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The value of interim 18F-FDG PET/CT (iPET)-guided treatment decisions in patients with diffuse large B-cell lymphoma (DLBCL) has been the subject of much debate. This investigation focuses on a comparison of the Deauville score and the change-in-SUV max (DSUV max) approach-2 methods to assess early metabolic response to standard chemotherapy in DLBCL. Methods: Of 609 DLBCL patients participating in the PET-Guided Therapy of Aggressive Non-Hodgkin Lymphomas trial, iPET scans of 596 patients originally evaluated using the DSUV max method were available for post hoc assessment of the Deauville score. A commonly used definition of an unfavorable iPET result according to the Deauville score is an uptake greater than that of the liver, whereas an unfavorable iPET scan with regard to the ΔSUV max approach is characterized as a relative reduction of the SUV max between baseline and iPET staging of less than or equal to 66%. We investigated the 2 methods' correlation and concordance by Spearman rank correlation coefficient and the agreement in classification, respectively. We further used Kaplan-Meier curves and Cox regression to assess differences in survival between patient subgroups defined by the prespecified cutoffs. Time-dependent receiver-operating-characteristic curve analysis provided information on the methods' respective discrimination performance. Results: Deauville score and DSUV max approach differed in their iPET-based prognosis. The ΔSUV max approach outperformed the Deauville score in terms of discrimination performance-most likely because of a high number of false-positive decisions by the Deauville score. Cutoff-independent discrimination performance remained low for both methods, but cutoff-related analyses showed promising results. Both favored the ΔSUV max approach, for example, for the segregation by iPET response, where the event-free survival hazard ratio was 3.14 (95% confidence interval, 2.22-4.46) for ΔSUV max and 1.70 (95% confidence interval, 1.29-2.24) for the Deauville score. Conclusion: When considering treatment intensification, the currently used Deauville score cutoff of an uptake above that of the liver seems to be inappropriate and associated with potential harm for DLBCL patients. The ΔSUV max criterion of a relative reduction in SUV max of less than or equal to 66% should be considered as an alternative.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.

Purpose Interim positron emission tomography (PET) using the tracer, [18F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan that was evaluated using the ΔSUVmax method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt’s lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.

Introduction: The PETAL trial is a multicenter randomized controlled study for patients with aggressive lymphomas of diverse histologies (EudraCT 2006-001641-33, NCT00554164). In the study population as a whole interim PET (iPET) reliably predicted time to treatment failure (TTTF) and overall survival (OS). Interim PET-based treatment changes, however, had no impact on outcome (ASH 2014, abstract 391). Here we report the exploratory analysis for aggressive B cell lymphomas. Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by iPET. The conditions of iPET were strictly defined: 3-week interval between the 2nd R-CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve reproducibility (favorable iPET response: reduction of maximum SUV by > 66 % compared to baseline; J Nucl Med 48:1626, 2007). Pts. with CD20+ lymphomas and a favorable iPET were randomized to receive 4 more cycles of R-CHOP or the same treatment plus 2 extra doses of R (part A of the trial). Pts. with an unfavorable iPET were randomized to continue R-CHOP for 6 additional cycles or receive 6 blocks of a more complex methotrexate-, cytarabine- and etoposide-based regimen originally designed for Burkitt lymphoma (Blood 124: 3870, 2014; part B). R was omitted in pts. with CD20- lymphomas. Sample size of the entire study population was based on the empirically derived assumption that treatment failure after 2 yrs. (TF: progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 80 % to 90 % in part A and from 30 % to 45 % in part B (alpha=0.05, power=0.8). Secondary endpoints included OS and toxicity. Results: Fifty-seven oncological centers and 23 nuclear medicine institutions participated in the trial. Between 2007 and 2012 1072 pts. were registered, and 862 (80.4 %) had a positive baseline PET, received 2 cycles R-CHOP, underwent iPET and were allocated to one of the post-iPET treatment arms detailed above. Reference pathology was available in 98 %, and median follow-up is 52 months. All in all, there were 779 patients with CD20+ aggressive B-cell lymphomas (90.4 % of all treated pts.) of whom 606 had diffuse large B-cell lymphoma (DLBCL), 42 primary mediastinal B-cell lymphoma (PMBCL) and 42 follicular lymphoma grade 3 (FL3). Interim PET was favorable in 691 pts. (88.7 %) and unfavorable in 88 pts. with CD20+ lymphomas (11.3 %). It was highly predictive of TTTF for CD20+ lymphomas in general and for each of the DLBCL, PMBCL and FL3 subgroups (Table). In CD20+ lymphomas and DLBCL, the iPET response predicted TF independently of the International Prognostic Index, and it was also predictive of OS. The groups of PMBCL and FL3 were too small for multivariate analyses. In part A, adding 2 extra doses of R failed to improve TTTF and OS in all histological entities. Separate analyses for subgroups defined by sex, age (< vs. > 60 yrs.) or a combination of the two showed no statistically significant benefit of extra doses of R in any of the subgroups. In pts. with an unfavorable iPET response, a switch from R-CHOP to the Burkitt regimen failed to improve TTTF or OS in CD20+ lymphomas in general (Figure) and in the DLBCL, PMBCL and FL3 subgroups. In part B, the Burkitt protocol was associated with more grade 3/4 leukopenia (82 % vs. 57 %, p=0.02), thrombocytopenia (59 % vs. 18 %, p=0.0001), infection (41 % vs. 16 %, p=0.017) and mucositis (39 % vs. 7 %, p=0.0007) than R-CHOP, but treatment-related mortality was similar in both arms (1 death each). Conclusion: In this large multicenter trial iPET proved highly predictive of outcome in pts. with CD20+ aggressive B-cell lymphomas, DLBCL, PMBCL or FL3 treated with R-CHOP. In pts. with a favorable iPET response, addition of 2 extra doses of R to 6 cycles R-CHOP failed to improve outcome in CD20+ lymphomas in general and in subgroups defined by histology, sex or age. In pts. with an unfavorable iPET response, switching to a more aggressive protocol also failed to improve outcome in any of the entities. Novel strategies are required for aggressive B-cell lymphomas failing to respond to the first 2 cycles of R-CHOP. Table Table. Figure Figure. Disclosures Duehrsen: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Giagounidis:Celgene Corporation: Consultancy. Grube:BMS, Sanofi: Consultancy. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Hüttmann:Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria; Gilead, Amgen: Other: Travel cost.

Aims We studied the effects of cardiac resynchronization therapy (CRT) on global and regional myocardial oxygen consumption (MVO2) and myocardial blood flow (MBF) in non-ischaemic (NICM) and ischaemic dilated cardiomyopathy (ICM). Methods and results Thirty-one NICM and 11 ICM patients, all of them acute responders, were investigated. MVO2 and MBF were obtained by 11C-acetate PET before and after 4 months of CRT. In NICM global MVO2 and MBF did not change during CRT, while the rate pressure product (RPP) normalized MVO2 increased ( P =0.03). Before CRT regional MVO2 and MBF were highest in the lateral wall and lowest in the septum. Under therapy, MVO2 and MBF decreased in the lateral wall ( P =0.045) and increased in the septum ( P =0.045) resulting in a more uniform distribution. In ICM, global MVO2, MBF, and RPP did not change under CRT. Regional MVO2 and MBF showed no significant changes but a similar tendency in the lateral and septal wall to that in NICM. Conclusion CRT induces changes of MVO2 and MBF on a regional level with a more uniform distribution between the myocardial walls and improved ventricular efficiency in NICM. Based on the investigated parameters, CRT appears to be more effective in NICM than in ICM.

Objective: In patients with dilated cardiomyopathy (DCM), left bundle branch block (LBBB) is a common finding. The characteristic feature is an asynchronous septal wall motion and most frequently a delay of the lateral and/or posterior wall segments. With the onset of cardiac resynchronization therapy, there is a focus on the specific pathophysiology of a LBBB. However, quantitative data on regional myocardial oxygen consumption (MVO2) and blood flow (MBF) are missing. Methods: We studied 31 patients with severe DCM and LBBB (ejection fraction 22.1±7.1%) and 14 patients with mild to moderate DCM without LBBB (ejection fraction 46.7±7.9%). Global and regional MVO2 as well as MBF were determined from a dynamic 11C-acetate positron emission tomography (PET) study. Results: Global MVO2 and MBF were lower in the DCM group with LBBB than in the control group (P

Background —Early stages of coronary atherosclerosis are characterized by a mainly functional impairment of coronary vasodilator capacity under the impact of such risk factors as hypercholesterolemia. The goal of this study was to determine whether 6-month cholesterol-lowering therapy improves coronary flow reserve in patients with angina, reduced flow reserve despite minimally diseased coronary vessels or even normal angiogram, and mild to moderately elevated LDL levels on average. Methods and Results —We noninvasively investigated 23 consecutive patients (18 men, 5 women; mean age, 56±7.6 years) with a mean LDL level of 165±34 mg/dL at baseline by PET for myocardial blood flow measurement with [ 13 N]ammonia at rest and under dipyridamole stress (0.56 mg/kg) before and after lipid-lowering therapy with simvastatin for 6 months. Between baseline and the 6-month follow-up, total cholesterol concentration fell from 241±44 to 168±34 mg/dL, and the LDL level decreased from 165±34 to 95±26 mg/dL ( P P P −1 · min×100 g ( P Conclusions —Our results suggest that cholesterol-lowering therapy with simvastatin may improve overall coronary vasodilator capacity assessed noninvasively by PET in patients with mild to moderate hypercholesterolemia. Consequently, intensive lipid-lowering therapy is considered a vasoprotective treatment for selected patients in very early stages of coronary atherosclerosis with the potential of preventing further disease progression.

Background. Compromised organ donors are generally not accepted for heart transplantation (HT) despite the increasing number of critically ill patients on the waiting lists. By extending the donor criteria to include certain cases of intoxication, the organ shortage may be reduced. Methods. The case of a successful orthotopic HT with an allograft from a donor poisoned by antidepressant overdose is presented. Results. Early graft function was satisfactory with anteroseptal dyskinesis and an ejection fraction of 75% on echocardiography. The cardiac allograft recipient suffered some postoperative complications including gastrointestinal problems. The following period was up to now uneventful. Discharge from the intensive care unit was after 4 days. In-hospital stay was prolonged at 26 days. Conclusions. Because of limited myocardial toxicity, donor hearts from certain victims of antidepressant intoxication may be safely used for HT. Existing cardiac organ donor criteria must be reevaluated to maximise the available organ pool.