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Extensive experience outside the United States as well as randomized phase II and phase III data demonstrate thatThis review discusses the development and studies leading to the approval of

Malignant pheochromocytomas (PHEOs)/paragangliomas (PGLs) are rare tumors for which clinical outcomes remain poorly defined and therapeutic options are limited. Approximately 27% carry pathogenic germline succinate dehydrogenase (SDHx) mutations; the presence of such mutations has been correlated with response to temozolomide (TMZ). We aimed to investigate the association between germline mutations in SDHx and response to TMZ. We retrospectively identified patients with metastatic malignant PHEO/PGLs treated with TMZ- based chemotherapy at Dana-Farber Cancer Institute between 2003 and 2020. The correlation between response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and PET Response Criteria in Solid Tumors (PERCIST) and the presence of SDHx mutations in the germline and tumor was evaluated. Nineteen patients received TMZ. Seventeen underwent germline assessment: 9 (53%) carried a pathogenic SDHx germline mutation. Fifteen patients were evaluable for response by RECIST 1.1: 6 (40%) partial response, 4 (27%) stable disease, and 5 (33%) progressive disease. Overall median progression-free survival was 2.2 years. Three-year overall survival (OS) was 58%. Median PFS was 1.3 years and 5.5 years for carriers and non-carriers, respectively and OS was 1.5 years and not estimable for carriers and non-carriers, respectively. The response by PERCIST criteria in nine patients correlated with the RECIST 1.1 assessment. Our series represents one of the largest analyses of patients with malignant PHEOs/PGLs treated with TMZ who have available germline data. The incidence of pathogenic germline SDHx mutations was similar to what has been previously published, though our analysis suggests that there may be a limited association between response to TMZ and pathogenic germline SDHx mutations.

Improved biomarkers are needed to guide the optimal use of autologous stem cell transplantation (ASCT) for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples or post-ASCT peripheral blood mononuclear cell (PBMC) and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, p

Background: Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis and repair of DNA, making RNR-targeted therapy a rationale therapeutic strategy for radiosensitization. ETCTN 10388 (NCT04234568) evaluated safety and efficacy of the combination of lutetium 177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. Method: This study was a multicenter phase 1 dose escalation trial [using the Bayesian optimal interval design (BOIN)] of triapine in combination with fixed dose lutetium Lu 177 DOTATATE for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment with an expansion cohort at the recommended phase 2 dose (RP2D). Oral triapine (100mg, 150mg, 200mg) was administered once daily on days 1-14 and Lu-177 DOTATATE [200 mCi] intravenously on day 1 of every 56-day cycle. A total of 4 cycles were administered. Response and adverse effects were assessed per RECIST and CTCAE 5.0, respectively. Exploratory correlative studies included tumor somatic and germline mutation testing, RNA sequencing, pharmacokinetics, deoxynucleosides and circulating cell free DNA analysis. Primary endpoints were safety and RP2D. Results: Overall, 31 patients were enrolled between 6 sites, 15 in the dose escalation phase and 16 in the dose expansion phase. Adverse events (AE) were assessed in all 31 patients per CTCAE 5.0. One DLT in dose level 1, seven DLTs in dose level 2, and one grade 5 DLT in dose level 3 were observed. The RP2D of the combination is triapine 150 mg QD (dose level 2) on days 1-14 in combination with Lu-177 DOTATATE on day 1 of every 56-day cycle. Detailed safety and adverse event data will be presented at the meeting. There were 28 patients evaluable for efficacy, of which 6 (21%) achieved a partial response. At 12 months, 6 patients had progressed, while 22 (86%) remained progression free. Median PFS has not been reached. PK data were available for 12 patients enrolled in the dose escalation cohort. The geometric mean (SD) AUC0-inf was 1159 (1.22) µg/L•h for the 100mg dose level and 1862 (1.76) µg/L•h for the 150 mg dose level, suggesting that exposure increased with dose, and inter-patient variability was as expected for an oral agent. Conclusion: The combination of triapine and Lu-177 DOTATATE was safe with preliminary efficacy signals, which will be further evaluated in ETCTN 10558, a randomized phase 2 study that is comparing the effectiveness of triapine and Lu-177 DOTATATE to Lu-177 DOTATATE alone. Citation Format: Aman Chauhan, Susanne Arnold, Jill Kolesar, William Carson, Heidi Weiss, Rani Jayswal, Donglin Yan, Riham El Khouli, Aman Khurana, Jan Beumer, Heloisa Soares, Mary Mulcahy, Thorvardur Halfdanarson, Daneng Li, Heather Jacene, Percy Ivy, Elise Kohn, John Wright, Larry Rubinstein, Zeta Chow, Piotr Rychahou, Mark B. Evers, Charles Kunos, Lowell Anthony, Bhavana Konda. ETCTN 10388: a first in human phase I trial of triapine and lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT194.

108 Background: LuPSMA received FDA approval in March 2022 for patients with PSMA-positive metastatic castrate-resistant prostate cancer (mCRPC). Clinical implementation of this treatment requires multidisciplinary team (MDT) involvement and has been beset by challenges in drug supply. We established a joint DFCI GU/Nuclear Medicine Tumor Board (GU-NM TB) to review patients for therapy, and our initial experiences are described. Methods: A joint GU-NM TB was established. All patients with mCRPC who had received at least one prior chemotherapy and a novel hormonal agent were considered eligible and referred to TB through an online referral system after undergoing PSMA-PET/CT. Case details, including prior treatment history, performance status and organ function, and PET/CT imaging were reviewed at TB, with patients either being approved, deferred, or declined for LuPSMA therapy. Patients were scheduled for therapy on a first-come first-served basis. Treatment was delivered per standard-of-care at 180-200 millicurie doses every 6 weeks within NM. A questionnaire was sent to 25 referring physicians 2 months after implementation of the TB to evaluate the referral process. Results: Between May-September 2022, a total of 108 patients were referred for LuPSMA therapy. Median age at time of referral was 73 (range 52-93), and 90% of patients were Caucasian. Median duration between PSMA-PET/CT and TB review was 10 days (IQR 6-17). 84 patients (78%) were approved for therapy, 16 (15%) were deferred and 7 (6%) were declined (reasons including absence of prior chemotherapy, high risk for toxicities, poor performance status); 1 patient died before TB review. Prior therapies included docetaxel (84%), cabazitaxel (56%), abiraterone (67%), enzalutamide (57%), darolutamide (23%), radium-223 (21%) and apalutamide (7%). Median number of prior treatments was 4 (range 2-12). Sites of disease on PSMA-PET/CT included bone (81%), pelvic lymph nodes (42%), extrapelvic lymph nodes (88%), lung (27%) and liver (22%). As of September 2022, a total of 40 patients (48%) have received at least 1 cycle of therapy and 17 (20%) have received 2 cycles; 6 patients (7%) approved for therapy died before receiving 177Lu-PSMA-617. Of the patients that have received 1 cycle of therapy, median duration between TB acceptance and C1 was 52 days (range 32-114). Out of 13 survey respondents, all 13 (100%) reported that their overall experience of the referral process was positive or very positive, and 12 (92%) noted that the Tumor Board had provided additional clinical insights on occasion or frequently. Conclusions: Due to drug supply shortages

68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) is a useful tool for diagnosing and staging neuroendocrine neoplasms (NEN). Unlike other PET tracers like FDG, the meaningfulness and use of standardized uptake values (SUVs) of 68Ga-DOTATATE is not well-established. This study aimed to determine if a correlation exists between intensity of 68Ga-DOTATATE uptake and markers of cellular proliferation.This retrospective study included 79 patients with positive 68Ga-DOTATATE PET/CT and Ki-67 and/or mitotic index (MI) available on pathology report. SUVA trend for an association between SUVThe association between 68Ga-DOTATATE SUV

Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive eitherAt the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in theTreatment with

Estimating organ residence times is an essential part of patient-specific dosimetry for radioimmunotherapy (RIT). Quantitative imaging methods for RIT are often evaluated using a single physical or simulated phantom but are intended to be applied clinically where there is variability in patient anatomy, biodistribution, and biokinetics. To provide a more relevant evaluation, the authors have thus developed a population of phantoms with realistic variations in these factors and applied it to the evaluation of quantitative imaging methods both to find the best method and to demonstrate the effects of these variations. Using whole body scans and SPECT∕CT images, organ shapes and time-activity curves of 111In ibritumomab tiuxetan were measured in dosimetrically important organs in seven patients undergoing a high dose therapy regimen. Based on these measurements, we created a 3D NURBS-based cardiac-torso (NCAT)-based phantom population. SPECT and planar data at realistic count levels were then simulated using previously validated Monte Carlo simulation tools. The projections from the population were used to evaluate the accuracy and variation in accuracy of residence time estimation methods that used a time series of SPECT and planar scans. Quantitative SPECT (QSPECT) reconstruction methods were used that compensated for attenuation, scatter, and the collimator-detector response. Planar images were processed with a conventional (CPlanar) method that used geometric mean attenuation and triple-energy window scatter compensation and a quantitative planar (QPlanar) processing method that used model-based compensation for image degrading effects. Residence times were estimated from activity estimates made at each of five time points. The authors also evaluated hybrid methods that used CPlanar or QPlanar time-activity curves rescaled to the activity estimated from a single QSPECT image. The methods were evaluated in terms of mean relative error and standard deviation of the relative error in the residence time estimates taken over the phantom population. The mean errors in the residence time estimates over all the organs were