Decrease In SUV Research Articles

Genomic Correlates of Radiosensitivity in Diffuse Large B Cell Lymphoma

Introduction Radiotherapy (RT) is beneficial for select patients with localized diffuse large B cell lymphoma (DLBCL), in both the early stage and relapsed/refractory settings. Although molecular subtyping plays a key role in classification of DLBCL, genomic predictors of local response to RT have yet to be adequately explored. To our knowledge, there are no existing studies investigating the genomic landscape of DLBCL patients treated with RT. Therefore, we sought to identify genomic signatures of radiosensitivity in localized DLBCL patients. Methods We analyzed an institutional database of DLBCL patients treated with RT for localized measurable disease treated between 2007-2022. All patients underwent next-generation sequencing using an institutional 505-gene panel (MSK-Impact). Clinical and radiographic characteristics were obtained from chart and imaging review. All patients had measurable disease on CT scan at time of RT and included both Ann Arbor stage I/II patients referred for consolidative radiotherapy and those with isolated sites of relapsed/refractory disease. Patients did not receive any systemic therapy between RT start and time of response assessment. The public NCI LymphGen algorithm was used to further classify genomic subgroups. Using Fisher's exact test and logistic regression, we tested for univariable correlation between specific gene alterations and LymphGen subgroups with initial radiation response, defined by Lugano criteria and decrease in maximum SUV. Results We identified 46 patients including 15 (33%) tumors treated in the early-stage setting (13% definitively without prior chemotherapy, 87% as consolidation), while 31 (60%) were treated in the localized relapsed/refractory setting. The majority were GCB subtype (57%) while 28% were non-GCB and 15% had missing immunohistochemistry data. The median number of prior lines of systemic therapy was 1 (0-2) in early stage and 1 (1-7) in localized relapsed/refractory diseases. The median RT dose was 36 Gy (4-54), with 38 (83%) tumors receiving at least 30Gy. The median lesion SUV at the time of RT was 4.11 (1.1-46.0). Complete response (CR) was achieved in 41% of tumors at the time of first imaging assessment (median 3.1 months) with a median of 90.3% (42-100%) decrease in SUV. The most commonly altered individual genes were KMT2D (35%), MYD88 (28%), and TP53 (35%). LymphGen classified 22% of cases as EZB subtype, 13% as MCD, 2% as BN2, 2% as ST2, and the remaining 61% were unclassified. Mutations in ETV6 (13% of tumors) were associated with a higher CR rate in response to RT (83% mutated vs 35% wildtype, p=0.068). Lesions from ETV6 mutated cases had similar SUVs (p=0.74) and sizes (p=0.92) as wildtype cases. Alterations in genes from the LymphGen MCD subgroup were associated with greater reductions in SUV (ETV6 p<0.0001, PIM1 p<0.0001, MYD88 p<0.001, and TNFAIP3 p=0.02) The MCD subgroup trended towards increased odds of CR post-RT (log odds 1.9, p=0.08) and greater reduction of SUV (p=0.07) compared to the EZB subgroup. Conclusions To our knowledge this is the first study evaluating the role of LymphGen subgrouping on radiotherapy response, and the first study to examine genomic alterations in DLBCL patients treated with radiation. Genomic biomarkers of radiosensitivity are needed to identify radioresponsive tumors which may benefit from better integration of RT into existing salvage paradigms such as CAR T cells. Our data suggest that alterations in MCD LymphGen subgroup genes (ETV6, PIM1, MYD88, TNFAIP3) may be associated with better response to radiotherapy. ETV6 is a strong hematopoietic transcription factor known to be altered in many human leukemias and myelodysplastic syndromes. Its role in DLBCL is not well defined, with preclinical studies suggesting a distinct role compared to leukemias. Due to the limited sample size, these findings are hypothesis generating and warrant further study with larger, prospective cohorts to validate the ability of genomic signatures to predict RT response.

FRI228 Primary Adrenal T-cell Lymphoma: A Case Report

Abstract Disclosure: H. Tabassum: None. S. Xu: None. A. Manavalan: None. Introduction: Primary T-cell adrenal lymphoma (PAL) is exceedingly rare. Adrenal insufficiency (AI) is common in these cases. Here we describe a patient with bilateral, large, T-cell PAL with rapid progression, without adrenal insufficiency. Clinical Case: A 62-year-old male, with coronary artery disease and recent coronary intervention, hyperlipidemia and hypertension presented to the hospital with abdominal pain, fever, night sweats and weight loss for a month. Work up revealed a 5.8 cm left adrenal mass with 14% absolute washout, measuring 34 Hounsfield Units (HU) pre-contrast, 68 HU postcontrast, and 63 HU on delayed images, and a 5.2 cm right adrenal mass with 42% absolute washout, measuring 35 HU pre-contrast, 81 HU postcontrast, and 62 HU on the delayed images with no other suspicious lesions or lymphadenopathy. The patient demonstrated no clinical symptoms or signs of adrenal hormone excess or deficiency. Levels of renin, aldosterone, serum cortisol, ACTH, 24-hour urine free cortisol, serum metanephrines, and thyroid function were normal. Additional tests to rule out adrenal cortical carcinoma (ACC) revealed normal levels of androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and estradiol. Persistent non-significant elevation of 11-deoxycortisol was observed at 51 ng/dL and 63ng/dL (Ref < 42 ng/dL). Adrenal biopsy was suggested but deferred due to the increased risk of hemorrhage given recent coronary revascularization and use of dual antiplatelet therapy. Follow up imaging in a few weeks revealed diffuse, retroperitoneal lymphadenopathy with unchanged adrenal masses. A lymph node biopsy confirmed a diagnosis of peripheral T-cell lymphoma. The left adrenal gland demonstrated an uptake SUV of 22.7 and the right, 19.17 on FDG PET. The patient was initiated on chemotherapy with etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin. Imaging three months later revealed a marked decrease in FDG activity SUV 6.98 g/mL on the left and SUV up to 3.32 g/mL on the right. Adrenal function remained intact on follow up. Conclusion: Peripheral T-cell lymphoma with adrenal involvement is an extremely rare and aggressive disease with rapid progression. Mostly seen in males over the age of 50, it may present with abdominal pain, B symptoms or both. While ACC is usually unilateral, lymphoma and metastatic disease may present bilaterally, however, other imaging features can be similar. AI is expected when 90% of the adrenal glands are destroyed by tumor infiltration, however, this does not always correlate with tumor size. In our patient, AI was not observed on presentation or follow up. As adrenal insufficiency can occur at any time in the disease course and may mimic symptoms of cancer or chemotherapy, the clinician should always be vigilant for its development in these cases. Presentation: Friday, June 16, 2023

Positive Predictive Value of PET CT in HPV Associated Oropharyngeal Cancers Treated with Definitive Proton Therapy

Proton therapy (PT) offers attractive dosimetric advantages but there is emerging literature suggesting relative biological effectiveness (RBE) differences at the distal end of the Bragg peak may result in increased posttreatment FDG avidity. While the utility of PET CT is well established, lingering posttreatment inflammation from PT may affect the interpretation of posttreatment scans (PTS). We seek to characterize the positive predictive value (PPV) and negative predictive value (NPV) for residual disease/locoregional recurrence in patients undergoing definitive PT with HPV associated oropharyngeal cancer. We performed a single institution retrospective analysis of patients with HPV associated oropharyngeal cancer treated with PT between 2016-2022. Patients were included if they had both pretreatment and initial posttreatment restaging PET/CT available for analysis. SUVmax was recorded in both the primary tumor and involved lymph nodes. Patients were considered to have a positive PET CT if there was an SUV decrease of less than 65% from the baseline exam or if there was SUV > 4.0 based on thresholds defined by previous studies. Chi-square analysis was used to compare patients who had a positive PTS to those who did not. Sixty-two patients were included for analysis with a median age of 62. The entire cohort had a median follow up of 21 months (Range 2-71 months) of whom 86% received chemotherapy. Eleven patients (17%) had PTS defined as positive, of whom only one (PPV 9%) was found to have residual/locoregionally recurrent disease within an area of FDG avidity on PTS. Another patient developed a new primary tumor 9 months later in an area outside of FDG avidity on PTS. The remainder were followed with serial clinical exam with or without the compliment of repeat imaging. They remained without evidence of residual/locoregionally recurrent disease at the time of last follow up. Fifty-one patients had negative posttreatment scans, with only one patient having residual/locoregionally recurrent disease (NPV 98%). On Chi-square analysis T1-2 vs T3-4 tumor, use of CTV margin vs no margin, chemotherapy vs no chemotherapy, smoking history, and tonsil vs base of tongue subsite were not statistically significant in association with positive PTS. PET/CT for post-treatment evaluation of patients treated with PT had an expectedly high NPV of 98% for residual/locoregionally recurrent disease; however, the PPV was 9% (1/11) which is much lower than would be expected with photon-based treatment. These findings may be the result of lingering acute inflammation caused by RBE differences at the distal end of the Bragg peak. Our findings are hypothesis generating and require validation with larger well-matched patient cohorts.

The significance of metabolic response to neoadjuvant androgen deprivation therapy detected with [68Ga]Ga-PSMA-11-PET/CT in high-risk prostate cancer patients treated with definitive radiotherapy.

We examined the prognostic significance of early changes in primary tumor SUV measured with Gallium-68-labeled prostate-specific membrane antigen positron emission tomography ([68Ga]Ga-PSMA-11-PET/CT) and serum PSA values after neoadjuvant androgen deprivation treatment (nADT) in high-risk prostate cancer (PCa) patients treated with definitive radiotherapy (RT). The clinical data and SUV parameters of 71 PCa patients were reviewed retrospectively. The serum PSA and primary tumor SUV values were calculated before and after the start of ADT. Using univariable and multivariable analyses, the prognostic factors predicting biochemical disease free survival (bDFS) and prostate cancer specific survival (PCSS) were investigated. In addition, logistic regression analysis was used to identify predictors of biochemical failure (BF). All but one patient responded with a 98.8% reduction in serum PSA (21.8ng/mL vs. 0.3ng/mL; p < 0.001), and 64 patients (91.1%) had a median 66.6% decrease in primary tumor SUV after ADT (13.2 vs. 4.8, p < 0.001). The primary tumor SUV response rate was significantly higher in patients with Gleason score (GS) of 7 than in patients with GS > 7 (59.5% vs. 40.5%; p = 0.04), and it was significantly lower in patients with inadequate treatment response than in those with complete (CR) or partial response (PR) (1.1% vs. 66.1%; p < 0.001). There was a strong and significant correlation (Spearman = 0.41, p < 0.001) and a high concordance (91.5%) between PSA response and SUV response after ADT. With a median follow-up time of 76.1months, the 5-year bDFS and PCSS rates were 77.2% and 92.2%, respectively. Nineteen patients (26.7%) patients had recurrence at a median of 44.6months after the completion of RT. In multivariate analysis, lymph node metastasis, GS greater than 7, and SD/PD after nADT were independent predictors of worse bDFS. However, no significant factor for PCSS was identified. In the multivariable logistic regression analysis, advanced age, GS of > 7 disease, lymph node metastasis, and SD or PD after nADT were independent predictors of BF. These results imply that the metabolic response measured with [68Ga]Ga-PSMA-11-PET/CT after nADT could be used to predict progression in high-risk PCa patients treated with definitive RT.

Report on the PET/CT Image-Based Radiation Dosimetry of [18F]FDHT in Women, a Validated Imaging Agent with New Applications for Evaluation of Androgen Receptor Status in Women with Metastatic Breast Cancer.

In a prospective clinical trial, [18F]fluoro-5α-dihydrotestosterone ([18F]FDHT), the radiolabeled analog of the androgen dihydrotestosterone, was used as a PET/CT imaging agent for invivo assessment of metastatic androgen receptor-positive breast cancer in postmenopausal women. To our knowledge, this article presents the first report of PET/CT image-based radiation dosimetry of [18F]FDHT in women. Methods: [18F]FDHT PET/CT imaging was performed on a cohort of 11 women at baseline before the start of therapy and at 2 additional time points during selective androgen receptor modulator (SARM) therapy for androgen receptor-positive breast cancer. Volumes of interest (VOIs) were placed over the whole body and within source organs seen on the PET/CT images, and the time-integrated activity coefficients of [18F]FDHT were derived. The time-integrated activity coefficients for the urinary bladder were calculated using the dynamic urinary bladder model in OLINDA/EXM software, with biologic half-life for urinary excretion derived from VOI measurements of the whole body in postvoid PET/CT images. The time-integrated activity coefficients for all other organs were calculated from VOI measurements in the organs and the physical half-life of 18F. Organ dose and effective dose calculations were then performed using MIRDcalc, version 1.1. Results: At baseline before SARM therapy, the effective dose for [18F]FDHT in women was calculated as 0.020 ± 0.0005 mSv/MBq, and the urinary bladder was the organ at risk, with an average absorbed dose of 0.074 ± 0.011 mGy/MBq. Statistically significant decreases in liver SUV or uptake of [18F]FDHT were found at the 2 additional time points on SARM therapy (linear mixed model, P < 0.05). Likewise, absorbed dose to the liver also decreased by a small but statistically significant amount at the 2 additional time points (linear mixed model, P < 0.05). Neighboring abdominal organs of the gallbladder wall, stomach, pancreas, and adrenals also showed statistically significant decreases in absorbed dose (linear mixed model, P < 0.05). The urinary bladder wall remained the organ at risk at all time points. Absorbed dose to the urinary bladder wall did not show statistically significant changes from baseline at any of the time points (linear mixed model, P ≥ 0.05). Effective dose also did not show statistically significant changes from baseline (linear mixed model, P ≥ 0.05). Conclusion: Effective dose for [18F]FDHT in women before SARM therapy was calculated as 0.020 ± 0.0005 mSv/MBq. The urinary bladder wall was the organ at risk, with an absorbed dose of 0.074 ± 0.011 mGy/MBq.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Radiotherapy (RT) is beneficial for select patients with localized diffuse large B cell lymphoma (DLBCL), in both early stage and in relapsed/refractory settings. Genomic predictors of local response to RT have yet to be adequately explored. We sought to identify genomic signatures of radiosensitivity in localized DLBCL. Methods: We analyzed our database of DLBCL patients with localized measurable disease treated with RT between 2007 and 2022 with pre-existing targeted exome sequencing. This included both Ann Arbor stage I/II patients and those with isolated sites of relapsed/refractory disease in order to increase cohort size. The public NCI LymphGen algorithm was used to further classify genomic subgroups. Using Fisher’s exact test and logistic regression we tested for univariable correlation between specific gene alterations and LymphGen subgroups with initial radiation response, defined by Lugano criteria and decrease in maximum SUV. Results: We identified 38 patients with 52 irradiated tumors. The median (range) RT dose was 36 Gy (4–54), with 35 (67%) tumors receiving at least 30 Gy. 21 (40%) tumors were treated in the early stage setting (10% definitively, 90% as consolidation), while 31 (60%) were treated in the localized relapsed/refractory setting. 54% of tumors were GCB subtype, 31% were ABC subtype, and 15% were not classified. The median (range) of prior lines of systemic therapy were 1 (0–2) and 1 (1–7) in the early stage and localized relapsed/refractory settings respectively. The median (range) lesion SUV at the time of RT was 7.7 (1.1–46.0). 48% of tumors were in complete response (CR) at time of first imaging after RT (median 3.12 months) and the mean (SD) percent decrease in SUV was 60% (43%). The most commonly altered individual genes were KMT2D (37%), MYD88 (33%), and TP53 (31%). LymphGen classified 21% of cases as EZB subtype, 14% as MCD, 2% as BN2, 2% as ST2; 62% were unclassified. Alteration in ETV6 (13% of tumors) was associated with a significantly higher CR rate in response to RT (86% with alteration, 42% without, p = 0.046). After restricting each patient to their first course of RT, ETV6 alteration trended towards significantly higher CR (83% with alteration, 34% without, p = 0.06). Lesions with vs. without ETV6 alteration had similar SUV (p = 0.88) and size (p = 0.8) at time of RT. Alteration in ETV6 (p < 0.0001), PIM1 (p < 0.0001), MYD88 (p < 0.0001), and TNFAIP3 (p = 0.01) were associated with greater reductions in SUV. The LympGen MCD subgroup trended towards increased odds of CR post-RT (log odds 1.9, p = 0.078) and greater reduction of SUV (p = 0.12) compared to the EZB subgroup. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Genomics, Epigenomics, and Other -Omics, Radiation Therapy Conflicts of interests pertinent to the abstract. G. Salles Consultant or advisory role: AbbVie, Aptitude Health, Bayer, BeiGene, Ltd., Bio Ascend, Bristol-Myers Squibb, Celgene, Epizyme, Everest Clinical Research Corporation, GenMab, Genentech, Gilead Pharmaceutical, Incyte, Ipsen, Janssen Pharmaceuticals, Inc., Loxo Oncology, Miltenyi Biotec Incorporated, MorphoSys AG, Nordic Nanovector ASA, Novartis, Physicians' Education Resource, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Roche, Scientific Education Support Ltd., Takeda Millennium Stock ownership: Owkin, Inc.

68Ga-Pentixafor PET/MRI for Treatment Response Assessment in Mantle Cell Lymphoma: Comparison Between Changes in Lesion CXCR4 Expression on PET and Lesion Size and Diffusivity on MRI.

The aim of this study was to compare CXCR4 imaging with 68Ga-pentixafor PET to MRI for treatment response assessment in patients with mantle cell lymphoma (MCL). Twenty-two posttreatment 68Ga-pentixafor PET/MRI scans of 16 patients (7 women and 9 men; mean age, 69.9 ± 7.9) with a total of 67 target lesions on baseline PET/MRI were analyzed. Rates of complete remission per lesion and per scan, according to MRI (based on lesion size) and 68Ga-pentixafor PET (based on SUV decrease to lower than liver and blood pool uptake), were compared using McNemar tests. The t tests and Pearson correlation coefficients (r) were used to compare rates of change in lesion diameter products (DPs) on MRI, and standardized uptake values (SUVmax, SUVmean) on PET, relative to baseline. At interim PET/MRI, 18/32 (56.3%) target lesions met CR criteria on 68Ga-pentixafor PET, and 16/32 (50.0%) lesions met size-based MRI criteria for CR (P = 0.63). At end-of-treatment PET/MRI, 40/57 (70.2%) target lesions met 68Ga-pentixafor PET criteria for CR, and 27/57 (47.4%) lesions met size-based MRI criteria for CR (P = 0.021). Complete remission after treatment was observed more frequently on 68Ga-pentixafor PET (11/22 scans, 54.5%) than on MRI (6/22 scans, 27.3%) (P = 0.031). Rates of change did not differ significantly between lesion DP (-69.20% ± 34.62%) and SUVmax (-64.59% ± 50.78%, P = 0.22), or DP and SUVmean (-60.15 ± 64.58, P = 0.064). Correlations were strong between DP and SUVmax (r = 0.71, P < 0.001) and DP and SUVmean (r = 0.73, P < 0.001). In MCL patients, 68Ga-pentixafor PET may be superior for assessment of complete remission status than anatomic MRI using lesion size criteria, especially at the end of treatment.

Lesion Characteristics and Patterns of Failure in Diffuse Large B Cell Lymphoma Patients Treated with Bridging Radiotherapy Prior to Chimeric Antigen Receptor T Cell Therapy

Lesion Characteristics and Patterns of Failure in Diffuse Large B Cell Lymphoma Patients Treated with Bridging Radiotherapy Prior to Chimeric Antigen Receptor T Cell Therapy

Quantitate Image Responses in High Risk p16+ Oropharyngeal Cancer Patients Treated With Definitive ChemoRT and Concurrent Nivolumab Compared to ChemoRT Alone

Biomarkers of immunotherapy response are increasingly important in oropharyngeal cancer with the rapid expansion of treatment in the R/M population and many ongoing upfront trials. CPS score is the most commonly used method to quantify immune infiltration and predict response to immunotherapy, although limited by its static nature and sampling error. Previous studies show that pre-RT to mid-treatment changes in MRI-derived blood volume (BV) and apparent diffusion coefficient (ADC) as well as FDG-PET derived metabolic tumor volume (MTV) and total lesion glycolysis (TLG) serve as imaging markers for pattern failure of HNC treated by CRT. The goal of this study is to evaluate changes in image metrics during concurrent immunotherapy and CRT compared to those from CRT.MRI and FDG-PET scans were acquired pre- and mid-treatment (fx 10) from 75 patients with high risk p16+ OPSCC (AJCC stage 3 or "matted nodes") who were treated with definitive concurrent CRT on 2 prospective institutional trials. The patients included: 1) the first 15 patients treated with definitive CRT 70Gy/concurrent carboplatin/taxol and concurrent nivolumab (iCRT) and 2) 60 patients treated with 70-80Gy/concurrent weekly cisplatin/carboplatin (CRT). Changes in quantitative image metrics from pre- to mid-treatment of primary tumors and individual lymph nodes were evaluated: gross tumor volume (GTV), MTV at 50% max SUV, TLG, mean SUV, mean BV and ADC between the two treatment groups using unpaired t test.Clinical characteristics and baseline quantitative image metrics were similar between CRT and iCRT groups, except the iCRT group had a lower BV value of primary tumors and a greater MTV of nodal tumors than CRT group (P = 0.05). However, at mid-treatment, iCRT patients had: 1) significantly greater increases in mean BV and ADC of primary tumors than CRT patients (49% vs. 23% and 21% vs. 12%, P < 0.007 and 0.03, respectively); but 2) less decreases in MTV, TLG and mean SUV of primary tumors than CRT patients, for which 11% of the TLG decrease was significantly different from 43% decrease of CRT group (P < 0.05); and 3) 12% decrease in mean SUV of nodal tumors that was significantly less than 25% in CRT group (P < 0.0001). With a mean follow-up of 11 months in the iCRT group, there has been only 1 DM in a patient with persistent low BV in the primary tumor, consistent with our previous findings in CRT patients.This analysis suggests that high risk p16+ OPSCC patients treated with iCRT had larger increases in BV and ADC and a smaller decrease in TLG in primary tumors mid-treatment compared to CRT group. Increases in BV and ADC have been identified to be associated with improved tumor control by previous studies of CRT. The minimal reduction of FDG metrics of iCRT group may be due to inflammatory response to anti-PD1. These findings warrant further investigation as predictive biomarkers for iCRT response to treatment.

Relationship between PET response and pathologic response in distal esophageal/gastroesophageal junction (DE/GEJ) cancers.

452 Background: The utility of PET scans (PETs) to predict outcomes after neoadjuvant treatment of DE/GEJ cancers is unclear. We aimed to explore the relationship between PET response and pathologic/clinical outcomes in a real-world setting. Methods: Patients (pts) with DE/GEJ cancer treated with curative intent perioperative chemotherapy or neoadjuvant chemoradiation followed by surgery in British Columbia from 2009-2018 were included. Retrospective chart review was conducted; pts were stratified into PET responder (R, ≥ 35% decrease in max SUV) and non-responder (NR, &lt; 35%) groups. Chi-square and Kaplan Meier were used to test for associations between variables and outcomes. Results: Of 576 pts identified, 52% had pre- and post-induction PETs; 232 pts proceeded to surgery and were included for analysis. Treatment regimens comprised of CROSS (72%), MAGIC (24%) and FLOT (4%). Median age was 66 (IQR 57-72), 85% male, 91% ECOG 0/1, 62% GEJ involvement, and 81% adenocarcinoma histology. Characteristics and treatment regimens were balanced between the PET-R and PET-NR groups (all p&gt;0.05). Median time from end of treatment to PET was 30 days (IQR 22-36); 67% were PET-R. Pathologic complete response (PCR) rates were similar for PET-R vs. PET-NR (14% vs. 13%, p=0.08). The discordance rate between PET vs. pathologic response was 34% (Table). Aborted surgery rate was higher in the PET-NR group (8% vs. 3%, p=0.03); 70% of aborted cases were due to peritoneal involvement. Median overall survival was similar between the two groups (PET-R 31.5 mo vs. PET-NR 36.1 mo, p=0.62). Conclusions: In our population-based cohort, PET response did not demonstrate prognostic utility and was associated with a significant pathology discordance rate. The role of PET/CT is evolving and the use of post-induction imaging for response assessment and prognostic value may be questionable. [Table: see text]

Inflammation-Based Index and 68Ga-DOTATOC PET-Derived Uptake and Volumetric Parameters Predict Outcome in Neuroendocrine Tumor Patients Treated with 90Y-DOTATOC.

We performed post hoc analyses on the utility of pretherapeutic and early interim 68Ga-DOTATOC PET tumor uptake and volumetric parameters and a recently proposed biomarker, the inflammation-based index (IBI), for peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumor (NET) patients treated with 90Y-DOTATOC in the setting of a prospective phase II trial. Methods: Forty-three NET patients received up to 4 cycles of 90Y-DOTATOC at 1.85 GBq/m2/cycle with a maximal kidney biologic effective dose of 37 Gy. All patients underwent 68Ga-DOTATOC PET/CT at baseline and 7 wk after the first PRRT cycle. 68Ga-DOTATOC-avid tumor lesions were semiautomatically delineated using a customized SUV threshold-based approach. PRRT response was assessed on CT using RECIST 1.1. Results: Median progression-free survival and overall survival (OS) were 13.9 and 22.3 mo, respectively. An SUVmean higher than 13.7 (75th percentile) was associated with better survival (hazard ratio [HR], 0.45; P = 0.024), whereas a 68Ga-DOTATOC-avid tumor volume higher than 578 cm3 (75th percentile) was associated with worse OS (HR, 2.18; P = 0.037). Elevated baseline IBI was associated with worse OS (HR, 3.90; P = 0.001). Multivariate analysis corroborated independent associations between OS and SUVmean (P = 0.016) and IBI (P = 0.015). No significant correlations with progression-free survival were found. A composite score based on SUVmean and IBI allowed us to further stratify patients into 3 categories with significantly different survival. On early interim PET, a decrease in SUVmean of more than 17% (75th percentile) was associated with worse survival (HR, 2.29; P = 0.024). Conclusion: Normal baseline IBI and high 68Ga-DOTATOC tumor uptake predict better outcome in NET patients treated with 90Y-DOTATOC. This method can be used for treatment personalization. Interim 68Ga-DOTATOC PET does not provide information for treatment personalization.

280P - Defining a SUV decrease cut-off in PET/CT response monitoring after one cycle of preoperative breast cancer chemotherapy

BackgroundA decrease in tumor metabolic activity have been shown to be an early indicator of treatment effectiveness for breast cancer. MethodsWe reviewed the records of patients enrolled to the prospective study of prediction of preoperative chemotherapy response (MILESTONE-BreastPred). In the whole group PET/CT was used as an initial method of staging and as response assessment after 1st cycle of chemotherapy. We analysed data of 425 patients, 19.8% TNBC, 12.2% nonluminal HER2-positive and 68% luminal cancers. 88% of patients were stage II or III. pCR rate was 24.8% (ypT0/is ypN0). 31.1% of patients showed progressive disease during follow-up. The aim of the study was to assess the clinical utility of various cut-offs of SUVmax decrease to predict both pCR and disease relapse. ResultsWe analysed SUVmax decrease cut-off of 20%, 30%, 40%, 50 and 60%. For pCR prediction, the sensititivity was above 50% for cut-offs 20%-40%, while specificity exceeded 50% for cut-off values 40-60%. In the whole range of cut-offs, there was highly statistically significant difference in pCR rate between low and high SUVmax decrease (p<0.001). Cut-off of 40% was chosen, providing optimal trade-off between sensitivity and specificity with positive likelihood ratio 1.89, negative likelihood ratio 0.49, PPV 38.4% and PPV 86.0%. Prediction of disease relapse based on 1st cycle SUVmax decrease was more challenging, with sensitivity above 50% for cut-offs 20-30% and specificity above 50% for cut-offs 40-60%. For cut-off 40% the difference in disease relapse between groups was closest to the limit of statistical significance (p=0.085) and provided PLR 0.81, NLR 1.17, PPV 26.6% and NPV 65.6%. ConclusionsPrediction of pCR by 1st cycle SUVmax decrease was feasible, with good balance of specificity and sensitivity for cut-off 40%. This cut-off provides the most prominent, although not significant in this analysis, association with the risk of disease relapse. The study was supported by the Polish National Center of Research and Development MILESTONE project–Molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant no.STRATEGMED2/267398/4/NCBR/2015. Legal entity responsible for the studyThe authors. FundingThe study was supported by the Polish National Center of Research and Development MILESTONE project – Molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant no. STRATEGMED 2/267398/4/NCBR/2015. DisclosureAll authors have declared no conflicts of interest.

Impact of PET/CT for Restaging Patients With Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiation

BackgroundA major challenge in identifying candidates for nonoperative management of locally advanced rectal cancer is predicting pathologic complete response (pCR) following chemoradiation. We evaluated pre- and post-CRT PET-CT imaging to predict pCR and prognosis in this set of patients undergoing resection after neoadjuvant therapy. MethodsWe retrospectively identified patients from 2002 to 2015 with locally advanced rectal cancer who underwent CRT, pre- and post-CRT PET-CT imaging, and resection. Univariate and multivariate analysis was performed and receiver operating characteristic (ROC) curves were generated to evaluate the association of PET-CT characteristics with pCR and survival. ROC curves were generated to define optimal cutoff points for predictive PET-CT characteristics. Results125 patients were included. pCR rate was 28%, and follow-up was 48 mo. On multivariable analysis, patients who had a pCR had lower median post-CRT maximal standardized uptake value (SUVmax) (3.2 versus 5.2, P = 0.009) and higher median %SUV decrease (72 versus 58%, P = 0.009). ROC curves were generated for %SUVmax decrease (AUC = 0.70) and post-CRT SUV (AUC = 0.69). Post-CRT SUVmax <4.3 and %SUVmax decrease of >66% were equally predictive of pCR with a sensitivity of 65%, specificity of 72%, PPV of 44%, and NPV of 86%. Median 5-y overall and relapse-free survival were improved for patients with post-CRT SUV <4.3 (OS: 86 versus 66%, P = 0.01; RFS: 75 versus 52%, P = 0.01) or %SUV decrease of >66% (OS, 82 versus 66%, P = 0.05; RFS, 75 versus 54%, P = 0.01). ConclusionsPET/CT may be useful in identifying patients who did not achieve pCR, as well as overall survival in patients undergoing CRT for rectal cancer. Patients with a post-CRT SUV of >4.3 should be considered for operative management, as an estimated 86% of these patients will not have a pCR.

Relationship between PET response and pathologic response in distal esophageal/gastroesophageal junction cancers: A provincial population-based analysis.

e15506 Background: The utility of PET scans (PETs) to predict outcomes after neoadjuvant treatment of DE/GEJ cancers is unclear. We aimed to explore the relationship between PET response and pathologic/clinical outcomes in a real-world setting. Methods: Patients (pts) with DE/GEJ cancer treated with curative intent perioperative chemotherapy or neoadjuvant chemoradiation followed by surgery in British Columbia from 2009-2018 were included. Retrospective chart review was conducted; pts were stratified into PET responders (R, ≥ 35% decrease in max SUV) or PET non-responders (NR, &lt; 35%) groups. Chi-square and Kaplan Meier were used to test for associations between variables and outcomes. Results: Of 576 pts with locally advanced DE/GEJ cancers, 232 pts were eligible for analysis. Treatment regimens comprised of CROSS (72%), MAGIC (24%) and FLOT (4%). Median age was 66 (IQR 57-72), 85% male, 91% ECOG 0/1, 62% GEJ involvement, and 81% adenocarcinoma histology. Characteristics and treatment regimens were balanced between the PET-R and PET-NR groups (all p&gt;0.05). Median time from end of treatment to PETs was 30 days (IQR 22-36); 67% were PET-R. Pathologic complete response rates (14% vs 13%, p=0.079) were similar for PET-R vs PET-NR, respectively. Discordance rate was 34% between PET vs pathologic response (Table). Aborted surgery rate was higher in the PET-NR group (8% vs 3%, p=0.03); 70% of aborted cases were due to peritoneal involvement. Median overall survival was similar between the groups (PET-R 31.5 mo vs PET-NR 36.1 mo, p=0.616). Conclusions: In our population-based cohort, PET response did not demonstrate prognostic utility. PET-NR were more likely to have their surgeries aborted. The predictive ability of PET in determining surgical resectability should be further investigated to avoid unnecessary high morbidity surgeries.[Table: see text]

A randomized phase 0 trial of the mitochondrial inhibitor ME344 or placebo added to the antiangiogenic (Aa) bevacizumab in early HER2-negative breast cancer (E-HERNEBC).

3100 Background: We have shown that when Aas induce vascular normalization (VN), tumors escape upregulating mitochondrial metabolism. Mitochondrial inhibition with ME344 induced synergy with various Aas. We also found that VN could be traced by showing a 10% decrease in tumor FDG-PET SUV from day (d) 0 to d8 of Aa. We studied the activity of adding ME344 or placebo to Bev (Ki67 decrease) in E-HERNEBC in a phase 0 randomized trial. As a secondary objective we measured the activity of the combination in patients (Pts) showing VN according to FDG-PET. Methods: Untreated E-HERNEBC Pts with T &gt; 1cm, any N, M0 underwent a baseline FDG-PET (d1) and received a single dose of Bev (15mg/kg) prior to randomization (1:1) to arm A (FDG-PET on d8 followed by ME344 10 mg/kg IV on d8, d15 and d21) or Arm B (FDG-PET on d8 followed by placebo on d8, d15 and d21). Tumors were biopsied on d0 and 28. A 40 Pts sample size was powered to detect a 30% relative difference between arms in digitally acquired Ki67 decrease from d0 to d28 (alpha 0.05, beta 0.2). Results: Arm A: 20 Pts; Arm B: 21 Pts. Baseline characteristics were in arm A vs B: age 58.4(41.5-75.3) vs 53.6(39-82.8); T1(30%)/T2(60%)/T3(10%) vs T1(52%)/T2(48%)/T3(0%); N0(80%)/N1(20%) vs N0(81%)/N1(19%); ER+(75%)/TNBC(25%) vs ER+(71.4%)/TNBC(28.6%); Ki67 31.6% (3.6%-70%) vs 25.2% (1.2% - 81.5%). PET-SUV decreased &gt; 10% from d0 to d8 in 6/20 (arm A) and 6/21 (arm B) Pts. Two G3 adverse events (blood pressure) were reported (1/arm) and deemed related to Bev. Results of the primary endpoint: table. Conclusions: ME344 showed significant biologic activity, enhancing the effect in Ki67 decrease vs placebo when added to Bev in E-HERNEBC. The activity was greater in TNBC. A trend for greater activity in patients experiencing VN according to FDG-PET was observed. Clinical trial information: NCT02806817. [Table: see text]

Lymphoid Interstitial Pneumonia in Common Variable Immune Deficiency - Case Report With Disease Monitoring in Various Therapeutic Options: Pleiotropic Effects of Rituximab Regimens.

Lymphoid interstitial pneumonia (LIP) is a rare lymphoproliferative disease. LIP in common variable immunodeficiency (CVID) was observed in a patient during immunomodulatory therapy after progression of the disease (i.e., glucocorticoids, immunoglobulin dose escalation, and finally rituximab). Due to humoral immunodeficiency and serious serum sickness rituximab was used initially at a low dose (150 mg/m2 weekly). It resulted in temporary remission with the decrease of serum paraproteinemia, β2-microglobulin (β2M) and SUV decrease as well as increase of FVC. Owing to the relapse after 6-month remission in the second cycle a standard dose of rituximab was used (375 mg/m2). Therapeutic regimen with 375 mg/m2 of Rtx in optimal schedule (i.e., every 3 weeks) resulted in no longer remission but higher incidence of opportunistic infections. Finally, after another cycle of immunotherapy FVC, paraproteinemia and β2M level normalization were observed as well as the decrease of severe splenomegaly. In laboratory and immunological progress the increase of NK and NKT cells was observed after the initial dose but the standard one caused NK cell increase only. Unfortunately, the decrease of CD19+Bcells was comparable between both doses, as was the decline of FoxP3+ regulatory T cell. On the contrary, after the low dose absolute T cell (both CD4 and CD8) number decreased but after the standard one – it normalized. Rtx (especially in low dose) brought further increase of persistent T cell activation (CD38+ T cells made up 79%). Innate immune response and the decrease of Treg are a compensatory pathways for the decrease of B and T cells. Immunodeficiency requires a different investigative approach to a immunotherapy.Clinical Trial Registration: ClinicalTrials.gov, NCT02789397.

Optimal time-point for 68Ga-PSMA-11 PET/CT imaging in assessment of prostate cancer: feasibility of sterile cold-kit tracer preparation?

In this prospective study, we evaluated the optimal time-point for 68Ga-PSMA-11 PET/CT acquisition in the assessment of prostate cancer. We also examined, for the first time the feasibility of tracer production using a PSMA-11 sterile cold-kit in the clinical workflow of PET/CT centres. Fifty prostate cancer patients (25 staging, 25 biochemical recurrence) were enrolled in this study. All patients received an intravenous dose of 2.0MBq/kg body weight 68Ga-PSMA-11 prepared using a sterile cold kit (ANMI SA, Liege, Belgium), followed by an early (20min after injection) semi-whole-body PET/CT scan and a standard-delay (100min after injection) abdominopelvic PET/CT scan. The detection rates with 68Ga-PSMA-11 were compared between the two acquisitions. The pattern of physiological background activity and tumour to background ratio were also analysed. The total preparation time was reduced to 5min using the PSMA-11 sterile cold kit, which improved the final radionuclide activity by about 30% per single 68Ge/68Ga generator elution. Overall, 158 pathological lesions were analysed in 45 patients (90%) suggestive of malignancy on both (early and standard-delay) 68Ga-PSMA PET/CT images. There was a significant (p < 0.001) increase in SUVmax on delayed images in suspicious prostates (11.6 ± 8.2 to 14.8 ± 1.0) and lymph nodes (LNs; 9.7 ± 5.9 to 12.3 ± 8.8), while bone lesions showed no significant increase (8.5 ± 5.6 to 9.2 ± 7.0, p = 0.188). However, the SUVmax of suspicious lesions on early images was adequate to support the criteria for correct interpretation (mean SUVmax 9.83 ± 6.7).In 26 of 157 lesions, but a decrease in SUV was seen, mostly in subcentimetre lesions in patients with multiple metastases. However, it did not affect the staging of the disease or patient management. The tumour to background ratio of primary prostate lesions and LNs showed a significant (p < 0.001) increase from the early to the standard-delay acquisition, but no significant increase was seen in bony lesions (p = 0.11). The PSMA-11 sterile cold kit seems to be feasible for use in routine clinical practice, and it has a shorter radionuclide preparation time and is less operator-dependent than the synthesizer-based production method. In addition, early 68Ga-PSMA-11 PET/CT imaging seems to provide a detection rate comparable with that of standard-delay imaging. Furthermore, the shorter preparation time using the 68Ga-PSMA-11 sterile cold kit and promising value of early PET/CT scanning could allow tailoring of imaging protocols which may reduce the costs and improve the time efficiency in PET/CT centres.

Limitations of dual time point FDG-PET imaging in the evaluation of focal abdominal lesions.

For the evaluation of the diagnostic potential of dual time point FDG positron emission tomography (PET) in patients with suspicious focal abdominal uptake, dual time point PET imaging was compared with clinical findings. In a prospective study, 56 patients exhibiting a solitary suspicious, intense abdominal FDG uptake, underwent dual time point PET imaging for staging or restaging of different malignant tumors, maximal standardized uptake value (SUVmax) measurements included. The first acquisition was started 64.8 +/- 19.5, the second 211.3 +/- 52.5 min after FDG injection. The final diagnosis based on CT or MRT imaging and a follow-up period of 12.6 +/- 2.8 months. Additionally, colonoscopy was done in 6 patients. In another 6 patients histopathology was obtained from CT guided biopsy. Malignant focal abdominal lesions with a SUVmax <2.5 (n = 4) showed an uptake increase of > or =30%. In the remaining malignant cases with an uptake of > or =2.5 (n = 11), uptake increased in 64% and decreased in 36%. Malignant lesions showing FDG uptake decrease (n = 4) had an initial SUVmax value > or =2.5 and remained with a SUVmax > or =2.5 in the second imaging. In benign lesions with an initial SUVmax > or =2.5 (n = 31), the uptake increased in 17 patients (55%) and decreased in 14 patients (45%). All lesions which changed configuration (33%) were confirmed as benign (n = 5). Using dual time point PET abdominal lesions show a very hetergenous uptake pattern regardless of their dignity. Malignancy can only be reliably excluded in lesions which change their configuration and in lesions with an initial SUVmax value <2.5 combined with an SUV decrease in the delayed imaging. Particularly abdominal lesions which show an initial SUVmax > or =2.5 combined with a SUV increase in the delayed imaging are suspicious for malignancy and need further clarification.

Giant cell tumour of the distal radius/ulna: response to pre-operative treatment with short-term denosumab

BackgroundTreatment of giant cell tumour of bone (GCTB) of the distal radius/ulna poses a surgical challenge, as complex reconstructive surgery may be required. This study evaluates the clinical, radiological and pathological findings in five cases of GCTB of the distal forearm where a 3 month course of denosumab was given prior to surgery.MethodsPatients with biopsy proven distal forearm GCTB, treated for 3 months with denosumab, followed by salvage surgery (curettage and cementation) were included. Wrist pain and function were assessed using the modified Mayo Wrist Score (MMWS). Plain radiographs, MRI and PET/CT were performed pre-treatment and 2 months after initiation of denosumab therapy. Histological comparison was made between the original biopsy and surgical curettage specimens.ResultsFive patients with an average age of 25 years were included in the study. Improvement in wrist pain and function was seen in all patients with the average MMWS increasing from 30 pre-treatment to 85 at 3 months. Plain radiographs demonstrated marginal sclerosis in all cases with reconstitution of cortical and subarticular bone by 2 months; internal matrix sclerosis and osseous consolidation was more variable. Increased tumour heterogeneity and low signal were observed on T2-weighted MR images. PET/CT revealed a decrease in average SUV from 14.8 pre-treatment to 4.7 at 2 months. Histology showed disappearance of osteoclasts and increased fibro-osseous tissue. Denosumab treatment has the potential to facilitate salvage surgery, thus avoiding bone resection and graft reconstruction. A good outcome was achieved apart from local recurrence in one case. Follow up ranged from 17 to 54 months.ConclusionDistal forearm GCTB responds clinically, radiologically and histologically to a short course of pre-operative denosumab therapy, which has the potential to facilitate salvage surgery.

Pharmacodynamic phase I study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel.

e14088 Background: Increased tumor proliferation has been observed during withdrawal of anti-angiogenic therapy, known as withdrawal flare, which has been demonstrated using [18-F] fluorothymidine [FLT] PET/CT . Sequencing chemotherapy may increase therapeutic window by better synchronizing treatment with tumor proliferation during the flare. This study utilizes FLT PET/CT to assess X-82, a novel VEGFR TKI, used in sequence with docetaxel. Methods: Pts with at least 1 lesion evaluable with FLT PET/CT underwent 21-day treatment cycles with X-82 daily on days 2-15. Starting in cycle 2 (C2), docetaxel was given on day 1 of each cycle. FLT PET/CTs were obtained on days 1 and 15 in cycles 1 and 2. Tumors were identified by a nuclear medicine physician and manually segmented. The maximum tumor FLT uptake SUVmax and the total tumor FLT uptake SUVtotal were extracted for each tumor. To quantify changes in tumor FLT uptake, SUVs were log transformed and included in mixed effects models with random effects accounting for intrapatient correlation of tumor responses. Results: 14 pts were treated with median 3.5 cycles (range 0-12). 4 pts with 13 metastatic tumors completed all PET scans and were included in the pharmacodynamic assessment. 1 pt had an unconfirmed PR and 7 pts had stable disease per RECIST 1.1. The mean percent (%) change in tumor SUV during C1 (X-82 monotherapy) was -13% for SUVmax (P = 0.04) and -17% for SUVtotal (P = 0.14). The mean % change in tumor SUV during C2 (X-82 + docetaxel) was -44% for SUVmax (P = 0.03) and -59% for SUVtotal (P &lt; 0.01). There was a significantly greater decrease in SUV in C2 than in C1 for both SUVmax (P = 0.03) and SUVtotal(P = 0.02). Ten grade 3 AEs possibly related to X-82 were noted in 6 pts, including infections, cytopenias, and vascular complications. Conclusions: Diminished tumor proliferation was observed during X-82 treatment, indicating successful targeting of VEGFRs. Sequential combination of X-82 plus docetaxel showed greater decreases in tumor proliferation compared to X-82 monotherapy indicating value in sequencing chemotherapy during VEGFR TKI treatment breaks. There is evidence that combination therapy is both safe and effective. Clinical trial information: NCT 02146222.