Diffuse large B-cell lymphoma involving osseous sites: utility of response assessment by PET/CT and good longterm outcomes.

Osseous involvement by diffuse large B-cell lymphoma (DLBCL-bone) is a heterogeneous disease. There is limited data regarding response assessment by positron emission tomography with fluorodeoxyglucose, which may demonstrate residual avidity despite a complete response. We analyzed clinical data of patients with newly diagnosed DLBCL and identified all cases with DLBCL-bone. End of treatment scans were reviewed by two independent experts classifying osseous lesions into Deauville (DV) ≤3; DV ≥4, or reactive uptake in the bone marrow (M), site of fracture (F) or surgery (S). We compared outcomes of DLBCL-bone to other extranodal sites (EN) matched on International Prognotic Index features and regimen. Of 1,860 patients with DLBCL (bone 16%; EN 45%; nodal 39%), 41% had localized disease and 59% advanced. Only 9% (n=27) of patients with initial bone involvement had residual fluorodeoxyglucose avidity at the osseous site. In half of these cases, the uptake was attributed to F/S/M, and of the remaining 13, only two were truly refractory (both with persistent disease at other sites). Overall survival and progression-free survival (PFS) were found to be similar for early- stage nodal DLBCL and DLBCL-bone, but inferior in EN-DLBCL. Advanced-stage disease involving the bone had a similar 5-year PFS to nodal disease and EN-DLBCL. After matching for International Prognotic Index and treatment regiments, PFS between bone and other EN sites was similar. Osseous involvement in DLBCL does not portend a worse prognosis. End of treatment DV ≥4 can be expected in 5-10% of cases, but in the absence of other signs of refractory disease, may be followed expectantly.

Correction to: 18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors.

The article 18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors written by Laure Michaud, B. J. Beattie, T. Akhurst, M. Dunphy, P. Zanzonico, R. Finn, A. Mauguen, H. Schöder, W. A. Weber, A. B. Lassman, R. Blasberg.

18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors.

PURPOSE: The aim of our study was to investigate the efficacy of 18F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [11C-methyl]-L-methionine (11C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection. METHODS: Twenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI. RESULTS: 18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5 ± 2.3), while 11C-Methionine's tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0 ± 2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p < 0.0001). This was due to 18F-Fluciclovine's lower background in normal brain tissue (0.5 ± 0.2 compared to 1.3 ± 0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7 ± 2.3 h), and achieving a consistent final distribution volume averaging 1.4 ± 0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57 ± 51 min), with an average distribution volume of 3.2 ± 1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine. CONCLUSION: Tumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.

Impact of sodium 18F-fluoride PET/CT, 18F-fluorocholine PET/CT and whole-body diffusion-weighted MRI on the management of patients with prostate cancer suspicious for metastasis: a prospective multicentre study.

PURPOSE: To compare the impact of 18F-sodium-fluoride (NaF) PET/CT, 18F-fluorocholine (FCH) PET/CT and diffusion-weighted whole-body MRI (DW-MRI) on the management of patients with prostate cancer (PCa) suspicious for distant metastasis. METHODS: Prostate cancer patients were prospectively included between December 2011 and August 2014 and benefited from these three whole-body imaging (WBI) modalities within 1 month in addition to the standard PCa workup. Management was prospectively decided by clinicians during two multidisciplinary meetings, before and after the whole-body imaging workup. Rates of induced changes of whole-body imaging modalities were compared by Cochran's Q test. RESULTS: One-hundred-one patients (27 at staging, 59 at first biochemical recurrence (BCR) and 15 at first episode of rising serum level of prostate-specific antigen during androgen-deprivation therapy) were included. The overall rate of management changes was 52%: 29% as a consequence of WBI, higher for FCH-PET/CT than for NaF-PET/CT or DW-MRI (p < 0.0001) and highest (41%) for FCH-PET/CT at BCR. Actual management was adequate in all patients but two. CONCLUSIONS: Whole-body imaging induced a change in management in approximately a third of PCa patients suspicious for metastasis. The impact rate was determined to be greatest at first BCR using FCH-PET/CT. NaF-PET/CT and DW-MRI seemed less useful in this context.

Consequence of the introduction of routine FCH PET/CT imaging for patients with prostate cancer: a dual centre survey.

BACKGROUND: Fluorocholine(18F) (FCH) was introduced at the beginning of April 2010 in France, Slovenia and three other EU member states for the localisation of bone metastases of prostate cancer with PET. The aim of the study was to compare the evolution of diagnostic imaging in patients with prostate cancer using a new radiopharmaceutical FCH, observed in France and in Slovenia, and to quantify the consequence of the results of new imaging modality on the detection rate of abnormal metastases and recurrences of prostate cancer. PATIENTS AND METHODS: In two centres (France/Slovenia), a survey of the number of nuclear medicine examinations in patients with prostate cancer was performed, covering 5 quarters of the year since the introduction of FCH. For each examination, the clinical and biological circumstances were recorded, as well as the detection of bone or soft tissue foci. RESULTS: Six hundred and eighty-eight nuclear medicine examinations were performed impatients with prostate cancer. Nuclear medicine examinations were performed for therapy monitoring and follow-up in 23% of cases. The number of FCH PET/CT grew rapidly between the 1(st) and 5(th) period of the observation (+220%), while the number of bone scintigraphies (BS) and fluoride(18F) PET/CTs decreased (-42% and -23% respectively). Fluorodeoxyglucose(18F) (FDG) PET/CT remained limited to few cases of castrate-resistant or metastatic prostate cancer in Paris. The proportion of negative results was significantly lower with FCH PET/CT (14%) than with BS (49%) or fluoride(18F) PET/CT (54%). For bone metastases, the detection rate was similar, but FCH PET/CT was performed on average at lower prostate-specific antigen (PSA) levels and was less frequently doubtful (4% vs. 28% for BS). FCH PET/CT also showed foci in prostatic bed (53% of cases) or in soft tissue (35% of cases). CONCLUSIONS: A rapid development of FCH PET/CT was observed in both centres and led to a higher detection rate of prostate cancer lesions.

Incidental uptake of (18)F-fluorocholine (FCH) in the head or in the neck of patients with prostate cancer.

BACKGROUND: Positron emission tomography-computed tomography (PET/CT) with (18)F-fluorocholine (FCH) is routinely performed in patients with prostate cancer. In this clinical context, foci of FCH uptake in the head or in the neck were considered as incidentalomas, except for those suggestive of multiple bone metastases. RESULTS: In 8 patients the incidental focus corresponded to a benign tumour. The standard of truth was histology in two cases, correlative imaging with MRI in four cases, (99m)Tc-SestaMIBI scintigraphy, ultrasonography and biochemistry in one case and biochemistry including PTH assay in one case. The final diagnosis of benign tumours consisted in 3 pituitary adenomas, 2 meningiomas, 2 hyperfunctioning parathyroid glands and 1 thyroid adenoma. Malignancy was proven histologically in 2 other patients: 1 papillary carcinoma of the thyroid and 1 cerebellar metastasis. CONCLUSIONS: To the best of our knowledge, FCH uptake by pituitary adenomas or hyperfunctioning parathyroid glands has never been described previously. We thus discuss whether there might be a future indication for FCH PET/CT when one such tumour is already known or suspected: to detect a residual or recurrent pituitary adenoma after surgery, to guide surgery or radiotherapy of a meningioma or to localise a hyperfunctioning parathyroid gland. In these potential indications, comparative studies with reference PET tracers or with (99m)Tc-sestaMIBI in case of hyperparathyroidism could be undertaken.

Development of 18F-Fluoromisonidazole Hypoxia PET/CT Diagnostic Interpretation Criteria and Validation of Interreader Reliability, Reproducibility, and Performance.

Tumor hypoxia, an integral biomarker to guide radiotherapy, can be imaged with 18F-fluoromisonidazole (18F-FMISO) hypoxia PET. One major obstacle to its broader application is the lack of standardized interpretation criteria. We sought to develop and validate practical interpretation criteria and a dedicated training protocol for nuclear medicine physicians to interpret 18F-FMISO hypoxia PET. Methods: We randomly selected 123 patients with human papillomavirus-positive oropharyngeal cancer enrolled in a phase II trial who underwent 123 18F-FDG PET/CT and 134 18F-FMISO PET/CT scans. Four independent nuclear medicine physicians with no 18F-FMISO experience read the scans. Interpretation by a fifth nuclear medicine physician with over 2 decades of 18F-FMISO experience was the reference standard. Performance was evaluated after initial instruction and subsequent dedicated training. Scans were considered positive for hypoxia by visual assessment if 18F-FMISO uptake was greater than floor-of-mouth uptake. Additionally, SUVmax was determined to evaluate whether quantitative assessment using tumor-to-background ratios could be helpful to define hypoxia positivity. Results: Visual assessment produced a mean sensitivity and specificity of 77.3% and 80.9%, with fair interreader agreement (κ = 0.34), after initial instruction. After dedicated training, mean sensitivity and specificity improved to 97.6% and 86.9%, with almost perfect agreement (κ = 0.86). Quantitative assessment with an estimated best SUVmax ratio threshold of more than 1.2 to define hypoxia positivity produced a mean sensitivity and specificity of 56.8% and 95.9%, respectively, with substantial interreader agreement (κ = 0.66), after initial instruction. After dedicated training, mean sensitivity improved to 89.6% whereas mean specificity remained high at 95.3%, with near-perfect interreader agreement (κ = 0.86). Conclusion: Nuclear medicine physicians without 18F-FMISO hypoxia PET reading experience demonstrate much improved interreader agreement with dedicated training using specific interpretation criteria.

Conventional and novel [18F]FDG PET/CT features as predictors of CAR-T cell therapy outcome in large B-cell lymphoma.

Relapse and toxicity limit the effectiveness of chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL), yet biomarkers that predict outcomes and toxicity are lacking. We examined radiomic features extracted from pre-CAR-T 18F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scans (n = 341) of 180 patients (121 male; median age, 66 years). Three conventional (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG]) and 116 novel radiomic features were assessed, along with inflammatory markers, toxicities, and outcomes. At both pre-apheresis and pre-infusion time points, conventional PET features of disease correlated with elevated inflammatory markers. At pre-infusion, MTV was associated with grade ≥ 2 cytokine release syndrome (odds ratio [OR] for 100 mL increase: 1.08 [95% confidence interval (CI), 1.01-1.20], P = 0.031), and SUVmax was associated with failure to achieve complete response (CR) (OR 1.72 [95% CI, 1.24-2.43], P < 0.001). Higher pre-apheresis and pre-infusion MTV values were associated with shorter progression-free survival (PFS) (HR for 10-unit increase: 1.11 [95% CI, 1.05-1.17], P < 0.001; 1.04 [95% CI, 1.02-1.07], P < 0.001) and shorter overall survival (HR for 100-unit increase: 1.14 [95% CI, 1.07-1.21], P < 0.001; 1.04 [95% CI, 1.02-1.06], P < 0.001). A combined MTV and LDH measure stratified patients into high and low PFS risk groups. Multiple pre-infusion novel radiomic features were associated with CR. These quantitative conventional [18F]FDG PET/CT features obtained before CAR-T cell infusion, which were correlated with inflammation markers, may provide prognostic biomarkers for CAR-T therapy efficacy and toxicity. The use of conventional and novel radiomic features may thus help identify high-risk patients for earlier interventions.

18F-fluorodihydroxyphenylalanine vs other radiopharmaceuticals for imaging neuroendocrine tumours according to their type.

6-Fluoro-((18)F)-L-3,4-dihydroxyphenylalanine (FDOPA) is an amino acid analogue for positron emission tomography (PET) imaging which has been registered since 2006 in several European Union (EU) countries and by several pharmaceutical firms. Neuroendocrine tumour (NET) imaging is part of its registered indications. NET functional imaging is a very competitive niche, competitors of FDOPA being two well-established radiopharmaceuticals for scintigraphy, (123)I-metaiodobenzylguanidine (MIBG) and (111)In-pentetreotide, and even more radiopharmaceuticals for PET, including fluorodeoxyglucose (FDG) and somatostatin analogues. Nevertheless, there is no universal single photon emission computed tomography (SPECT) or PET tracer for NET imaging, at least for the moment. FDOPA, as the other PET tracers, is superior in diagnostic performance in a limited number of precise NET types which are currently medullary thyroid cancer, catecholamine-producing tumours with a low aggressiveness and well-differentiated carcinoid tumours of the midgut, and in cases of congenital hyperinsulinism. This article reports on diagnostic performance and impact on management of FDOPA according to the NET type, emphasising the results of comparative studies with other radiopharmaceuticals. By pooling the results of the published studies with a defined standard of truth, patient-based sensitivity to detect recurrent medullary thyroid cancer was 70 % [95 % confidence interval (CI) 62.1-77.6] for FDOPA vs 44 % (95 % CI 35-53.4) for FDG; patient-based sensitivity to detect phaeochromocytoma/paraganglioma was 94 % (95 % CI 91.4-97.1) for FDOPA vs 69 % (95 % CI 60.2-77.1) for (123)I-MIBG; and patient-based sensitivity to detect midgut NET was 89 % (95 % CI 80.3-95.3) for FDOPA vs 80 % (95 % CI 69.2-88.4) for somatostatin receptor scintigraphy with a larger gap in lesion-based sensitivity (97 vs 49 %). Previously unpublished FDOPA results from our team are reported in some rare NET, such as small cell prostate cancer, or in emerging indications, such as metastatic NET of unknown primary (CUP-NET) or adrenocorticotropic hormone (ACTH) ectopic production. An evidence-based strategy in NET functional imaging is as yet affected by a low number of comparative studies. Then the suggested diagnostic trees, being a consequence of the analysis of present data, could be modified, for some indications, by a wider experience mainly involving face-to-face studies comparing FDOPA and (68)Ga-labelled peptides.

Prognostic Value of 18F-FDG PET/CT in Diffuse Large B-Cell Lymphoma Treated with a Risk-Adapted Immunochemotherapy Regimen.

Early identification of patients with diffuse large B-cell lymphoma (DLBCL) who are likely to experience disease recurrence or refractory disease after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) would be useful for improving risk-adapted treatment strategies. We aimed to assess the prognostic value of 18F-FDG PET/CT parameters at baseline, interim, and end of treatment (EOT). Methods: We analyzed the prognostic impact of 18F-FDG PET/CT in 166 patients with DLBCL treated with a risk-adapted immunochemotherapy regimen. Scans were obtained at baseline, after 4 cycles of R-CHOP or 3 cycles of RR-CHOP (double dose of R) and 1 cycle of CHOP alone (interim) and 6 wk after completing therapy (EOT). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier and the impact of clinical/PET factors assessed with Cox models. We also assessed the predictive ability of the recently proposed International Metabolic Prognostic Index (IMPI). Results: The median follow-up was 7.9 y. International Prognostic Index (IPI), baseline metabolic tumor volume (MTV), and change in maximum SUV (ΔSUVmax) at interim scans were statistically significant predictors for OS. Baseline MTV, interim ΔSUVmax, and EOT Deauville score were statistically significant predictors of PFS. Combining interim PET parameters demonstrated that patients with Deauville 4-5 and positive ΔSUVmax ≤ 70% at restaging (∼10% of the cohort) had extremely poor prognosis. The IMPI had limited discrimination and slightly overestimated the event rate in our cohort. Conclusion: Baseline MTV and interim ΔSUVmax predicted both PFS and OS with this sequential immunochemotherapy program. Combining interim Deauville score with interim ΔSUVmax may identify an extremely high-risk DLBCL population.

Bridging Radiation Rapidly and Effectively Cytoreduces High-Risk Relapsed/Refractory Aggressive B Cell Lymphomas Prior to Chimeric Antigen Receptor T Cell Therapy.

Greater tumor burden before CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy predicts lower complete response rate and shorter overall survival (OS) in patients with aggressive non-Hodgkin lymphoma (NHL). Recent patterns of failure studies have identified lesion characteristics, including size, standard uptake value (SUV), and extranodal location, as associated with post-CAR-T therapy failure. Here we analyzed the effect of bridging radiation-containing treatment (BRT) on pre-CAR-T therapy lesion- and patient-level characteristics and post-CAR-T therapy outcomes, including patterns of failure. Consecutive NHL patients who received radiation therapy from 30 days before leukapheresis until CAR T cell infusion were reviewed. Metabolic tumor volume (MTV) was contoured with a threshold SUV of 4. The first post-CAR-T therapy failures were categorized as preexisting/new/mixed with respect to pre-CAR-T therapy disease and in-field/marginal/distant with respect to BRT. Forty-one patients with diffuse large B cell lymphoma (DLBCL; n = 33), mantle cell lymphoma (n = 7), or Burkitt lymphoma (n = 1) were identified. BRT significantly improved established high-risk parameters of post-CAR-T therapy progression, including in-field median MTV (45.5 cc to .2 cc; P < .001), maximum SUV (18.1 to 4.4; P < .001), diameter (5.5 cm to 3.2 cm; P < .001), and lactate dehydrogenase (LDH; 312 to 232; P = .025). DLBCL patients with lower LDH levels post-BRT had improved progression-free survival (PFS; P = .001). In DLBCL, first failures were new in 7 of 19 patients, preexisting in 5 of 19, and mixed in 7 of 19; with respect to BRT, 4 of 19 were in-field and 4 of 19 were marginal. Post-CAR-T therapy survival was similar in patients with initially low MTV and those with newly low MTV post-BRT using a statistically determined threshold of 16 cc (PFS, 26 months versus 31 months; OS unreached for both). BRT produced significant cytoreductions in diameter, SUV, MTV, and LDH, all predictors of poor post-CAR-T therapy outcomes. Similar PFS and OS in patients with initially low MTV and those who achieved newly low MTV after BRT suggest that BRT may "convert" poor-risk patients to better risk. In the future, the response to BRT may allow for risk stratification and individualization of bridging strategies.

Outcomes of Patients with Positive Interim Positron Emission Tomography (PET) Continuing ABVD in the Clinical Setting.

Recent prospective clinical trial data suggest that patients with Hodgkin's lymphoma who continue treatment with ABVD, despite failing to attain a complete metabolic response on interim PET (PET2+), may fare better than previously published. We describe the outcomes of PET2+ patients who continued ABVD and compare the performance of a quantitative measure based on the lesion-to-liver SUV ratio (LLS qPET2+) to that of the subjective Deauville criteria (dvPET2+). We analyzed all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at the Memorial Sloan Kettering Cancer Center between 2008 and 2017. Eligibility was set to correspond with the RATHL inclusion criteria. Images were reviewed by two nuclear medicine physicians and discordant cases were resolved with a third expert in consensus. qPET2+ was defined as LLS ≥ 1.3. We identified 227 patients of whom 25% (57) were qPET2+, but only 14% (31) were dvPET2+. Forty-eight patients (84%) continued ABVD with a 3-year PFS of 70% for qPET2+ and 64% for dvPET2+. In conclusion, interim PET interpretation in clinical practice may be associated with a higher rate of scans deemed positive. Irrespective of the criteria for PET2 positivity, a subset of patients may continue ABVD without a dismal outcome.

Interim Positron Emission Tomography During Frontline Chemoimmunotherapy for Follicular Lymphoma.

While most patients with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of patients will experience early progression, which is associated with poor subsequent outcomes. Novel biomarkers are needed to identify high-risk patients earlier. We hypothesized that interim positron emission tomography (PET) would predict progression-free survival (PFS) in this population. We retrospectively identified 128 patients with grade 1-3A FL who had an interim PET after 2-4 cycles of frontline CIT at 2 academic centers. PET scans were analyzed using Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Interim PET DS was a significant predictor of PFS (P < 0.003). Patients with a DS of 3 had outcomes similar to those of patients with a DS of 4, so were categorized as PET-positive for additional analyses. Interim PET remained a strong predictor of PFS (DS 3-5, hazard ratio [HR] 2.4, P = 0.006) in a multivariable analysis and was also an early predictor of both a positive end-of-treatment PET (P < 0.001) and progression of disease within 24 months (POD24) (P = 0.006). An optimal ΔSUVmax cutoff of 75% was selected using the bootstrap method. ΔSUVmax <75% was also a significant predictor of PFS on univariable and multivariable analyses (HR 2.8, P < 0.003). In a separate cohort of 50 patients with high-grade FL, interim PET interpreted using either DS (P < 0.001) or ΔSUVmax75% (P = 0.034) was also a significant predictor of inferior PFS. In conclusion, interim PET is an independent predictor of PFS and may be useful as a tool for response-adapted treatment strategies in FL.

Phase I/Ib Study of the Efficacy and Safety of Buparlisib and Ibrutinib Therapy in MCL, FL, and DLBCL with Serial Cell-Free DNA Monitoring.

PURPOSE: Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition. PATIENTS AND METHODS: We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247. RESULTS: Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance. CONCLUSIONS: BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.

Baseline FDG-PET/CT detects bone marrow involvement in follicular lymphoma and provides relevant prognostic information.

In follicular lymphoma (FL), detection of bone marrow (BM) involvement (BMI) by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) improves the accuracy of staging vs BM biopsy (BMB) alone. Our objective was to determine the diagnostic utility of PET for BMI FL and the prognostic value of BMI by PET (positive PET result [PET+]). Records of patients (2002-2016) with PET and BMB at the time of initial treatment were reviewed. BMI was identified by positive BMB result (BMB+) and/or unifocal or multifocal BM FDG uptake on blindly reviewed PET scans with no corresponding CT abnormality (PET+). Among 261 patients, BMI was diagnosed in 78 patients (29.9%) by PET+, in 81 patients (31.0%) by BMB+, and in 113 patients (43.3%) by either PET+ or BMB+. PET+ upstaged 24 patients to stage IV, including 10 from stages I or II to stage IV. Median duration of follow-up was 6.0 years (range, 0-16.6 years). In univariate analysis, a high Follicular Lymphoma International Prognosis Index (FLIPI) score, PET+, and BMB+ correlated with shorter progression-free survival (PFS; all P ≤ .03), and high FLIPI, PET+, and combined PET+ and BMB+ with shorter overall survival (OS; all P ≤ .01). In multivariate analysis, PET+ was the only independent predictor of PFS, whereas high FLIPI score and PET+ predicted OS (P ≤ .03). Combined PET and BMB identify BMI more accurately than either BMB or PET alone, but BMB rarely adds critical information. For patients initiating treatment of FL, identification of BMI by PET is predictive of PFS and OS.

11C-Choline PET/CT in Recurrent Prostate Cancer: Retrospective Analysis in a Large U.S. Patient Series.

Our purpose was to evaluate the performance of 11C-choline PET/CT in detecting biochemically recurrent prostate cancer (PCa) in a large non-European cohort (in the context of emerging evidence for prostate-specific membrane antigen PET in this setting) and to map patterns of PCa recurrence. Methods: We retrospectively analyzed 11C-choline PET/CT scans from 287 patients who were enrolled in an imaging protocol based on rising prostate-specific antigen (PSA) levels (mean, 3.43 ng/mL; median, 0.94 ng/mL; range, 0.15-89.91 ng/mL) and suspected recurrent PCa. A total of 187 patients had undergone primary radical prostatectomy (RP) (79/187 had secondary radiotherapy), 30 had undergone primary radiotherapy, and 70 had a persistent PSA elevation after receiving initial treatment (69 after RP, 1 after radiotherapy). The level of suspicion for recurrence on 11C-choline PET/CT was scored (0, negative; 1, equivocal; 2, positive) by 2 readers. The correlation between 11C-choline PET/CT positivity and initial treatment, Gleason score, National Comprehensive Cancer Network stage, PSA level, PSA doubling time, PSA velocity, and time between initial treatment and PET imaging was evaluated. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were used to map 11C-choline recurrence patterns. Results: Considering scores 1 and 2 as positives, consensus between the 2 readers deemed 66% of the 11C-choline PET/CT scans as positive. When sorted by PSA level, 45% of patients with a PSA of less than 0.5 ng/mL, 56% of patients with a PSA of 0.5-0.99 ng/mL, 70% of patients with a PSA of 1.0-1.99 ng/mL, and 90% of patients with a PSA of at least 2.0 ng/mL scored either 1 or 2 on 11C-choline PET/CT scans. When considering scores of 2 only, 11C-choline PET/CT positivity was 54% (28%, 46%, 62%, and 81%, respectively, for patients with PSA < 0.5 ng/mL, 0.5-0.99 ng/mL, 1.0-1.99 ng/mL, and ≥ 2.0 ng/mL). In multivariate analysis, only PSA level was significantly associated with scan positivity. Pattern analysis showed that pelvic lymph nodes were the most common site of recurrence, and 28% of patients had 11C-choline-positive suspected recurrences outside the initial treatment field. Conclusion:11C-choline PET/CT can detect PCa recurrence even among patients with low PSA levels when interpretation accounts for the clinical context, providing a certain pretest probability. Until prostate-specific membrane antigen agents are fully approved for PCa, choline PET/CT may provide clinical utility.

68Ga-DOTATOC PET/CT in detecting neuroendocrine tumours responsible for initial or recurrent paraneoplastic Cushing's syndrome.

PURPOSE: Paraneoplastic Cushing's syndrome (PCS) is frequently caused by neuroendocrine tumours (NETs). Approximately 20% of tumours are still occult years later. Gallium-68 somatostatin receptor-PET/CT is promising for the detection of the causal primary NET, but its role in case of recurrent PCS is rarely reported. We report our experience with DOTATOC PET/CT in localising the causal NET in cases of initial but also recurrent PCS, and its clinical impact. METHODS: A retrospective review of all DOTATOC PET/CTs performed in consecutive patients referred for PCS to our centre, between January 2011 and June 2017, was done. Nineteen patients underwent 26 PET/CTs, 13 for detection of a primary NET, seven for persistent or recurrent PCS after resection, and six for surveillance after resection of NETs previously detected on a DOTATOC PET/CT in our centre. RESULTS: Among the 13 PET/CTs performed to search for primary NET, five were positive: four carcinoid lung tumours were confirmed after resection and one lung focus was not confirmed since surgery would have carried a high risk. Clinical impact was 23% (3/13). Among the seven PET/CTs performed for persistent or recurrent PCS, six were true-positive, with confirmation of metastatic lymph nodes after resection. Clinical impact was 57% (4/7). All PET/CTs performed for surveillance were true-negative. CONCLUSIONS: DOTATOC PET/CT seems to be a valuable tool for detection of the NET responsible for persistent or recurrent PCS after surgery. In this context, DOTATOC PET/CT was more effective than for the detection of the causal tumour in initial PCS.

The geriatric syndrome of sarcopenia impacts allogeneic hematopoietic cell transplantation outcomes in older lymphoma patients.

Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT) yet their survival outcomes remain suboptimal. We and others have previously shown that pre-HCT multi-morbidity and functional limitation and post-HCT geriatric syndromes significantly impact outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized in older cancer patients. We identified 146 lymphoma patients 50 years or older who were allografted from 2008 to 2018 at our institution and found that before allo-HCT, 80 (55%) patients were sarcopenic. Pre-HCT sarcopenia was significantly associated with overall survival, progression-free survival, and nonrelapse mortality independent of multi-morbidity and functional limitation. In 6-month landmark analysis, post-HCT sarcopenia remained significantly associated with survival. Our findings illustrate the high prevalence and profound impact of sarcopenia on survival. While requiring prospective confirmation, preemptive, longitudinal, and multidisciplinary interventions for sarcopenia are warranted to improve HCT outcomes for older patients.

18F-FDG PET/CT for Monitoring of Ipilimumab Therapy in Patients with Metastatic Melanoma.

Immune checkpoint inhibitors (ICIs) are now commonly used to treat patients with metastatic malignant melanoma. Although concerns have been raised that the inflammatory response induced by ICIs may limit the ability of 18F-FDG PET/CT to assess tumor response, systematic analyses on the use of 18F-FDG PET/CT in this setting are mostly lacking. Thus, we set out to evaluate the association between tumor response on 18F-FDG PET/CT and prognosis in patients with metastatic malignant melanoma treated with ipilimumab. Methods: We analyzed 60 consecutive patients with metastatic melanoma who underwent 18F-FDG PET/CT scans both before and after treatment to evaluate treatment response after completion of ipilimumab therapy. Tumor response was assessed by the change in the sum of SULpeak (voxels with the highest average SUL [SUV normalized to lean body mass]) of up to 5 lesions according to PERCIST5. New lesions on PET that appeared suggestive of metastases were considered progressive metabolic disease (PMD). Because immunotherapy may cause new inflammatory lesions that are detectable on 18F-FDG PET/CT, we also evaluated an immunotherapy-modified response classification (imPERCIST5). In this classification, new lesions do not define PMD per se; rather, PMD requires an increase in the sum of SULpeak by 30%. The correlation between tumor response according to these 3 definitions and overall survival (OS) was evaluated and compared with known prognostic factors. Results: In responders and nonresponders, the 2-y OS was 66% versus 29% for imPERCIST5 (P = 0.003). After multivariate analysis, imPERCIST5 remained prognostic (hazard ratio, 3.853; 95% confidence interval, 1.498-9.911; P = 0.005). New sites of focal 18F-FDG uptake occurred more often in patients with PMD (n = 24) by imPERCIST5 than in those with stable metabolic disease (n = 7) or partial metabolic response (n = 4). In patients with partial metabolic response, 2 of 4 isolated new lesions regressed spontaneously during follow-up. Conclusion: In patients with metastatic melanoma treated with ipilimumab, tumor response according to PERCIST was associated with OS. Our data suggest that PMD should not be defined by the appearance of new lesions, but rather by an increase in the sum of SULpeak.

Prospective Study of the Radiolabeled GRPR Antagonist BAY86-7548 for Positron Emission Tomography/Computed Tomography Imaging of Newly Diagnosed Prostate Cancer.

BACKGROUND: Current imaging techniques may not detect all prostate cancer (PCa) lesions. OBJECTIVE: To evaluate positron emission tomography (PET)/computed tomography (CT) using the radiolabeled GRPR antagonist probe BAY86-7548 (68Ga-RM2) for localization of newly diagnosed PCa in comparison with multiparametric magnetic resonance imaging (mpMRI), histopathology, and immunohistochemistry (IHC). DESIGN, SETTING, AND PARTICIPANTS: This was a prospective study of 16 men with biopsy-proven PCa (2 low, 8 intermediate, and 6 high risk). 68Ga-RM2 PET/CT was performed within 4 wk after mpMRI and within 2 wk before radical prostatectomy and extended bilateral pelvic lymph node dissection. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The presence of cancer was evaluated by blinded specialists using a 5-point Likert scale, with lesions scoring 4 or 5 considered positive, on 68Ga-RM2 PET/CT, mpMRI, and 68Ga-RM2 PET/CT-mpMRI fused images for each of 12 anatomic areas of the prostate. Whole-mount, step-section pathology served as the reference standard. Expression of GRPR and prostate-specific membrane antigen (PSMA) was analyzed via IHC of tumor paraffin sections. RESULTS AND LIMITATIONS: Of 192 areas analyzed, 128 contained cancer. The sensitivity, specificity, and accuracy of 68Ga-RM2 PET/CT imaging and mpMRI did not differ significantly; fusing the images maximized the sensitivity and accuracy (85.2% and 83.9%, respectively) and averaged the specificity (81.3%). The area under the receiver operating characteristic curve was 0.76 for PET visual analysis, 0.72 for PET quantitative analysis, 0.76 for mpMRI, and 0.85 for combined PET/CT and mpMRI analysis. 68Ga-RM2 uptake did not correlate with Gleason score. IHC analysis revealed weaker staining for GRPR than for PSMA, and the expression of these markers was not correlated (r=0.3882). The major limitation is the small sample size. CONCLUSIONS: 68Ga-RM2 PET/CT is promising for detection and localization of primary PCa, and complements mpMRI. GRPR expression appears to be independent from PSMA expression, suggesting that GRPR- and PSMA-targeted PET imaging may be complementary. PATIENT SUMMARY: This pilot prospective study shows that a positron emission tomography probe that binds to a marker of prostate cancer, GRPR, improves the ability of magnetic resonance imaging to detect prostate cancer.