic CT in patients with pulmonary tumors.

BACKGROUND: (18)F-fluoro-2-deoxyglucose positron emission tomography ((18)F-FDG PET) imaging has been shown to be an accurate method for diagnosing pulmonary lesions, and the standardized uptake value (SUV) has been shown to be useful in differentiating benign from malignant lesions. PURPOSE: To survey the interobserver variability of SUV(max) and SUV(mean) measurements on (18)F-FDG PET/CT scans and compare them with tumor size measurements on diagnostic CT scans in the same group of patients with focal pulmonary lesions. MATERIAL AND METHODS: Forty-three pulmonary nodules were measured on both (18)F-FDG PET/CT and diagnostic chest CT examinations. Four independent readers measured the SUV(max) and SUV(mean) of the (18)F-FDG PET images, and the unidimensional nodule size of the diagnostic CT scans (UD(CT)) in all nodules. The region of interest (ROI) for the SUV measurements was drawn manually around each tumor on all consecutive slices that contained the nodule. The interobserver reliability and variability, represented by the intraclass correlation coefficient (ICC) and coefficient of variation (COV), respectively, were compared among the three parameters. The correlation between the SUV(max) and SUV(mean) was also analyzed. RESULTS: There was 100% agreement in the SUV(max) measurements among the 4 readers in the 43 pulmonary tumors. The ICCs for the SUV(max), SUV(mean), and UD(CT) by the four readers were 1.00, 0.97, and 0.97, respectively. The root-mean-square values of the COVs for the SUV(max), SUV(mean), and UD(CT) by the four readers were 0%, 13.56%, and 11.03%, respectively. There was a high correlation observed between the SUV(max) and SUV(mean) (Pearson's r=0.958; P <0.01). CONCLUSION: This study has shown that the SUV(max) of lung nodules can be calculated without any interobserver variation. These findings indicate that SUV(max) is a more valuable parameter than the SUV(mean) or UD(CT) for the evaluation of therapeutic effects of chemotherapy or radiation therapy on serial studies.

The utility of the nonattenuation corrected 18F-FDG PET images in the characterization of solitary pulmonary lesions.

OBJECTIVE: To determine the accuracy of nonattenuation corrected (NAC) F-fluorodeoxyglucose positron emission tomography (F-FDG PET) images in the evaluation of solitary pulmonary lesion as compared with more established methods. METHODS: Fifty-six patients received F-FDG PET/CT for diagnosing solitary pulmonary nodules or mass lesions based on histopathology (n=39) and clinical follow-up (n=17). Visual pulmonary lesion FDG uptake was graded by consensus of two nuclear medicine physicians on both attenuation corrected (AC) [absent, less than mediastinal blood pool (MBP), equal to MBP, greater than MBP] and NAC (absent, less than skin, equal to skin, greater than skin) images. Standardized uptake values (SUV) were also measured from AC images. SUV, visual AC, and visual NAC methods' diagnostic performances were compared, distinguishing benign from malignant pulmonary nodules. RESULTS: There were 34 malignant and 22 benign lesions. Lesion diameter varied from 5 to 100 mm (mean ± SD, 24.0 ± 17.9 mm). The NAC, AC, and SUV method sensitivities and specificities were 100/64%, 91/59%, and 79/77%, respectively. For lesions less than 3 cm, NAC, AC, and SUV methods yielded accuracies of 85%, 78%, and 73%, respectively. The NAC method was the most sensitive and accurate especially for small nodules. CONCLUSION: Visual assessment of NAC F-FDG PET images alone may provide a more accurate characterization of solitary pulmonary lesions.

FDG-PET/CT findings of a metastatic pituitary tumor.

The authors report the fluorodeoxyglucose (FDG)-positron emission tomography(PET)/computed tomography (CT) findings of a rare case of growth hormone-secreting pituitary carcinoma with multiple metastatic lesions to the skeleton. A 31-year-old male had presented with acromegaly and had received transsphenoidal resection of a pituitary tumor and adjuvant radiotherapy. However, the tumor recurred with local invasions and the patient underwent more resections and adjuvant chemotherapy. Several months later, the patient developed rising levels of insulin-like growth factor 1 and whole-body FDG-PET/CT scanning revealed multiple hypermetabolic lesions throughout the skeleton compatible with metastasis.

Positron emission tomography (PET) used to image subclinical inflammation associated with ulcerative colitis (UC) in remission.

BACKGROUND: Positron emission tomography (PET) using 18-fluorodeoxyglucose (18-FDG) is a noninvasive, functional imaging modality most often used to assess cancer. The aim of this study was to perform PET/computed tomography (CT) on patients with quiescent ulcerative colitis (UC) to understand the limits of this technology for assessing inflammatory activity. METHODS: We identified patients diagnosed with UC in a strictly defined remission state. PET/CT was performed in standard fashion, using approximately 10 mCi of 18-FDG with a 60-minute uptake delay. Uptake in each of 4 colonic segments (recto-sigmoid [r-s], descending, transverse, and ascending), and distal small bowel were scored on a 3-point scale (0 = no uptake or uptake liver; 2 = uptake much greater than liver). RESULTS: Ten patients participated in this study, 6 male. Eight had pancolitis, 1 had extensive colitis, and 1 had procto-sigmoiditis, with a median disease duration was 32 years. A PET scan was performed mean 37 days after endoscopy. Six patients had no increased 18-FDG uptake, 3 had increased uptake in the r-s region, 1 patient with r-s uptake also had ascending colon uptake, and 1 had ileal uptake with no colonic signal. CONCLUSIONS: In this study, PET demonstrated inflammatory activity in the colon despite negative endoscopic, histologic, and symptom assessment. This has important implications in the understanding of UC disease quiescence. Further exploration of this highly sensitive modality should be performed.

Delayed 99mTc-labeled erythrocyte scintigraphy in patients with lower gastrointestinal tract hemorrhage: effect of positive findings on clinical management.

RATIONALE AND OBJECTIVES: This study was performed to determine whether the results of delayed technetium 99m (99mTc)-labeled erythrocyte scintigraphy for lower gastrointestinal tract hemorrhage resulted in different clinical management and outcome from that in cases in which the results of initial scintigraphy were negative or equivocal. MATERIALS AND METHODS: The authors retrospectively reviewed all 398 99mTc-labeled erythrocyte scintigraphic studies obtained emergently for lower gastrointestinal tract hemorrhage at their institution between January 1, 1994, and December 7, 2001. Of 67 patients who underwent delayed studies, 37 had positive findings (average delay, 18.4 hours; range, 6-25 hours) and 30 had negative findings (average delay, 20.1 hours; range, 8-26 hours). Clinical management and outcome were compared between these two groups with respect to duration of hospitalization, volume of blood transfusion, mortality, and the percentage who were treated conservatively or referred for angiography, endoscopy, and/or surgery. RESULTS: Patients with positive delayed studies were referred more frequently for angiography than those with negative studies (35% vs 0%, P < .01). There were no significant differences between patients with positive findings and patients with negative findings with respect to mortality (8% vs 0%, P < .32), transfusion requirements (5.6 vs 3.2 units, P < .20), hospitalization (9.5 vs 6.1 days, P < .11), the percentage treated conservatively (35% vs 37%, P < .90), or the percentages referred for endoscopy (49% vs 60%, P < .50) or for surgery (24% vs 17%, P < .64). CONCLUSION: Positive findings at delayed scintigraphy resulted in increased referrals for angiography but had no other effect on clinical course or outcome of lower gastrointestinal tract hemorrhage.