Changes In FDG Uptake Research Articles

Is local review of positron emission tomography scans sufficient in diffuse large B-cell lymphoma clinical trials? A CALGB 50303 analysis.

Quantitative methods of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) interpretation, including the percent change in FDG uptake from baseline (ΔSUV), are under investigation in lymphoma to overcome challenges associated with visual scoring systems (VSS) such as the Deauville 5-point scale (5-PS). In CALGB 50303, patients with DLBCL received frontline R-CHOP or DA-EPOCH-R, and although there were no significant associations between interim PET responses assessed centrally after cycle 2 (iPET) using 5-PS with progression-free survival (PFS) or overall survival (OS), there were significant associations between central determinations of iPET ∆SUV with PFS/OS. In this patient cohort, we retrospectively compared local vs central iPET readings and evaluated associations between local imaging data and survival outcomes. Agreement between local and central review was moderate (kappa=0.53) for VSS and high (kappa=0.81) for ∆SUV categories (<66% vs. ≥66%). ∆SUV ≥66% at iPET was significantly associated with PFS (p=0.03) and OS (p=0.002), but VSS was not. Associations with PFS/OS when applying local review vs central review were comparable. These data suggest that local PET interpretation for response determination may be acceptable in clinical trials. Our findings also highlight limitations of VSS and call for incorporation of more objective measures of response assessment in clinical trials.

The Usefulness of Short-Interval Sequential FDG PET/CT Studies in Defining the Benignity of Hypermetabolic Lipomatous Tumor.

We present an interesting case of incidentally detected lipomatous tumor in an oncological patient that could result in a false-positive interpretation by exhibiting intense FDG activity similar to that of a malignant neoplasm. Careful evaluation of FDG uptake changes on sequential short-interval PET/CT studies was helpful in defining the benign nature of the tumor as the hypermetabolism was gradually disappearing obviating the need for a major surgery.

P1174: THE COMBINATION OF QUALITATIVE AND QUANTITATIVE METABOLIC PARAMETERS PREDICTS PROGRESSION-FREE SURVIVAL IN PATIENTS WITH LARGE B-CELL LYMPHOMAS (LBCL) TREATED WITH ANTI-CD19 CAR-T CELLS.

Background: Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an effective therapy for 40% of patients (pts) with relapsed/refractory (R/R) LBCL. Qualitative and quantitative metabolic parameters from the 18-FDG PET-CT scan are tools able to predict outcomes in lymphomas, but their value in the CAR-T setting is still under investigation. Aims: Prognostic role of PET-CT performed before lymphodepletion and 1 month after CAR-T cell infusion, analyzed by qualitative and quantitative parameters Methods: We conducted an observational a prospective study on pts affected by R/R aggressive lymphomas receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). PET-CT was evaluated before lymphodepletion, at 1 month (M1) and at 3 months (M3) post-infusion using visual assessment with a 5-point Deauville score (DS). Quantitative PET parameters were evaluated with PET-VCAR software (GE Healthcare). The contour of pathological lesions was delineated using semiautomatic contouring systems including a gradient-based algorithm. SUVmax, SUVmean, Metabolic tumor volume (MTV), and Total lesions glycolysis (TLG) were automatically recorded. Total MTV (TMTV) and total TLG (TTLG) were calculated as the sum of all individual lesions. The percentage change in FDG uptake of each parameter between baseline and M1 was defined as Δ=(baseline-M1)/baseline x 100%. Logistic and Cox regression models were applied to evaluate the association between PET parameters at baseline, at M1 and in terms of Δ with respect to clinical response and progression free survival (PFS), respectively. Results: 47 pts were analyzed: median age was 55 years (range, 22-70); histologies included diffuse-large B-cell lymphomas (n=33) and primary mediastinal B-cell lymphomas (n=14); pts received treatment with axi-cel (n=31) or tisa-cel (n=16). Before infusion, 18 (38%) had high LDH, 14 (30%) had extranodal disease and 16 (34%) had bulky disease. Majority of pts [n=41 (84%)] received bridging therapy. At a median follow-up of 12 months (range, 3-29 months), 38 patients are alive and 9 died of disease progression with an estimated 1-year PFS and OS of 46% (95%CI; 30%-60%) and 83% (95%CI; 66%-92%), respectively. Baseline values of SUVmax, but not SUVmean, TTLG, TMTV correlated with poor clinical response [HR 1,49; (95%CI; 1,01-2,2), p=0,04]. By univariate logistic model, a higher ΔSUVmean between baseline and M1 was associated with better response at M3 [odds ratio 3,49, (95%CI; 1,25-9,77), p=0.02]. Univariable Cox analyses showed that a higher ΔSUVmean and ΔTMTV between baseline and M1 were associated with a better PFS [HR 0,63, (95%CI; 0,41-0,96), p=0,03; HR 0,67 (95%CI; 0,48-0,94), p=0,02], respectively. In terms of visual assessment, pts with DS 4-5 at M1 had a significantly higher risk of failure as compared to those with DS 1-3 [HR 2,92, (95%CI; 1,12-7,64), p=0,02]. A combination of M1 DS score and ΔSUV mean showed a better prognosis for patients with DS1-3 (PFS 60%), an intermediate prognosis for those with DS4/5 and high ΔSUVmean (PFS 49%) and a poor prognosis for those with DS4/5 and low ΔSUVmean (PFS 22%), [p=0,009]. In a multivariable analyses, evaluating clinical prognostic factors and PET parameters, a higher risk of failure was observed in pts with high LDH [HR 3,2 (95%CI; 1,30-8,14), p=0,01] whereas a higher ΔSUVmean was associated to a better PFS [HR 0,61 (95%CI, 0,41-0,92), p=0,02]. Summary/Conclusion: Assessment of DS combined with variation of SUVmean at M1 provides informations about early risk of CAR-T failure. A validation group are needed to extend and confirm our observations.

Use of Fluoro-[18F]-Deoxy-2-D-Glucose Positron Emission Tomography/Computed Tomography to Predict Immunotherapy Treatment Response in Patients With Squamous Cell Oral Cavity Cancers

Neoadjuvant immunotherapy is a novel approach with the potential to improve outcomes for patients with oral cavity squamous cell cancer (OCSCC). Adverse events of varying severity are reported with immunotherapy, and a biomarker to predict response would be clinically useful to avoid toxic effects in those unlikely to benefit. To correlate changes on fluoro-[18F]-deoxy-2-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans with primary tumor pathologic response and immunologic biomarkers in patients with OCSCC receiving neoadjuvant immunotherapy. This was a retrospective analysis of serial FDG-PET/CT scans obtained prospectively as part of a phase 2 open-label randomized clinical trial investigating neoadjuvant immunotherapy in patients with untreated OCSCC between 2016 and 2019. Included were a total of 29 patients from a single academic medical center with untreated OCSCC (≥T2, or clinically node positive) randomized 1:1 to receive neoadjuvant therapy with single agent nivolumab or combination nivolumab and ipilimumab followed by surgery and standard of care adjuvant therapy. The interventions in this study were FDG-PET/CT scans before (T0) and after (T1) preoperative immunotherapy. Data collected from FDG-PET/CT scans included maximum standardized uptake value (SUVmax) of primary OCSCC and cervical lymph nodes (LNs) at T0 and T1 and new LN uptake and uptake consistent with radiologic immune-related adverse events (irAEs) at T1. Primary OCSCC pathologic response reported as percentages of viable vs nonviable tumor. The number of CD8+ cells/mm2 was determined in the primary tumor biopsy specimen and at surgery. There was no correlation between pathologic response and change in SUVmax in the primary OCSCC between T0 and T1. Out of 27 total participants, 13 had newly FDG-avid ipsilateral LNs at T1, most negative on pathology. A total of 9 had radiologic irAEs, most commonly sarcoid-like LN (7 of 27). No correlations were found between primary OCSCC SUVmax at T0 and CD8+ T-cell number in the primary tumor biopsy, and no correlations were found between primary OCSCC SUVmax at T1 and CD8+ T-cell number in the primary tumor at surgery. There were no correlations between changes in FDG uptake after neoadjuvant immunotherapy and pathologic primary tumor response. Importantly, newly FDG-avid ipsilateral LNs following neoadjuvant immunotherapy were commonly observed but did not represent progressive disease or indicate pathologically disease positive nodes in most cases. These findings argue against altering surgical plans in this setting and suggest that the role of FDG-PET/CT may be limited as an early imaging biomarker for predicting pathologic response to preoperative immunotherapy for OCSCC. ClinicalTrials.gov Identifier: NCT02919683.

FDG PET/computed tomography can detect region-specific neuronal changes following antiretroviral therapy in HIV-infected patients.

FDG PET/computed tomography can detect region-specific neuronal changes following antiretroviral therapy in HIV-infected patients.

Phase I expansion study of the first-in-class monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).

3115 Background: Tumours rely on lactate transporters (MCT1-4) to maintain glycolytic flux and avoid intracellular acidification. In haematological tumours the MCT1 transporter acts as a lactate and pyruvate exporter. AZD3965 is a potent and specific inhibitor of MCT1 causing intracellular lactate accumulation. In vivo efficacy was observed in xenografts of DLBCL and BL, expressing high levels of MCT1 and no or low levels of MCT4. In the AZD3965 phase I (NCT01791595) dose-escalation an oral recommended phase 2 dose (RP2D) of 10mg twice-daily (bd) was determined. Pharmacokinetic (PK) showed exposure estimated to produce a minimum MCT1 occupancy of 90% (based on modelling). DLTs were primarily on-target dose-dependent, reversible, asymptomatic alterations in retinal function seen on ERG. Methods: This expansion cohort enrolled patients with relapsed/refractory DLBCL and BL. Expression of MCT1/MCT4 was assessed by immunohistochemistry. Pharmacokinetic (PK) sampling was performed and pharmacodynamic assessments included [18F]FDG-PET/CT imaging and plasma/urine metabolomics. Results: 11 DLBCL patients were treated with AZD3965 10mg bd. PK showed exposure to be broadly in line with the escalation cohort. No significant ERG changes were observed. One patient experienced a dose-limiting SUSAR of Troponin I increase. MCT1 is expressed in erythrocytes, however no serious events of anaemia were seen, with one non-clinically significant episode of grade 3 anaemia reported. Urine analysis showed increased excretion of lactate and ketone bodies post AZD3965 treatment consistent with renal target engagement. No alteration was detected in plasma. Ongoing stable disease at cycle 5 was observed in one patient and an additional patient had a confirmed complete response (CR) lasting 15 months, with no significant toxicity. In the patient showing CR a reduction in tumour FDG uptake was observed on day 3 of cycle 1. The other four patients who consented to research imaging did not have a clinical response and no changes were observed on FDG-PET. Conclusions: AZD3965 can be safely administered at 10mg bd. In one DLBCL patient monotherapy activity was observed with changes in FDG-PET providing evidence indicative of proof of mechanism. These changes in FDG uptake as early as on day 3 in the responding patient warrant further investigation of FDG-PET as a predictive biomarker. Further biomarker analysis and preclinical studies are ongoing to understand the biology and explore effective combinations with other agents targeting tumour cell metabolism Clinical trial information: NCT01791595.

Positron emission tomography and single photon emission computed tomography imaging of tertiary lymphoid structures during the development of lupus nephritis.

Lymphoid neogenesis occurs in tissues targeted by chronic inflammatory processes, such as infection and autoimmunity. In systemic lupus erythematosus (SLE), such structures develop within the kidneys of lupus-prone mice ((NZBXNZW)F1) and are observed in kidney biopsies taken from SLE patients with lupus nephritis (LN). The purpose of this prospective longitudinal animal study was to detect early kidney changes and tertiary lymphoid structures (TLS) using in vivo imaging. Positron emission tomography (PET) by tail vein injection of 18-F-fluoro-2-deoxy-D-glucose (18F-FDG)(PET/FDG) combined with computed tomography (CT) for anatomical localization and single photon emission computed tomography (SPECT) by intraperitoneal injection of 99mTC labeled Albumin Nanocoll (99mTC-Nanocoll) were performed on different disease stages of NZB/W mice (n = 40) and on aged matched control mice (BALB/c) (n = 20). By using one-way ANOVA analyses, we compared two different compartmental models for the quantitative measure of 18F-FDG uptake within the kidneys. Using a new five-compartment model, we observed that glomerular filtration of 18FFDG in lupus-prone mice decreased significantly by disease progression measured by anti-dsDNA Ab production and before onset of proteinuria. We could not visualize TLS within the kidneys, but we were able to visualize pancreatic TLS using 99mTC Nanocoll SPECT. Based on our findings, we conclude that the five-compartment model can be used to measure changes of FDG uptake within the kidney. However, new optimal PET/SPECT tracer administration sites together with more specific tracers in combination with magnetic resonance imaging (MRI) may make it possible to detect formation of TLS and LN before clinical manifestations.

Local Review Versus (vs) Central Review of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in Diffuse Large B-Cell Lymphoma (DLBCL): Results from the CALGB 50303 Trial [Alliance

Local Review Versus (vs) Central Review of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in Diffuse Large B-Cell Lymphoma (DLBCL): Results from the CALGB 50303 Trial [Alliance

Rebound adenotonsillar and thymic uptake of 18F-FDG in paediatric patients with lymphoma

PurposeTo evaluate the treatment-dependent changes in FDG uptake in the adenoid, palatine tonsils, and thymus in paediatric patients with lymphoma. MethodsEight hundred PET/CT scans of 212 paediatric patients between 2007 and 2019 (mean age, 11.9 years; median follow-up, 26.2 months) were retrospectively reviewed for discernible FDG uptake in the adenoid (A+), palatine tonsils (P+), and thymus (T+). The distribution of metabolic activity in the interested lymphoid organs was examined. Statistical analysis was performed using SPSS packages. ResultsThere were 513 (64 %) A + scans, 548 (69 %) P + scans, 270 (48 %) T + scans identified. The percentage of A + was 88 % at baseline, decreased to 48 % at the end of treatment, and then rebounded to 73 % during follow up; P + went from 79 % to 45 % then to 82 %; and for T + was 75 %, 21 %, 72 %. SUVmax was significantly higher (P < 0.001) in scans performed during follow-up than that of the baseline (A + 7.0 ± 3.5 vs. 5.8 ± 2.5; P + 9.4 ± 3.5 vs. 8.2 ± 2.8; T + 4.0 ± 1.4 vs. 3.4 ± 1.1). A + and P + peaked between 6–12 months of follow-up with a SUVmax of 7.6 ± 3.2, 10.6 ± 3.2, accordingly; T + peaked within 3–12 months with a SUVmax of 4.4 ± 1.4. Despite that A + and T + were more commonly seen in younger patients at any given study time, evident uptake rebound persisted in patients aged ≥16. ConclusionsIn paediatric patients with lymphoma, evident and benign rebound adenotonsillar and thymic 18F-FDG uptake commonly occur during post-treatment surveillance.

Prognostic value of interim FDG-PET in diffuse large cell lymphoma: results from the CALGB 50303 Clinical Trial

AbstractAs part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.

Combined tumor plus nontumor interim FDG-PET parameters are prognostic for response to chemoradiation in squamous cell esophageal cancer.

We have investigated the prognostic value of two novel interim 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) parameters in patients undergoing chemoradiation (CRT) for esophageal squamous cell carcinoma (ESCC): one tumor parameter (maximal standardized uptake ratio rSUR) and one normal tissue parameter (change of FDG uptake within irradiated nontumor-affected esophagus ∆SUVNTO ). PET data of 134 European and Chinese patients were analyzed. Parameter establishment was based on 36 patients undergoing preoperative CRT plus surgery, validation was performed in 98 patients receiving definitive CRT. Patients received PET imaging prior and during fourth week of CRT. Clinical parameters, baseline PET parameters, and interim PET parameters (rSUR and ∆SUVNTO ) were analyzed and compared to event-free survival (EFS), overall survival (OS), loco-regional control (LRC) and freedom from distant metastases (FFDM). Combining rSUR and ∆SUVNTO revealed a strong prognostic impact on EFS, OS, LRC and FFDM in patients undergoing preoperative CRT. In the definitive CRT cohort, univariate analysis with respect to EFS revealed several staging plus both previously established interim PET parameters as significant prognostic factors. Multivariate analyses revealed only rSUR and ∆SUVNTO as independent prognostic factors (p = 0.003, p = 0.008). Combination of these parameters with the cutoff established in preoperative CRT revealed excellent discrimination of patients with a long or short EFS (73% vs. 17% at 2 years, respectively) and significantly discriminated all other endpoints (OS, p < 0.001; LRC, p < 0.001; FFDM, p = 0.02), even in subgroups. Combined use of interim FDG-PET derived parameters ∆SUVNTO and rSUR seems to have predictive potential, allowing to select responders for definitive CRT and omission of surgery.

Behavior of FDG-avid supradiaphragmatic lymph nodes in PET/CT throughout primary therapy in advanced serous epithelial ovarian cancer: a prospective study

BackgroundEpithelial ovarian cancer (EOC) typically spreads intra-abdominally, but preoperative evaluation with FDG PET/CT often reveals metabolically active supradiaphragmatic lymph nodes (sdLNs). Their clinical significance and behavior during treatment has not been established.MethodsEOC patients with PET positive sdLNs at diagnosis were prospectively followed with PET/CT after primary chemotherapy and at the first recurrence. In each patient, 2 most active LNs in 5 different supradiaphramatic regions were evaluated and the size and changes in FDG uptake (SUVmax) were recorded. The patients´ overall response to primary treatment was defined with RECIST criteria. The behavior of sdLNs during chemotherapy were compared in treatment responders and non-responders. Recurrence patterns were monitored.ResultsForty-one patients with 127 PET/CT scans were systematically evaluated. In pretreatment scan, 76% (31/41) of patients had FDG-avid sdLNs in multiple anatomical sites. Only a minority (22/136) of the sdLNs were enlarged in size, but their histopathologic confirmation by biopsy was not possible. Only 6/41 patients had FDG-avid sdLNs in a single surgically approachable site. The sdLNs became inactive during primary chemotherapy more often in the RECIST responders compared to the non-responders (HR 1.46 (95%CI: 1.09–1.96), p = 0.002). The size and SUVmax values did not predict treatment outcome. In 50% of the responders the same sdLNs reactivated when recurrence occurred. Persistent post-treatment metabolic activity did not predict earlier disease relapse (p = 0.59).ConclusionThe behavior of metabolically active sdLNs during chemotherapy supports their metastatic nature. Due to their distribution to multiple regions, the benefit of removal of reachable sdLNS seems unlikely.Trial registrationNCT, NCT01276574. Registered 1 September 2010.

PS02.110: PREDICTION OF PROGNOSIS BY EVALUATING RELATIVE CHANGE IN FDG-UPTAKE OF THE METASTATIC LYMPH NODES AFTER NEOADJUVANT CHEMOTHERAPY IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Prognosis of patients with esophageal squamous cell carcinoma (ESCC) can be significantly improved by neoadjuvant chemotherapy (NAC). The current best clinical method to predict pathologic response of chemotherapy is the maximum standardized uptake value (SUVmax) in 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET). However, most of the FDG-PET evaluation has been focused on the primary tumors, but not on other metastatic lesions. The aim of this study was to determine the predictive value of FDG-uptake measured prior and after NAC both in the primary tumors and in the metastatic lymph modes (mLN) in ESCC. Methods Forty-five consecutive potentially resectable ESCC patients treated with NAC, which consisted of 2 courses of continuous infusion of 5-FU for days 1–5 and CDDP on day 1, between 2009 and 2016 were evaluated. FDG-uptake was measured at baseline and after chemotherapy in the primary tumors and in the mLN, and all patients underwent esophagectomy with R0 resection. The predictive values of FDG-PET and clinicopathological characteristics were determined with univariate and multivariate analyses. Results The median age was 66 years, with 35 males and 9 females. Pretreatment clinical classification of tumor depth was T1 in 9, T2 in 10, T3 in 26, respectively, and that of lymph modes metastases was N0 in 9, N1 in 12, N2 in 18, N3 in 6, respectively. The average SUVmax before and after NAC in the primary tumors was 13.9 and 7.9, respectively, and the average SUVmax reduction was 39.8% after chemotherapy. Pathological response was found to correlate well with the SUVmax reduction in the primary tumors, however, relative change in FDG uptake after chemotherapy was not associated with overall survival (OS). The average SUVmax before and after NAC in the mLN was 6.9 and 3.3, respectively, and the average SUVmax reduction was 46.2% after chemotherapy. Univariate and multivariate analyses revealed that both of the SUVmax and relative change in FDG uptake after chemotherapy in the mLN were well correlated with OS. Conclusion Post-NAC SUVmax and relative change in FDG uptake after chemotherapy in the mLN are valuable independent preoperative predictor of prognosis for patients with ESCC who received chemotherapy before surgery. Disclosure All authors have declared no conflicts of interest.

Tumor metabolism assessed by FDG-PET/CT and tumor proliferation assessed by genomic grade index to predict response to neoadjuvant chemotherapy in triple negative breast cancer.

Survival is increased when pathological complete response (pCR) is reached after neoadjuvant chemotherapy (NAC), especially in triple-negative breast cancer (TNBC) patients. Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) and the genomic grade index (GGI), each separately, showed good potential to predict pCR. Our study was designed to evaluate the predictive value for the therapeutic response of a combination of parameters based on FDG-PET, histoclinical features and molecular markers of proliferation. Molecular parameters were measured on pre-treatment biopsy. Tumor metabolic activity was measured using two PET/CT scans, one before and one after 2cycles of NAC. The pCR was determined on specimen after NAC. Event-free survival (EFS) was estimated using the Kaplan Meier method. Of 55 TNBC patients, 19 (35%) reached pCR after NAC. Tumor grade and Ki67 were not associated with pCR whereas GGI (P = 0.04) and its component KPNA2 (P = 0.04) showed a predictive value. The change of FDG uptake between PET1 and PET2 (ΔSUVmax) was highly associated with pCR (P = 0.0001) but the absolute value of baseline SUVmax was not (P = 0.11). However, the AUC of pCR prediction increased from 0.63 to 0.76 when baseline SUVmax was combined with the GGI (P = 0.016). The only two parameters associated with EFS were ΔSUVmax (P = 0.048) and pathological response (P = 0.014). The early tumor metabolic change during NAC is a powerful parameter to predict pCR and outcome in TNBC patients. The GGI, determined on pretreatment biopsy, is also predictive of pCR and the combination GGI and baseline SUVmax improves the prediction.

Prognostic role of serial quantitative evaluation of 18F-fluorodeoxyglucose uptake by PET/CT in patients with cardiac sarcoidosis presenting with ventricular tachycardia.

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has shown to be useful in diagnosis, staging and monitoring of cardiac sarcoidosis (CS) but its interpretation is not standardized. We sought to investigate the clinical impact of serial quantitative FDG uptake analysis in patients with CS presenting with ventricular tachycardia (VT) treated by catheter ablation (CA). We followed 20 patients (51 ± 9years, 70% males) with CS and VT who underwent CA, with 92 serial FDG-PET scans (3-10 per patient). Myocardial FDG-avid lesions were quantified using three parameters: maximum standardized uptake value (SUVmax), partial-volume corrected mean standardized uptake value (SUVmean) and partial-volume corrected volume-intensity product [lesion metabolic activity (LMA)]. The volume-intensity product of the entire heart [global cardiac metabolic activity (gCMA)] and the background cardiac metabolic activity (bCMA: difference between gCMA and LMA) were also calculated. The primary end-point was the occurrence of major adverse cardiac events (MACE), including death, heart transplant, hospitalization for heart failure and implantable cardioverter defibrillator (ICD) appropriate interventions. Evolution of echocardiographic parameters over follow-up was also assessed. During a median follow-up of 35 (20-66) months, 18 MACE (1 death, 2 heart transplants, 12 ICD appropriate interventions, 3 hospitalizations) occurred in 12 (60%) patients. At univariable analysis, lack of PET improvement (defined by decrease in LMA of at least 25%) was the only variable associated with cardiac events during follow-up. In particular, non-responders had a 20-fold higher risk of MACE at follow-up (HR 18.96, 95% CI 2.26-159.27; p = 0.007). Moreover, a significant linear inverse relationship was observed between changes in LMA and changes in left ventricular ejection fraction over follow-up (β = -20.11; p = 0.003). In patients with CS and VT, temporal change in FDG uptake evaluated by a quantitative approach is associated with parallel change in systolic function. Moreover, reduction in FDG uptake is strongly associated with fewer MACE at long-term follow-up.

18FDG-PET/CT and molecular markers to predict response to neoadjuvant chemotherapy and outcome in HER2-negative advanced luminal breast cancers patients.

BackgroundThe efficacy of neoadjuvant chemotherapy regimens in advanced luminal breast cancer patients is difficult to predict. Intrinsic properties of breast tumors, including altered gene expression profile and dynamic evaluation of metabolic properties of tumor cells using positron emission tomography/computed tomography (PET/CT) of tumor cells, have been identified to guide patient’s prognosis. The aim of this study is to determine if both analyses may improve the prediction of response to neoadjuvant chemotherapy in ER-positive / HER2-negative breast cancers (BCs) patients.MethodsWe used metabolic PET parameters, at diagnosis and after two cycles of chemotherapy and proliferation gene expression profile on biopsy at diagnosis, in particular, the genomic grade index (GGI) analyzed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). The pathological response was the surrogate endpoint.ResultsThe change of FDG uptake between baseline PET and interim PET after 2 cycles of neoadjuvant chemotherapy (ΔSUVmax) was highly associated with pCR (p=0.008). We also observed an ability of P53 mutated status (p=0.042), in addition to histological grade (p=0. 0004), and PR expression (p=0.01) to predict pCR in ER-positive BCs, whereas no proliferation marker predicted pCR (P=0.39 for GGI). Finally, only ΔSUVmax was significantly associated with event free survival (p=0.047).ConclusionsOur results confirm the predictive and prognostic value of tumor ΔSUVmax in ER-positive /HER2-negative advanced BCs patients. These findings can be helpful to select high-risk patients within trials investigating novel treatment strategies.

Amyloid and tau signatures of brain metabolic decline in preclinical Alzheimer\u2019s disease

PurposeWe aimed to determine the amyloid (Aβ) and tau biomarker levels associated with imminent Alzheimer’s disease (AD) - related metabolic decline in cognitively normal individuals.MethodsA threshold analysis was performed in 120 cognitively normal elderly individuals by modelling 2-year declines in brain glucose metabolism measured with [18F]fluorodeoxyglucose ([18F]FDG) as a function of [18F]florbetapir Aβ positron emission tomography (PET) and cerebrospinal fluid phosphorylated tau biomarker thresholds. Additionally, using a novel voxel-wise analytical framework, we determined the sample sizes needed to test an estimated 25% drugeffect with 80% of power on changes in FDG uptake over 2 years at every brain voxel.ResultsThe combination of [18F]florbetapir standardized uptake value ratios and phosphorylated-tau levels more than one standard deviation higher than their respective thresholds for biomarker abnormality was the best predictor of metabolic decline in individuals with preclinical AD. We also found that a clinical trial using these thresholds would require as few as 100 individuals to test a 25% drug effect on AD-related metabolic decline over 2 years.ConclusionsThese results highlight the new concept that combined Aβ and tau thresholds can predict imminent neurodegeneration as an alternative framework with a high statistical power for testing the effect of disease-modifying therapies on [18F]FDG uptake decline over a typical 2-year clinical trial period in individuals with preclinical AD.

Pharmacokinetic-driven phase I study of DCC-2618 a pan-KIT and PDGFR inhibitor in patients (pts) with gastrointestinal stromal tumor (GIST) and other solid tumors.

2515 Background: DCC-2618 is a potent switch control inhibitor of KIT and PDGFR kinases active in a broad range of mutations. GIST is an important disease to achieve a proof-of-concept due to the heterogeneity of KIT resistance mutations, which emerge on treatment with approved KIT inhibitors. Methods: This was a PK-guided dose escalation study of oral DCC-2618 (QD or BID q28 days) in advanced solid tumors. FDG-PET scans were used to assess changes in FDG uptake in GIST pts after 3 wks of therapy. Next generation sequencing (NGS) of plasma cell-free (cf) DNA was performed throughout the study to assess and quantify KIT and other molecular alterations in drug targets and potential mechanisms of resistance. Results: 38 pts were enrolled (30 GIST; 4 glioma; 1 mastocytosis, 3 other carcinoma) to 8 dose levels: BID doses: 20 (4 pts), 30 (4), 50 (5), 100 (6), 150 (6) and 200 mg (3); QD doses: 100 (5) and 150 mg (4). Safety of evaluable pts is as follows: G3 or G4 adverse effects (regardless of attribution and occurring in &gt; 1 pt) included anemia (5), lipase increase (4), hypertension (2). Two of the G3/4 lipase increase at 100 mg BID and 200 mg BID were DLTs. All G3/4 lipase increase were asymptomatic. G1/2 AEs (considered at least possibly related to DCC-2618) and occurring in ≥15% (n &gt; 5) of pts include fatigue (12), alopecia &amp; lipase increase (7), weight decrease (6). Starting with 50 mg BID dose level, trough concentrations of total drug exceeded the IC90 of the least sentivitive KIT mutations. Plasma concentrations &gt; 5μM were achieved starting at 100 mg BID and the selection of the expansion phase dose is being finalized. Of 18 pts with KIT mutant GIST assessed by FDG PET, 14 (78%) had partial metabolic response per EORTC criteria. RANO/RECIST partial responses (PRs) were reported in 3 patients (1 GBM with PDGFRA/KIT amplifications and 2 GIST with Ex 11 &amp; 17 / Ex 11 &amp; 18 mutations, respectively). NGS of plasma cfDNA revealed 44 KIT mutations in baseline samples from 19 of 21 pts with GIST. Conclusions: DCC-2618 is well tolerated with encouraging preliminary activity in GIST pts with a broad spectrum of mutations and prior therapies. PR was also seen in a pt with GBM with PDGFRA/KIT amplifications. Clinical trial information: NCT02571036.

The response of FDG uptake to immunosuppressive treatment on FDG PET/CT imaging for cardiac sarcoidosis

BackgroundImmunosuppression is used to treat cardiac sarcoidosis, despite limited data. FDG PET/CT is used for detecting cardiac inflammation in patients with CS, yet there is variability in interpretation of FDG PET/CT. Our aim was to compare quantitative and qualitative interpretation of FDG PET/CT for CS in defining the FDG response to immunosuppression. Methods and ResultsPatients with CS (N = 43 total studies from 17 patients) had serial FDG PET/CT studies before/after immunosuppression. FDG uptake was analyzed qualitatively (visually; FDG-positive segments) and quantitatively (SUVmax; cardiac metabolic volume and activity (CMV, CMA); volume above SUV thresholds 2.7 and 4.1 g/mL). Complete resolution of FDG uptake was common using CMA (10/17), CMV (10/17), but a 2.7 g/mL SUV threshold (13/17) and SUVmax (14/17) were more likely to define partial responses. In six patients imaged after a reduction in immunosuppression, 4/6 had a rebound quantitative FDG uptake. ConclusionsQuantitative interpretation of FDG PET/CT in CS can detect changes in FDG uptake in response to immunosuppression. Further studies are needed to see if quantitative changes in FDG uptake are associated with improved outcomes.

Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE for Metastatic Neuroendocrine Tumor Occurring in Association with Multiple Endocrine Neoplasia Type 1 and Cushing's Syndrome.

Neuroendocrine tumor (NET) occurring in association with other endocrine syndromes forms a distinct entity. The aim was to assess the therapy response profile of the routine peptide receptor radionuclide therapy (PRRT) in this relatively uncommon but clinically challenging subgroup of patients. A retrospective analysis was undertaken from the case records from those who were treated with 177Lu-DOTATATE for metastatic NET. In addition to assessing the therapeutic efficacy, emphasis was also given to study lesional sites and scan pattern. A total of 5 cases were found: In this series of five cases, four belonged to multiple endocrine neoplasia type 1 (MEN1) syndrome; in these four MEN1 syndrome patients, the primary site of NET was thymic region (n = 1), duodenum (n = 1), and pancreas (n = 2). The fifth case was of Cushing's syndrome with the primary site of NET in the thymus. A good symptomatic response was observed in all MEN1 syndrome cases (100%) and progression of symptoms in the patient with Cushing's syndrome. The biochemical response (assessed by measurement of tumor marker serum chromogranin A) demonstrated very good partial response (defined by more than 75% reduction of tumor marker) in 2 MEN1 cases and Cushing's syndrome, good partial response (25–75% reduction of tumor marker) in the remaining 2 MEN1 cases. Scan wise (assessed by technetium [99mTc]-hydrazinonicotinamide [HYNIC]-tektrotyd [TOC]/68Ga-DOTA-NOC/TATE positron emission tomography-computed tomography [PET-CT] and fluorodeoxyglucose [FDG] PET-CT) partial response was observed in 3 MEN1 cases, stable disease was noted in one MEN1 case and disease progression was noted in the patient with Cushing's syndrome. The change in FDG uptake was found to be an important sensitive scan parameter in the treatment evaluation of NETs compared to somatostatin receptor-based imaging in the cases with low MiB1 index. In our series, good palliative response to 177Lu-DOTA-octreotate (DOTATATE) PRRT was observed in most NET patients associated with MEN1 syndrome without any major hematological or renal toxicity.