Post-treatment Positron Emission Tomography Research Articles

CtDNA as an Adjunct to Posttreatment PET for Head and Neck Cancer Recurrence Risk Assessment.

Circulating tumor DNA (ctDNA) detection is an emerging technique that identifies minimal residual disease in patients with solid tumors. ctDNA can act as an adjunct method to help overcome the limitations of positron emission tomography (PET) and select patients who are at high risk for recurrence. Retrospective Single Institutional Study. University Hospital Setting. Twenty-nine patients who underwent definitive treatment for squamous cell carcinoma of the head and neck (HNSCC) from 8/2021 to 01/2023 had ctDNA levels analyzed at 1 to 3, 6, 9, and 12 months after definitive treatment. A personalized, tumor-informed, multiplex polymerase chain reaction (PCR) next-generation sequencing (NGS) assay was used to detect the ctDNA levels. The primary outcome was recurrence-free probability (RFP), and the secondary outcomes were overall survival (OS), sensitivity, specificity, and the test's negative (NPV) and positive predictive values (PPV). The median age of patients was 65 years (interquartile range: 56-69), with majority being males (n = 22, 76%). The primary sites were larynx (n = 12), oropharynx (n = 10), and oral cavity (n = 6). Posttreatment ctDNA was detected in 7 patients, all of whom had disease recurrence. ctDNA detection after definitive treatment was associated with a higher risk of disease recurrence (hazard ratio: 9.94, 95% confidence interval: 1.56-63.3, P = .015). ctDNA identified recurrence with 100% specificity and 78% sensitivity. The NPV and PPV were 91% and 100%. PET had 78% sensitivity but only 68% specificity with 86% NPV, and 54% PPV. Based on our data, ctDNA can be an excellent adjunct test for posttreatment PET and can help guide physicians in cases where PET results are inconclusive and difficult to interpret.

Prospective comparison of positron emission tomography (PET)/magnetic resonance and PET/computed tomography dosimetry in hepatic malignant neoplastic disease after 90Y radioembolization treatment.

90Y radioembolization is an established treatment modality for hepatic malignancies. Successful radioembolization requires optimal dose delivery to tumors while minimizing dosages to parenchyma. Post-treatment positron emission tomography (PET)/computed tomography (CT) dosimetry is the established benchmark, whereas PET/magnetic resonance (MR) is an emerging modality. The goal of this study was to assess the intermodality agreement between PET/MR and PET/CT 90Y dosimetry. In this single-institution study, 18 patients (20 treatment sessions) with a primary or metastatic hepatic malignancy underwent both PET/MR and PET/CT after 90Y radioembolization. Patients were randomized to undergo one modality first, followed by the other. The region of interest was delineated using MR images and tumor and liver dosimetry was calculated. Intermodality agreement was assessed using the Bland-Altman method. A generalized linear model was used to assess the effect of baseline variables on intermodality dose differences. PET/MR underestimated tumor and liver absorbed doses when compared to PET/CT by -3.7% (P=0.042) and -5.8% (P=0.029), respectively. A coverage probability plot demonstrated that 80% and 90% of tumor dose measurements fell within intermodality differences of 11% and 18%, respectively. PET/MR underestimated tumor dose at both low (<1 GBq) and high (>3 GBq) injected activity levels (P<0.001) by -22.3 [standard deviation (SD) =13.5] and -24.3 (SD =18.7), respectively. Although PET/MR significantly underestimated the absorbed dose when compared to PET/CT, the intermodality agreement was high and the degree of underestimation was better than previously reported. Intermodality differences were more pronounced at low and high injected doses. Additional studies are required to assess the clinical implications of these findings.

An Optimized Methodology for Patient-Specific Therapeutic Activity Administration in Liver Radioembolization

Radioembolization (RE) with glass microspheres (MS) loaded with Yttrium-90 (90Y) has been used to treat tumors in the liver with some reported success. However, assessing absorbed doses (AD) in the planning tumor volume (PTV) and normal liver volume (NLV) is a key problem to address in RE. In clinical practice, the computation of 90Y activity to be administered follows the manufacturer’s recommendations, which do not consider the specific characteristics of MS deposition in each patient’s liver. Our main aim is to develop a methodology to estimate the optimal activity for each patient treatment. It uses the absorbed dose distribution (ADD) derived from the Technetium-99m (99mTc)-labeled macroaggregated albumin (MAA) obtained from pre-treatment planning single-photon emission computed tomography (SPECT) images. Post-treatment positron emission tomography (PET) images of the 90Y-MS distribution were used to estimate the ADD for treatment verification. Sixteen RE treatments were retrospectively selected. The agreement between the estimated mean AD based on the planning imaging and real post-treatment mean AD was good in PTV with an intraclass correlation coefficient (ICC) of 0.79 and excellent in NLV (ICC = 0.97). The optimization of 90Y activity using pre-defined clinical AD thresholds (&lt;70 Gy in NLV and &gt;80 Gy in PTV) imposed on the PTV and NLV voxels showed remarkably high agreement (ICC = 0.96, p &lt; 0.001) in eleven out of the sixteen RE treatments between SPECT-MAA-based and PET-MS-based optimal activity estimates. In conclusion, under well-controlled conditions, pre-treatment SPECT-MAA imaging predicts well the treatment of ADD. In addition, SPECT-MAA imaging can be used to optimize the 90Y-MS activity to be administered to the liver.

Lymphopenia and outcomes of bendamustine-based therapy in follicular lymphoma.

e19540 Background: Bendamustine plus rituximab (BR) is the preferred first-line immunochemotherapy for follicular lymphoma (FL) due to its efficacy and generally favorable adverse effect profile. However, it often causes prolonged lymphopenia, and impaired lymphocyte recovery after BR therapy has been recognized as a risk factor for opportunistic infections. On the other hand, little is known about the impact of profound lymphopenia on the overall treatment outcomes of BR. We examined the relationship between lymphopenia and treatment response in patients with FL who received BR at our institution. Methods: We retrospectively identified patients who received BR as first-line therapy for FL at the Lifespan Cancer Institute between October 2008 and November 2020. We used log-transformed absolute lymphocyte count (ALC) as the potential prognostic variable, integrated as the area under curve based on all available laboratory tests over the typical duration of BR (6 months). Outcomes included complete response to BR determined by post-treatment positron emission tomography or computed tomography, survival, and occurrence of hospitalization or herpes zoster on therapy. The association between ALC and survival or binary endpoints was examined using Cox or logistic models, respectively, adjusting for age, sex, cumulative bendamustine dose, and baseline ECOG performance status (PS). Results: We included 53 patients followed for a median of 69 months from start of BR. At treatment initiation, most patients had a PS of 0-1, stage III or IV disease, and high-risk lymphoma as defined by the Follicular Lymphoma International Prognostic Index (FLIPI) (Table). We observed an association between higher ALC during treatment and increased rates of CR (adjusted odds ratio, 2.50, 95% CI 1.04 – 6.00; p = 0.040), longer progression free survival (PFS) (adjusted hazard ratio [HR], 0.53, 95% CI 0.31 – 0.92, p = 0.023), and overall survival (OS) (HR, 0.45, 95% CI 0.23 – 0.87, p = 0.018). Higher ALC values during treatment and 1 month after treatment initiation were also associated with lower probability of hospitalization (p = 0.048 and p = 0.028, respectively). We did not find a statistically significant association between ALC and rates of zoster infection, but the number of observed events was low (n = 6). Conclusions: Our results suggest an association between higher ALC values during bendamustine therapy and improved treatment outcomes. Improvement in PFS, OS, and hospitalization rates with higher ALC values may be due relative preservation of nutritional balance and immune reserve. The association with survival should be confirmed in larger datasets and its potential mechanism elucidated.[Table: see text]

The Predictive Value of Post-Treatment PET-CT Imaging for Patients With Curable Anal Canal Cancer

<h3>Purpose/Objective(s)</h3> According to 2020 "NCCN" guidelines, post-treatment positron emission tomography (PET) – computed tomography (CT) imaging of the body is <b>not</b> recommended to predict outcomes of patients undergoing curative intent chemoradiation therapy (CRT) for anal canal cancer. This study used PERCIST (Positron Emission tomography Response Criteria In Solid Tumors) to evaluate CRT response and outcomes for our patient population at a single institution. <h3>Materials/Methods</h3> Our "IRB"-approved anal canal database was queried for patients who have undergone CRT, modified "NIGRO" protocol, for carcinoma of the anal canal. The evaluable patient dataset comprised those with both pre- and post-CRT PET-CT imaging of the body. The primary study endpoint was relapse-free survival (RFS) calculated from date of diagnosis to date of first known appearance of disease or death from any cause. Overall survival (OS) was defined using elapsed time between date of diagnosis and date of death and surviving patients were censored using date of last follow-up. Also, the range and median time to first post-CRT PET-CT imaging was determined. RFS and OS were analyzed using Kaplan-Meier method. Complete response rate (CRR) and objective response rate (ORR) were calculated along with 95% confidence intervals using Fisher's exact method. All tests were two-sided, and statistical significance was considered when <i>P</i> < 0.05. <h3>Results</h3> Out of an initial 392 patients in our database registry, 62 had pre/post-CRT PET-CT imaging from June 2008 until May 2020. There were 18 males and 44 females. The median age at diagnosis was 57.7 years (range: 38-84 years). "AJCC" (7^th edition) staging distribution was as follows: 3 Stage I, 13 Stage II, 41 Stage III, and 5 Stage IV. The median total dose of external beam irradiation was 54 Gy (range: 45-60 Gy). Time to post-CRT PET-CT imaging ranged from 0.2 to 27.8 months (mos) [median: 2.9 mos]. Respective PET-response rates regarding primary tumor (N = 62); largest groin node (N = 33); and largest pelvic node (N = 39) were as follows: 31 CR (Complete Response), 26 PR (Partial Response), 5 SD (Stable Disease), and 0 DP (Disease Progression); 30 CR, 3 PR, 0 SD, 0 DP; and 36 CR, 1 PR, 2 SD, 0 DP. Patient follow-up ranged from 6.8 to 114 mos (median: 38.6 mos). At time of last follow-up, there were 53 alive and 9 dead. Estimated 3-year RFS was 72% (95% "CI": 58.2-81.9%). Estimated 3-year OS was 88.8% (95% CI: 76.6-94.9%). Respective CRRs and ORRs for the primary tumor were 50% (95% CI = 37-63%) and 91.9% (95% CI = 82.2-97.3%); for the groin node 48.4% (95% CI = 35.5-61.4%) and 53.2% (95% CI = 40.1-66%); and for the pelvic node 58.1% (95% CI = 44.8-70.5%) and 59.7% (95% CI = 46.4-71.9%). CRRs and ORRs were not significant prognostic factors for either RFS or OS. <h3>Conclusion</h3> After applying PERCIST to our institutional study cohort, the use of post-treatment PET-CT imaging to predict outcomes for this patient population remains unproven.

[18F](2S,4R)-4-Fluoroglutamine as a New Positron Emission Tomography Tracer in Myeloma.

The high glycolytic activity of multiple myeloma (MM) cells is the rationale for use of Positron Emission Tomography (PET) with 18F-fluorodeoxyglucose ([18F]FDG) to detect both bone marrow (BM) and extramedullary disease. However, new tracers are actively searched because [18F]FDG-PET has some limitations and there is a portion of MM patients who are negative. Glutamine (Gln) addiction has been recently described as a typical metabolic feature of MM cells. Yet, the possible exploitation of Gln as a PET tracer in MM has never been assessed so far and is investigated in this study in preclinical models. Firstly, we have synthesized enantiopure (2S,4R)-4-fluoroglutamine (4-FGln) and validated it as a Gln transport analogue in human MM cell lines, comparing its uptake with that of 3H-labelled Gln. We then radiosynthesized [18F]4-FGln, tested its uptake in two different in vivo murine MM models, and checked the effect of Bortezomib, a proteasome inhibitor currently used in the treatment of MM. Both [18F]4-FGln and [18F]FDG clearly identified the spleen as site of MM cell colonization in C57BL/6 mice, challenged with syngeneic Vk12598 cells and assessed by PET. NOD.SCID mice, subcutaneously injected with human MM JJN3 cells, showed high values of both [18F]4-FGln and [18F]FDG uptake. Bortezomib significantly reduced the uptake of both radiopharmaceuticals in comparison with vehicle at post treatment PET. However, a reduction of glutaminolytic, but not of glycolytic, tumor volume was evident in mice showing the highest response to Bortezomib. Our data indicate that [18F](2S,4R)-4-FGln is a new PET tracer in preclinical MM models, yielding a rationale to design studies in MM patients.

P-016: The role [18F]-(2S,4R)-4-Fluoroglutamine as a new positron emission tomography tracer in Myeloma in vivo models.

<h3>Background</h3> The high glycolytic activity of multiple myeloma (MM) cells is the rationale for use of Positron Emission Tomography (PET) with 18F-fluorodeoxyglucose ([18F]FDG) to detect both bone marrow (BM) and extramedullary disease. However, FDG-PET has some limitations, since there is a portion of MM patients who are negative, and new tracers are actively searched. Glutamine (Gln) addiction has been recently described as a peculiar metabolic feature of MM cells. Yet, the possible exploitation of Gln as a PET tracer in MM has never been assessed thus far and is investigated in this study. <h3>Methods</h3> We have firstly synthesized enantiopure (2S,4R)-4-fluoroglutamine (4-FGln) and validated it as a Gln transport analogue in human MM cell lines, comparing its uptake with that of 3H-labelled Gln. We then radiosynthesized of [18F]4-FGln and tested its uptake for MM detection by PET in two different murine models and we checked the effect of Bortezomib treatment. <h3>Results</h3> Both [18F]4-FGln and [18F]FDG clearly identified the spleen as site of MM cell colonization in C57BL/6 mice challenged with syngeneic Vk12598 cells and assessed by PET. NOD.SCID mice subcutaneously injected with human MM JJN3 cells, showed high values of both [18F]4-FGln and [18F]FDG uptake to T/M: 2.3 ± 0.3 and 7.1 ± 2.6, respectively. With both [18F]4-FGln and [18F]FDG radiotracers, BOR treated animals displayed Standard Uptake Values (SUV) mean values significantly lower than controls at post treatment PET. However, [18F]4-FGln better correlated with the tumour volume in NOD.SCID mice, and a reduction of glutaminolytic, but not of glycolytic, tumour volume was evident in mice showing the highest response to Bortezomib. <h3>Conclusion</h3> Our data indicate that [18F](2S,4R)-4-FGln is a new PET tracer in pre-clinical MM models, yielding a rationale to design studies in MM patients.

Outcome of Locally Advanced Esophageal Cancer Patients Treated With Perioperative Chemotherapy and Chemoradiotherapy Followed by Surgery.

Perioperative chemotherapy (P-CT) or neoadjuvant chemoradiation (C-RT) followed by surgical resection is the standard of care for locally advanced esophageal cancer (LAEC). We present an institutional review and outcome of patients with LAEC treated with neoadjuvant C-RT or P-CT followed by surgery. Patients were identified through the Manitoba Cancer Registry. Overall survival (OS), recurrence-free survival (RFS), and time to recurrence (TTR) were compared using proportion hazard regression analysis. Metabolic and pathologic response rates were compared by the Fisher exact test. Sixty-seven patients were treated with C-RT and 32 with P-CT. Fifty-two percent of the patients had pretreatment and posttreatment positron emission tomography scans before surgery. Ninety-five percent of the patients in C-RT and 91% in P-CT had a partial metabolic response or stable disease. Sixty-one percent of C-RT and 34% of P-CT patients had tumor regression grade (TRG) 0 to 1; 39% of C-RT and 66% of P-CT had TRG 2 to 3 (P=0.018). Median OS was 37 and 18 months for patients with TRG 0 to 1 and 2 to 3, respectively (P=0.013, hazard ratio [HR]=1.96). Three-year OS was 43% versus 37% (P=0.37, HR=1.30), RFS was 34% versus 26% (P=0.87, HR=0.96), and median TTR was 30 versus 13 months (P=0.07, HR=0.59) for C-RT and P-CT, respectively. C-RT was associated with a higher degree of pathologically tumor regression. Patients with major tumor regression had a better outcome than those with minimal to poor response. There was a trend toward improved TTR with C-RT but no difference in OS or RFS.

Patient Outcomes With Dose Escalation Using Modern Radiotherapy Techniques: A Retrospective Review of Anal Cancer Treated at a Large Academic Institution Between 2010 and 2016

Introduction: The use of modern radiotherapy techniques (MRTs) has contributed to reduced treatment-related toxicities through better avoidance of normal structures and dose tapering, and has enabled the delivery of higher doses continuously. The purpose of this study was to review retrospectively (1) outcomes for anal cancer treated at BC Cancer (Canada) using MRT, and (2) the utilization and effect of dose escalation on cancer-related outcomes.Methods: Patients between 2010 and 2016 with biopsy-proven anal cancer, aged >18 years, and treated with primary curative-intent chemoradiation using intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) were included. Primary end points included overall survival (OS), relapse-free survival (RFS), and colostomy-free survival (CFS). Kaplan-Meier curves were created for prognostic factors, as well as dose escalation (>54 Gy vs. ≤54 Gy). Univariate and multivariate analyses were performed to evaluate predictors of the outcome.Results: A total of 273 patients were assessed. The median age was 61 years with 70% being female, 6% HIV positive, and 68% with locally advanced cancer (T3-4, or node positive). The median follow-up time was 41.3 months. Time from diagnosis to treatment was 60 days, and treatment duration 42 days. Dose escalation was prescribed for 22, of whom 15 were locally advanced cases. A total of 97% completed their radiation, including all who were dose-escalated; 11% required unplanned treatment breaks, with over half of breaks <5 days. More than 90% completed at least half of their chemotherapy; 41% had pre-treatment, and 34% post-treatment positron emission tomography (PET) scans. For primary tumor response, 88% were complete and 10% partial; 23% relapsed, with 15% locoregional, 5% distant, and 3% both, and 12% had salvage surgery. The colostomy rate was 15%, with 4% pre-treatment, 10% relapse related, and only 1% treatment-toxicity related. On univariate analysis, male sex was associated with a higher risk of death (p=0.02) and relapse (p=0.041). Non-squamous histology was consistently a strong predictor of all outcomes (OS, p=0.0089; RFS, p<0.0001; CFS, p<0.0001) as was advanced T stage (OS, p=0.0075; RFS, p=0.0019; CFS, p=0.0099), and node positivity (OS, p=0.0014; RFS, p=0.001; CFS, p=0.0071). Age, HIV status, grade, longer treatment times (>42-day median), and lack of a pre- or post-treatment PET scan were not associated with the outcome. Dose escalation beyond 54 Gy was not significant, even among locally advanced tumors. On multivariate analysis, non-squamous histology (OS, p=0.043; RFS, p<0.001; CFS, p=0.01), T4 (OS, p=0.049; RFS, p=0.026; CFS, p=0.042) and node positivity (OS, p=0.05; RFS, p=0.006) remained significant predictors of the outcome, although node positivity was no longer significant for CFS (p=0.10).Conclusion: BC Cancer outcomes for anal cancer treated with MRTs are comparable to what has been previously reported. Unplanned breaks were notably few, and short. Treatment-related colostomies were rare. Dose-escalated regimens were infrequently prescribed, appeared tolerable, but more often required a break. Prospective trials are needed to clarify efficacy of such regimens.

[18f]-(2S,4R)-4-Fluoroglutamine As a New Positron Emission Tomography Tracer in Multiple Myeloma

High glycolitic activity of multiple myeloma (MM) cells is the rationale for the use of Positron Emission Tomography (PET) with 18F-fluorodeoxyglucose ([18F]FDG) to detect both medullary and extramedullary disease. However, FDG-PET has some limitations, since there is a good portion of MM patients who are false-negative. Besides enhanced glycolysis, glutamine (Gln) addiction has been recently described as a metabolic feature of MM by our group. To sustain high Gln demand, MM cells increase the expression of several Gln transporters (ASCT2, SNAT1, LAT1) and are endowed with fast Gln uptake. Yet, at variance with other Gln-addicted cancers, the possible exploitation of Gln as a PET tracer in MM has never been assessed and was investigated in this study. To this purpose, we have firstly synthesized enantiopure (2S,4R)-4-Fluoroglutamine (4-FGln) and validated it as a Gln analogue in human MM cell lines (RPMI8226 and JJN3) comparing its uptake with that of 3H-labelled Gln. The intracellular levels of 4-FGln were determined by HPLC-MS/MS employing a HILIC gradient separation and multiple reaction monitoring (MRM) detection. Both Gln and 4-FGln were actively accumulated by MM cells and exhibited a strong reciprocal competition, pointing to shared transporters. Inhibition analysis revealed that ASCT2 was the major entry route of both compounds, with minor contributions from the other transporters. However, compared with Gln, 4-FGln exhibited higher affinity for both ASCT2 and LAT1 transporters. On the basis of these results, we then tested [18F]4-FGln uptake for MM detection by Positron Emission Tomography (PET) in two different in vivo murine models. Firstly, to investigate sensitivity of human MM to [18F]4-FGln in vivo, JJN3 cells were subcutaneously injected in immunodeficient NSG mice In this xenograft model, [18F]4-FGln- and[18F]FDG-PET scans were performed after plasmacytomas became palpable and repeated after one week. All the tumours were positive for [18F]FDG and displayed [18F]4-FGln uptake with Standard Uptake Values (SUV) of 1.21±1.9 and 0.99±0.07 after 2 weeks, respectively. Thereafter, the effect of bortezomib (BOR) was investigated to evaluate the potential use of [18F]4-FGln to monitor anti-MM treatment. Ten NGS mice were injected with JJN3 cells and, after 14 days, treated twice weekly with BOR, 1mg/kg, or vehicle for two weeks. PET scans were performed before and after 5 and 12 days of BOR treatment. As expected, BOR reduced tumour size as compared to vehicle. At the first post-BOR PET scan, [18F]4-FGln (SUV mean: pre 0.85±0.31; post 0.45±0.10, P&lt;0.05), but not [18F]FDG (SUV mean: pre 0.97±0.38, post 0.75±0.14) was already significantly reduced: [18F]FDG and [18F]4-FGln uptake was reduced of 22 and 45% respectively. With both radiotracers, BOR treated animals displayed SUV mean values significantly lower than those of vehicle treated animals at post treatment PET (SUV means [18F ]FDG: BOR 0.75±0.14; vehicle 1.27±0.34, P&lt;0.05; SUV mean [18F]4-FGln: BOR 0.45±0.10 ; vehicle: 0.73±0.18 ; P &lt;0.05). Thereafter, to mimic BOR-resistant MM in a syngeneic mouse model, C57BL/6 mice were injected intravenously with Vk12598 cells obtained from transgenic Vk*MYC mice repeatedly treated with sub-optimal doses of BOR. Upon injection into C57BL/6 mice, Vk12598 cells colonize the BM without lytic lesions and extensively colonize the spleen generating an aggressive MM that brings animals to death within five weeks. PET scans were performed with [18F]4-FGln and [18F]FDG before Vk*MYC MM cells injection and after three, four and five weeks. Blood samples for M-spike evaluation were obtained in parallel. Four weeks after MM cells injection a significant increase of both [18F]4-FGln and [18F]FDG uptake was detected in spleens (SUV mean: 1.14±0.23, P=0.018; 0.94±0.24, P= 0.005). In both MM models, the volume of distribution of [18F]4-F-Gln did not overlap that of [18F]FDG. In conclusion, our data indicate that [18F]-(2S,4R)-4-Fluoroglutamine is a new potential PET tracer in pre-clinical MM models especially of extramedullary disease, either in a BOR-sensitive or in a BOR-resistant context, supporting the exploitation of Gln addiction for diagnostic purposes in MM patients. Disclosures Giuliani: Janssen: Research Funding.

Response Assessment with 18F-FDG PET/CT Scan in Patients with Anal Cancer Treated with Radical Radiotherapy

Functional imaging like positron emission tomography (PET) in combination with computed tomography (CT) has been found to be an important tool in post-treatment response assessment in several malignancies. The objective of this study was to identify the utility of early post-treatment response assessment with 18F-FDG PET/CT scan in patients with squamous cell carcinoma (SCC) of anal canal primarily treated with radical radiotherapy. We reviewed the provincial population database for anal cancer patients who were treated with radical radiotherapy (2005-2015) and subsequently underwent post-treatment 18F-FDG PET/CT scans (majority within 12-17 weeks after treatment completion) for response assessment. Information related to patient and tumor characteristics, treatment regimen were collected. Disease free survival (DFS) and cancer specific survival (CSS) were estimated using Kaplan-Meier product limit method. Cox multivariable proportional hazard model was used to determine the association of post-treatment maximum standardized uptake value (SUVmax) as a continuous variable with DFS and CSS after adjustment for age at diagnosis, stage, radiotherapy dose, use of concomitant chemotherapy, use of salvage surgery, sex and performance status. A total of 287 patients were treated with radical radiotherapy over the time period of the study and 56 had post-treatment response assessment with PET/CT. Median age of the study cohort was 60.5 years (IQR, 53-66 years). Median radiotherapy dose was 54 Gy (IQR, 53.6-54 Gy). Among a total of 56 patients, concurrent chemotherapy was offered in 53 (95%) patients. Mean post-treatment SUVmax for the primary tumor and node were 2.6(±3.9) and 4.3(±6.7). On multivariable analysis (MVA), post-treatment SUVmax for the primary tumor had a significant association with CSS (hazard ratio (HR): 1.39, 95% confidence interval (CI): 1.13-1.70, p=0.002). The HR for post-treatment nodal SUVmax was 1.09 (95% CI: 0.88-1.36, p=0.4). The association of post-treatment SUVmax of tumor (HR: 1.01, 95% CI: 0.86-1.18, p=0.88) or node (HR: 1.10, 95% CI: 0.92-1.31, p=0.31) with DFS was not statistically significant. The current population-based study shows significant correlation of presence of FDG avid residual tumor with cancer specific survival. Every 1 unit increase in post-treatment SUVmax of the primary tumor was associated with 39% increase in the relative risk of death. Although post-treatment residual FDG avid node showed similar direction of association, the overall association was not statistically significant which could be attributed to the limited sample size. The study alludes to the importance of post-treatment PET based response assessment in patients with anal SCC and early institution of salvage treatment in presence of FDG avid residual tumor to avoid potentially fatal consequences. Further prospective validation with randomized clinical trial is worthwhile to prove this hypothesis.

FDG PET based prediction of response in head and neck cancer treatment: Assessment of new quantitative imaging features.

Introduction18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is now a standard diagnostic imaging test performed in patients with head and neck cancer for staging, re-staging, radiotherapy planning, and outcome assessment. Currently, quantitative analysis of FDG PET scans is limited to simple metrics like maximum standardized uptake value, metabolic tumor volume, or total lesion glycolysis, which have limited predictive value. The goal of this work was to assess the predictive potential of new (i.e., nonstandard) quantitative imaging features on head and neck cancer outcome.MethodsThis retrospective study analyzed fifty-eight pre- and post-treatment FDG PET scans of patients with head and neck squamous cell cancer to calculate five standard and seventeen new features at baseline and post-treatment. Cox survival regression was used to assess the predictive potential of each quantitative imaging feature on disease-free survival.ResultsAnalysis showed that the post-treatment change of the average tracer uptake in the rim background region immediately adjacent to the tumor normalized by uptake in the liver represents a novel PET feature that is associated with disease-free survival (HR 1.95; 95% CI 1.27, 2.99) and has good discriminative performance (c index 0.791).ConclusionThe reported findings define a promising new direction for quantitative imaging biomarker research in head and neck squamous cell cancer and highlight the potential role of new radiomics features in oncology decision making as part of precision medicine.

Standardization of multivariate Gaussian mixture models and background adjustment of PET images in brain oncology

In brain oncology, it is routine to evaluate the progress or remission of the disease based on the differences between a pre-treatment and a post-treatment Positron Emission Tomography (PET) scan. Background adjustment is necessary to reduce confounding by tissue-dependent changes not related to the disease. When modeling the voxel intensities for the two scans as a bivariate Gaussian mixture, background adjustment translates into standardizing the mixture at each voxel, while tumor lesions present themselves as outliers to be detected. In this paper, we address the question of how to standardize the mixture to a standard multivariate normal distribution, so that the outliers (i.e., tumor lesions) can be detected using a statistical test. We show theoretically and numerically that the tail distribution of the standardized scores is favorably close to standard normal in a wide range of scenarios while being conservative at the tails, validating voxelwise hypothesis testing based on standardized scores. To address standardization in spatially heterogeneous image data, we propose a spatial and robust multivariate expectation-maximization (EM) algorithm, where prior class membership probabilities are provided by transformation of spatial probability template maps and the estimation of the class mean and covariances are robust to outliers. Simulations in both univariate and bivariate cases suggest that standardized scores with soft assignment have tail probabilities that are either very close to or more conservative than standard normal. The proposed methods are applied to a real data set from a PET phantom experiment, yet they are generic and can be used in other contexts.

Comparison of the 90Y-labelled glass microspheres liver radioembolisation dosimetry with the estimated dosimetry obtained from pre-treatment 99mTc-MAA SPECT images reconstructed with and without attenuation correction

ABSTRACT90Y-labelled glass microspheres liver radioembolisation is an effective treatment for unresectable hepatic tumours. Its treatment planning is based on 99mTc-macro-aggregated albumin (MAA) single photon emission computed tomography (SPECT) imaging. However, photons interaction with human tissues may significantly compromise the accuracy of radioactivity quantification in nuclear medicine. The aim of this work is to evaluate the impact of a patient-specific attenuation correction on pre-treatment 99mTc-MAA SPECT images and, consequently, on the estimation of radioembolisation dosimetry. The methodology developed for attenuation correction was firstly validated on phantom models. Following this, a data set of eight patients was retrospectively selected from our database and the pre-treatment images were reconstructed with and without attenuation correction. Then, the liver dosimetry maps were estimated and compared with the liver dosimetry maps estimated from the post-treatment 90Y positron emission tomography images. Results show that the attenuation corrected phantom images were greatly improved, originating higher contrast, signal-to-noise ratio and contrast-to-noise ratio comparatively to non-attenuation corrected images. Attenuation corrected clinical pre-treatment images significantly increase the agreement, measured with the intraclass correlation coefficient, between predictive and post-treatment dosimetry maps comparatively to the non-attenuation corrected ones (Wilcoxon test, p = 0.008). In conclusion, a statistically significant increase in the agreement was achieved; however, poor correlation is still observed at the single-voxel level in some patients. Thus, future research should be addressed to investigate the reasons of this and manage to optimise the agreement between the predictive and post-treatment dosimetry.

Positron Emission Tomography–Adjusted Intensity Modulated Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

Toperform a prospective trial examining positron emission tomography (PET)-based, dose-painted intensity modulated radiation therapy (IMRT) in the setting of locally advanced non-small cell lung cancer (NSCLC). Patients with stage IIB-III NSCLC were treated with 25 fractions of dose-painted IMRT. Tumors or lymph nodes with metabolic tumor volume exceeding 25cm3 were deemed "high risk" and received 65Gy. Smaller lesions were treated with 57Gy or 52.5Gy (after November 2014). Patients received concurrent weekly carboplatin (area under the curve=2) and paclitaxel (45mg/m2). The primary study endpoint was the absence of high residual metabolic activity (maximum standardized uptake value>6) in treated lesions on PET 12 to 16weeks after completion of IMRT. Thirty-five subjects with 116 hypermetabolic lesions were eligible for analysis. The primary endpoint was met for 24 of 30 patients (80%) who underwent posttreatment PET, satisfying our efficacy objective. With a median follow-up duration of 23.8months for living patients, progression in a lesion targeted with radiation therapy has been observed in 5 patients (14%). Treating progression in other sites and death without progression as competing risks, 2-year cumulative incidence rates of local disease progression in high-risk lesions (n=24) and low-risk lesions (n=92) are 9% and 3%, respectively. The actuarial rate of overall survival at 2years is 52%. Dose-painted IMRT based on pretreatment PET metrics with concurrent chemotherapy yields high rates of metabolic response and local disease control for locally advanced NSCLC. Future trials should test this approach to maximize the therapeutic ratio of thoracic radiation therapy.

Uptake of Radium-223 Dichloride and Early [18F]NaF PET Response Are Driven by Baseline [18F]NaF Parameters: a Pilot Study in Castration-Resistant Prostate Cancer Patients.

The purpose of this study is to identify predictive factors on baseline [18F]NaF positron emission tomography (PET)/computed tomography (CT) of early response to radium-223 dichloride after 3 cycles of treatment in metastatic castration-resistant prostate cancer patients. Analysis of 152 metastases was performed in six consecutive patients who underwent [18F]NaF PET/CT at baseline and for early monitoring after 3 cycles of radium-223 dichloride. All metastases depicted on whole-body [18F]NaF PET/CT were contoured and CT (density in Hounsfield units, sclerotic, mixed, or lytic appearance) as well as [18F]NaF [maximum standardized uptake value (SUVmax), SUVmean, and lesion volume (V18F-NaF)] patterns were recorded. Tumor response was defined as percentage change in SUVmax and SUVmean between baseline and post-treatment PET. Bone lesions were defined as stable, responsive, or progressive, according to thresholds derived from a recent multicentre test-retest study in [18F]NaF PET/CT. Total [18F]NaF uptake in metastases, defined as MATV×SUVmean, was correlated to uptake of radium-223 on biodistribution scintigraphy performed 7days after the first cycle of treatment. Among metastases, 116 involved the axial skeleton and 36 the appendicular skeleton. Lesions were sclerotic in 126 cases and mixed in 26 cases. No lytic lesion was depicted. ROC analysis showed that SUVmax and SUVmean were better predictors of lesion response than V18F-NaF and density on CT (P<0.0001 and P=0.001, respectively). SUVmax and SUVmean were predictors of individual tumor response in separate multivariate models (P=0.01 and P=0.02, respectively). CT pattern (mixed versus sclerotic) and lesion density were independent predictors only when assessing response with delta SUVmax (P=0.002 and 0.007, respectively). A good correlation between total [18F]NaF uptake within metastases and their relative radium-223 uptake assessed by two observers 7days after treatment (r=0.72 and 0.77, P<0.0001) was found. SUVmax and SUVmean on baseline [18F]NaF PET/CT are independent predictors of bone lesions' response to 3 cycles of radium-223 dichloride, supporting the use of NaF to select patients more likely to respond to treatment.

Predicting Outcomes Using Pre- and Post-treatment PET/CT in Locoregionally Advanced Non-oropharyngeal Head and Neck Cancer

To determine if pre- and post-treatment positron emission tomography and computed tomography (PET/CT) is predictive of outcomes including overall survival (OS) and development of metastasis in non-oropharyngeal head and neck cancers. We gathered pre- and post-treatment PET/CT data on 47 patients with non-oropharyngeal head and neck cancer from 2005-2016 who were treated with definitive chemoradiation. Post-treatment PET/CT was obtained 3 months after the completion of treatment. We recorded the primary tumor size, dominant lymph node size, max SUV of both the primary tumor and the dominant node. Analysis was performed to determine the predictive utility of each parameter for OS and the development of metastasis. Forty-seven patients with non-oropharyngeal head and neck cancer underwent pre- and post-treatment PET/CT. The primary tumor sites were hypopharynx (9), larynx (24), nasopharyngeal (9), oral cavity (3), and paranasal sinus (2). Four patients were stage II, 17 were stage III, 18 were stage IVA, and 7 were stage IVB. For the primary tumor, the mean size was 3.1 cm (range, 1.0 – 7.5 cm) and mean max SUV was 21.85 (range, 5.9 – 48.1). The dominant node was used representing all nodal disease. For the dominant node, the mean size was 1.94 cm (0.7 cm – 5.8 cm) and mean max SUV was 12.6 (2.3 – 28.5). Patients were most commonly treated with simultaneous in-field boost SIB-IMRT technique with median dose 6750 cGy with concurrent weekly cisplatin. Mean follow-up time was 43.6 months. Of the 12 patients who experienced a treatment failure, 3 failed locally only, 4 failed distantly only, 1 failed locally and distantly, 1 failed distantly and had nodal failure, 2 had isolated nodal failure, and 1 failed synchronously at all three sites. Eighteen patients died during the follow-up period. On the pre-treatment PET/CT, only the max SUV of the dominant node (HR 1.06, p=0.02) was predictive of OS. The decrease from pre- to post-treatment of the nodal SUV (HR 1.06, p=0.03) was also predictive of OS. On post-treatment PET/CT, the SUV of the primary tumor (HR 1.13, p=0.03) and the size of the primary tumor (HR 3.05, p=0.02) were predictive for OS. No pre-treatment PET/CT data was predictive for the development of metastasis. Only the post-treatment size of the primary tumor (HR 18.3, p<0.01) was predictive for the development of metastasis. In non-oropharyngeal head and neck cancer, both pre-treatment and post-treatment PET/CT are valuable for predicting OS. Only post-treatment PET/CT data is useful for predicting the development of metastasis.

RISK STRATIFICATION BASED ON NCCN‐IPI AT THE TIME OF DIAGNOSIS IN COMBINATION WITH POST‐TREATMENT PET‐CT SCAN FOR THE TREATMENT OF NODAL PERIPHERAL T‐CELL LYMPHOMA

Background: Nodal peripheral T-cell lymphomas (PTCLs) consist of PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large-cell lymphoma-anaplastic lymphoma kinase positive (ALCL-ALK+), and ALCL-ALK−. Clinical assessments before and after treatment are essential to predict survival in nodal PTCL. However, limited data are available regarding the prognostic significance of National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) as a pre-treatment clinical tool and post-treatment PET-CT scan indicating tumor viability in patients with nodal PTCL. The primary aim was to establish a risk model for nodal PTCL based on NCCN-IPI and post-treatment PET-CT scan. Method: In this retrospective, multicenter, cohort study, patients were eligible if they were diagnosed with nodal PTCL from Jan 2005 to June 2016, received systemic chemotherapy, and had the results of PET-CT scan at the time of diagnosis and at the end of treatment, which was assessed using 5-point Deauville score. The study excluded ALCL-ALK+. Results: A total of 396 patients were screened. Seventy patients were excluded from the analysis: unavailable pre- or post-treatment PET scans, no systemic treatment, uncertain histology, and ALCL-ALK+. Thus, 326 patients were analyzed. The median age was 61 years (range, 18–86) and 209 (64%) were male. PTCL-NOS (N = 172, 53%) was the most common subtype, and AITL (N = 111, 34%) and ALCL-ALK− (N = 43, 13%) followed. Patients were categorized into low (N = 42, 13%), low-intermediate (LI, N = 108, 33%), high-intermediate (HI, N = 136, 42%), and high (N = 40, 12%) risk groups according to the NCCN-IPI. Based on the Deauville criteria, post-treatment PET-CT scan was scored as 1 (N = 130, 40%), 2 (N = 47, 14%), 3 (N = 60, 18%), 4 (N = 27, 8%), and 5 (N = 62, 19%). Because the number of progression in Deauville score 3 (40/60, 67%) was significantly different from score 2 (21/47, 45%; P = 0.023) and 4 (24/27, 89%; P = 0.030), we categorized patients into 3 groups: Deauville score 1–2, 3, and 4–5. With a median follow-up of 54.7 months (IQR, 30.2–84.5), 5-year PFS rate was 35.7% (95% CI, 30.0–41.4), and OS rate was 47.1% (95% CI, 40.8–53.4). NCCN-IPI risk and post-treatment PET-CT scan were independently associated with PFS in multivariate analysis (for LI NCCN-IPI, hazard ratio [HR] 1.615, 95% CI 0.838–3.113; HI NCCN-IPI, HR 3.063, 95% CI 1.626–5.769; high NCCN-IPI 4.475, 95% CI 2.231–8.977; P < 0.001: for post-treatment Deauville score 3, HR 1.895, 95% CI 1.281–2.801; score 4–5, HR 6.916, 95% CI 4.948–9.667; P < 0.001). We stratified patients into 5 groups based on risk of progression: low (low NCCN-IPI and Deauville score 1–2), INT-1 (low NCCN-IPI and score 3, or LI NCCN-IPI and score 1–2), INT-2 (HI NCCN-IPI and score 1–2), high (high NCCN-IPI and score 1–2, or LI to high NCCN-IPI and score 3), and very high (score 4–5). The risk model showed a strong association with PFS and OS (Figure 1). Keywords: peripheral T-cell lymphomas (PTCL); positron emission tomography (PET); prognostic indices.

Prognostic value of post treatment PET scan in small cell lung cancer.

e20013 Background: In most lymphomas, improving patient outcome rely on an assessment of response to therapy. Functional imaging with 18-fluoro-deoxyglucose (FDG) positron emission tomography (PET) increases sensitivity and specificity of disease assessment, predicts outcome and directs future therapies. Lately, PET-scan is more utilized in small cell lung cancer (SCLC) both for initial staging and to assess response to therapy. However, limited data in the literature have evaluated the prognostic value of post-therapy response on PET-scan in SCLC. Methods: This is a retrospective chart-review of SCLC patients who received their first-line chemotherapy between January-2007 and December-2013. Inclusion criteria included complete data on age, sex, race, cancer stage, histologic grade, chemotherapy, radiotherapy, and PET images pre- and post-therapy. CR was defined as either 100% drop in FDG uptake on post-therapy PET-scan. Results: Fifty patients met the inclusion criteria, and served as the basis for this study. 46% had Limited Stage Small Cell Lung Cancer (LS-SCLC), and 54% had Extensive stage small cell lung cancer (ES-SCLC). All were treated with platinum-based chemotherapy in addition to concurrently radiation therapy for the LS-SCLC group. Eleven patients out of the whole cohort achieved CR. Using COX regression model, we evaluated the correlation between achieving CR on post-therapy PET-scan and survival outcome. We found that achieving CR was significantly correlated with worse outcome in ES-SCLC group (HR = 2.70; 95%CI: 1.26-5.81; p = 0.01). While, in the whole cohort and LS-SCLC group, P-value was not statistically significant, nevertheless achieving CR indicated unfavorable outcome (HR = 1.18; 95%CI: 0.51-2.69; p = 0.49) and (HR = 1.99; 95%CI: 0.77-5.13; p = 0.15) respectively. Conclusions: Unlike lymphomas, achieving CR on post-therapy PET-scan in SCLC was associated with worse survival outcome. This might indicate that in aggressive small cell lung cancer, despite excellent response to first-line therapy, the prognosis is still dismal. These results suggest that further prospective studies are warranted to identify the prognostic rule of post-therapy PET-scan in SCLC patients particularly those with ES-SCLC.

Usefulness of Positron Emission Tomography in Patients with Syphilis: A Systematic Review of Observational Studies.

Background:Diagnosis of syphilis is difficult. Follow-up and therapy evaluation of syphilitic patients are poor. Little is known about positron emission tomography (PET) in syphilis. This review was to systematically review usefulness of PET for diagnosis, disease extent evaluation, follow-up, and treatment response assessment in patients with syphilis.Methods:We searched PubMed, EMBASE, SCOPUS, Cochrane Library, Web of Science, ClinicalTrials.gov, and three Chinese databases (SinoMed, Wanfang, and CNKI) for English and Chinese language articles from inception to September 2016. We also collected potentially relevant studies and reviews using a manual search. The search keywords included the combined text and MeSH terms “syphilis” and “positron emission tomography”. We included studies that reporting syphilis with a PET scan before and/or after antibiotic treatment. The diagnosis of syphilis was based on serological criteria or dark field microscopy. Outcomes include pre- and post-treatment PET scan, pre- and post-treatment computed tomography, and pre- and post-treatment magnetic resonance imaging. We excluded the articles not published in English or Chinese or not involving humans.Results:Of 258 identified articles, 34 observational studies were included. Thirty-three studies were single-patient case reports and one study was a small case series. All patients were adults. The mean age of patients was 48.3 ± 12.1 years. In primary syphilis, increased fluorodeoxyglucose (FDG) accumulation could be seen at the site of inoculation or in the regional lymph nodes. In secondary syphilis with lung, bone, gastrointestinal involvement, or generalized lymphadenopathy, increased FDG uptake was the most commonly detected changes. In tertiary syphilis, increased glucose metabolic activity, hypometabolic lesions, or normal glucose uptake might be seen on PET. There were five types of PET scans in neurosyphilis. A repeated PET scan after treatment revealed apparent or complete resolution of the asymmetry of radiotracer uptake.Conclusion:PET is helpful in targeting diagnostic interventions, characterizing disease extent, assessing nodal involvement, and treatment efficacy for syphilis.