Tumor To Normal Ratio Research Articles

NIMG-24. PRECISION GLIOBLASTOMA MANAGEMENT USING MET AND FMISO PET SCANS

Abstract OBJECTIVE Positron Emission Tomography (PET) may be useful in diagnosing glioblastoma, determining resection areas, and evaluating therapeutic efficacy. This study evaluated the usefulness of PET scans using 11C-Methionine (MET) to assess amino acid metabolism and 18F-Fluoromisonidazole (FMISO) to assess hypoxic regions in glioblastoma treatment. METHODS Thirty glioblastoma patients who underwent MET and FMISO PET studies from July 2013 to March 2024 were included. Patients underwent the Stupp regimen post-tumor resection and were treated with temozolomide (TMZ) and bevacizumab (Bev) upon recurrence. PET scans were performed before and after two courses of Bev treatment. Changes in tumor to normal ratio (TNR) for MET, tumor to blood ratio (TBR) for FMISO, and metabolic tumor volume (MTV) for both MET and FMISO were evaluated. Progression-free survival (PFS) and overall survival (OS) were compared based on the rate of change in MTV for MET and FMISO. RESULTS The residual volumes (contrast-enhanced MRI, MET, and FMISO) with a MET removal rate of >90% were 0.08 ml, 0.1 ml, and 0.08 ml, respectively. For FMISO removal rates of >90%, residual volumes were 0.36 ml, 1.54 ml, and 0.05 ml, respectively. Groups with a decreased rate of change in MET MTV had significantly better outcomes: PFS (months) 10.7 vs. 2.8 (p=0.19) and OS (months) 18.6 vs. 4.9 (p=0.09). In the FMISO groups, decreased TBR change rates correlated with better outcomes: PFS (months) 16.6 vs. 2.5 (p<0.01) and OS (months) 22.8 vs. 4.9 (p<0.01). MTV change rates also showed significant differences in outcomes: PFS (months) 10.5 vs. 3.7 (p=0.76) and OS (months) 14.9 vs. 7.0 (p=0.87). CONCLUSION Higher MET removal rates correlate with fewer contrast-enhanced MRI and FMISO accumulation areas, suggesting MET as a reliable tumor removal indicator. Both MET and FMISO PET scans are valuable in determining glioblastoma treatment response.

Injectable and Sprayable Fluorescent Nanoprobe for Rapid Real-Time Detection of Human Colorectal Tumors.

The development of minimally invasive surgery has greatly advanced precision tumor surgery, but sometime suffers from restricted visualization of the surgical field, especially during the removal of abdominal tumors. A 3-D inspection of tumors could be achieved by intravenously injecting tumor-selective fluorescent probes, whereas most of which are unable to instantly distinguish tumors via in situ spraying, which is urgently needed in the process of surgery in a convenient manner. In this study, this work has designed an injectable and sprayable fluorescent nanoprobe, termed Poly-g-BAT, to realize rapid tumor imaging in freshly dissected human colorectal tumors and animal models. Mechanistically, the incorporation of γ-glutamyl group facilitates the rapid internalization of Poly-g-BAT, and these internalized nanoprobes can be subsequently activated by intracellular NAD(P)H: quinone oxidoreductase-1 to release near-infrared fluorophores. As a result, Poly-g-BAT can achieve a superior tumor-to-normal ratio (TNR) up to 12.3 and enable a fast visualization (3min after in situ spraying) of tumor boundaries in the xenograft tumor models, Apcmin/+ mice models and fresh human tumor tissues. In addition, Poly-g-BAT is capable of identifying minimal premalignant lesions via intravenous injection.

Association Between Pretreatment 11C-Methionine Positron Emission Tomography Metrics, Histology, and Prognosis in 125 Newly Diagnosed Patients with Adult-Type Diffuse Glioma Based on the World Health Organization 2021Classification

To clarify the relationships between 11C-methionine (MET) positron emission tomography (PET) metrics and the histology, genetics, and prognosis of adult-type diffuse glioma (ADG) based on the World Health Organization (WHO) 2021 classification. A total of 125 newly diagnosed patients with ADG were enrolled. We compared the maximum standardized uptake value (SUVmax), tumor-to-normal background ratio (TNR), metabolic tumor volume (MTV), and total lesion methionine uptake (TLMU) to the histology and genetics of the patients with ADG. We also evaluated the prognoses of the 93 surgically treated patients. The patients with isocitrate dehydrogenase wild ADG showed significantly higher MET-PET metrics (P < 0.05 for all parameters), significantly shorter overall survival and progression-free survival (P < 0.0001 for both) than those of the patients with isocitrate dehydrogenase mutant (IDHm) ADG. In the IDHm ADG group, the SUVmax, MTV, and TLMU values were significantly higher in patients with IDHm grade (G) 4 astrocytoma than patients with IDHm G2/3 astrocytoma (P < 0.05 for all), but not than patients with G2-3 oligodendroglioma. The progression-free survival was significantly shorter in the patients with G4 astrocytoma versus the patients with G2/3 astrocytoma and G3 oligodendroglioma (P < 0.05 for both). The SUVmax and TNR values were significantly higher in recurrent patients than nonrecurrent patients (P < 0.01 for both), but no significant differences were found in MTV or TLMU values. MET-PET metrics well reflect the histological subtype, WHO grade and prognosis of ADG based on the 2021 WHO classification, with the exception of oligodendroglial tumors. Volumetric parameters were not significantly associated with recurrence, unlike the SUVmax and TNR.

Simultaneous evaluation of brain metastasis and thoracic cancer using semiconductor 11C-methionine PET/CT imaging.

To investigate the potential of whole-body digital 11C-methionine (MET) PET/CT imaging for simultaneous evaluation of thoracic cancer patients suspected of local recurrence (LR) after stereotactic radiosurgery (SRS) for brain metastasis. A total of 45 lung or breast cancer patients suspected of LR after SRS were investigated using brain and whole-body MET-PET/CT scans. We compared the tumor-to-normal ratio (TNR) and maximum standardized uptake values (SUVmax) between patients with LR and radiation necrosis (RN) and performed receiver operating characteristic (ROC) analyses. We also investigated associations among extracranial recurrence, intracranial recurrence, primary site, and initial treatment type. A total of 44 LR and 14 RN lesions were analyzed. In the ROC analyses for differentiating LR from RN, TNR showed higher area under the curve (AUC) (0.82) than SUVmax (0.79), and the cutoff TNR value (2.12) was higher than current cutoff values of conventional PET systems. The whole-body scans detected extracranial recurrences in 31.1% of the patients. Recurrence rates were not significantly correlated with existence of intracranial recurrence or primary site, but patients who underwent non-surgical treatment (consisting of stage III/ IV patients according to the Union for International Cancer Control TNM classification or small-cell lung cancer patients) showed significantly higher recurrence than the surgically treated patients (68.8% vs. 10.3%, p = 0.0001). In digital MET-PET/CT imaging, TNR was a more useful parameter to differentiate LR from RN than SUVmax, and the cutoff value was higher than those with conventional PET systems. Additional whole-body scans could detect extracranial recurrence and would be especially useful for advanced thoracic cancer patients who underwent non-surgical treatment.

MIDOS: a novel stochastic model towards a treatment planning system for microsphere dosimetry in liver tumors.

Transarterial radioembolization (TARE) procedures treat liver tumors by injecting radioactive microspheres into the hepatic artery. Currently, there is a critical need to optimize TARE towards a personalized dosimetry approach. To this aim, we present a novel microsphere dosimetry (MIDOS) stochastic model to estimate the activity delivered to the tumor(s), normal liver, and lung. MIDOS incorporates adult male/female liver computational phantoms with the hepatic arterial, hepatic portal venous, and hepatic venous vascular trees. Tumors can be placed in both models at user discretion. The perfusion of microspheres follows cluster patterns, and a Markov chain approach was applied to microsphere navigation, with the terminal location of microspheres determined to be in either normal hepatic parenchyma, hepatic tumor, or lung. A tumor uptake model was implemented to determine if microspheres get lodged in the tumor, and a probability was included in determining the shunt of microspheres to the lung. A sensitivity analysis of the model parameters was performed, and radiation segmentectomy/lobectomy procedures were simulated over a wide range of activity perfused. Then, the impact of using different microspheres, i.e., SIR-Sphere®, TheraSphere®, and QuiremSphere®, on the tumor-to-normal ratio (TNR), lung shunt fraction (LSF), and mean absorbed dose was analyzed. Highly vascularized tumors translated into increased TNR. Treatment results (TNR and LSF) were significantly more variable for microspheres with high particle load. In our scenarios with 1.5 GBq perfusion, TNR was maximum for TheraSphere® at calibration time in segmentectomy/lobar technique, for SIR-Sphere® at 1-3 days post-calibration, and regarding QuiremSphere® at 3 days post-calibration. This novel approach is a decisive step towards developing a personalized dosimetry framework for TARE. MIDOS assists in making clinical decisions in TARE treatment planning by assessing various delivery parameters and simulating different tumor uptakes. MIDOS offers evaluation of treatment outcomes, such as TNR and LSF, and quantitative scenario-specific decisions.

10213-GMC-16 A DECADE REVIEW: BEVACIZUMAB'S IMPACT ON GLIOBLASTOMA TREATMENT

Abstract OBJECTIVE This study aims to assess the efficacy of Bevacizumab (Bev) therapy, ten years after its initiation in treating glioblastoma patients at our department. METHODS Eighty-four patients treated with Bev from July 2013 to December 2022 were classified into three groups: the initial treatment group given the Stupp regimen with Bev (first-dose group), the group given the Stupp regimen plus Bev followed by tumor resection (neoadjuvant group), and those receiving the Stupp regimen post tumor resection (recurrence group). PET scans were conducted pre- and post- Bev therapy, and variations in Tumor-to-Normal ratio (TNR), Tumor-to-Blood ratio (TBR), and Metabolic Tumor Volume (MTV) were investigated. RESULTS The median Progression-Free Survival (PFS) and Overall Survival (OS) rates in the first, neoadjuvant, and recurrence groups were respectively (7.86, 14.27, 4.33) and (12.53, 21.57, 13.23) months. Notably, changes in MET and FMISO MTV in the first-treatment group, MET MTV and FMISO TBR changes in the recurrence group, and MET MTV change in the neoadjuvant group significantly influenced prognosis. In the recurrence group, patients who underwent total resection during initial treatment experienced a prolonged period of 25.9 months from initial treatment to the administration of Bev due to recurrence. Furthermore, cases where the FMISO TBR at recurrence was higher than at the initial treatment observed an extended median OS of 18.63 months upon administering Bev treatment at recurrence. CONCLUSION Bev neoadjuvant therapy demonstrated a significant correlation with enhanced PFS and OS outcomes, notably in patients subjected to total resection. In the context of recurrent disease, while the initiation of Bev administration was delayed, a distinct elevation in treatment effectiveness was observed in patients exhibiting an augmented FMISO TBR at the point of recurrence. The observed decreases in MET MTV and FMISO TBR emerge as robust predictors of the efficacy of Bev treatment.

NIMG-58. PET IMAGING AS A RELIABLE INDICATOR FOR EVALUATING BEVACIZUMAB TREATMENT RESPONSE IN GBM

Abstract OBJECTIVE PET scans are crucial for glioma diagnosis and treatment planning, but assessing the efficacy of Bevacizumab (Bev) treatment using MRI alone is challenging. Our study aimed to evaluate the effectiveness of Bev-based glioblastoma treatment using PET scans. METHODS We included ninety glioblastoma patients treated with Bev between July 2013 and May 2023. Patients were divided into three groups: the first group received Bev in addition to the Stupp regimen after biopsy or subtotal resection (first-dose group), the second group received Bev after biopsy followed by tumor resection (neoadjuvant group), and the third group received the Stupp regimen followed by TMZ + Bev at recurrence (recurrent group). PET scans (FDG, MET, FLT, and FMISO) were performed before and 4 weeks after starting Bev treatment. Tumor-to-normal ratio (TNR) was calculated for FDG, MET, and FLT, and tumor-to-blood ratio (TBR) was determined for FMISO. We used the Cox proportional hazards model to assess the percent change in TNR, TBR, and metabolic tumor volume (MTV) as prognostic factors. RESULTS The median PFS and OS (month) from Bev treatment were as follows: first-dose group (PFS: 8.87, OS: 12.53), neoadjuvant group (PFS: 16.53, OS: 22.13), and recurrent group (PFS: 4.0, OS: 8.0). In the first-line group, significant differences were found in the percent change in MTV for MET, FLT, and FMISO. In the recurrent group, significant differences were observed in the percent change in MTV for FDG and MET, as well as in FDG TNR and FMISO TBR. In the neoadjuvant group, significant differences were found in the percent change in MTV for MET and FLT. CONCLUSION Neoadjuvant Bev treatment led to prolonged PFS and OS in glioblastoma patients. Decreases in MET MTV change rate and FMISO TBR change rate were identified as potential indicators for assessing Bev treatment efficacy after recurrence.

Targeted delivery of cathepsin-activatable near-infrared fluorescence probe for ultrahigh specific imaging of peritoneal metastasis

Inadequate cytoreductive surgery (CRS) has been identified as a prognostic factor for poor patient outcomes in cases of peritoneal metastasis. While imaging probes are used to identify peritoneal metastasis to facilitate CRS, many of these probes exhibit high background signals, resulting in a significant delay in achieving a satisfactory tumor-to-normal ratio (TNR) due to prolonged clearance time. In this study, we designed a novel fluorescent probe named Tras-AA-Cy NH2, which enables the relatively rapid imaging of subcutaneous tumors and peritoneal tumors while maintaining a high TNR. Mechanistically, Tras-AA-Cy NH2 exhibits selective targeting towards the Human epidermal growth factor receptor 2 on the surface of cancer cells. Following internalization, it undergoes enzymatic cleavage catalyzed by the overexpressed cathepsin, leading to the subsequent release of near-infrared fluorophores. Consequently, Tras-AA-Cy NH2 achieved a TNR of 7.8 at 6 h and 21.4 at 24 h in subcutaneous tumor mice. Even after 522 h of in vivo circulation, the TNR remained above 5, indicating an ultralong imaging time window. It is noteworthy that Tras-AA-Cy NH2 has demonstrated successful utilization for peritoneal tumor-specific imaging and further affirmed its tumor tissue-specific recognition capability using human resected tissues. In summary, these findings underscore the rational design of Tras-AA-Cy NH2 for visualizing peritoneal tumors.

NI-16 RESPONSE ASSESSMENT OF BEVACIZUMAB THERAPY FOR GLIOBLASTOMA BY USING MULTIPLE PET TRACERS

Abstract Objective PET scans are useful for the diagnosis and treatment planning of glioma. Introduced in 2013, bevacizumab (Bev) treatment efficacy can be difficult to determine using MRI imaging. We instead performed PET scans to determine the efficacy of Bev-based glioblastoma treatment. Methods Eighty glioblastoma patients treated with Bev from July 2013 to December 2021 were included. The patients were divided into the following three groups: the first group received Bev added to the Stupp regimen after biopsy or subtotal resection (first-dose group), the second group received Bev added to the Stupp regimen after biopsy followed by tumor resection (neoadjuvant group), and the third group received the Stupp regimen after tumor resection followed by TMZ + Bev at recurrence (recurrent group). PET scans (FDG, MET, FLT, and FMISO) were performed before and 4 weeks after the start of the Bev treatment. FDG, MET, and FLT measured tumor-to-normal ratio (TNR), and FMISO measured tumor-to-blood ratio (TBR), as well as the percent change in SUVmax, TNR, TBR, and MTV before and after Bev treatment. Using the Cox proportional hazards model, we examined which of these rates of change were the prognostic factors. Results The median PFS (months) and median OS from Bev treatment were 8.87, 16.53, and 4.0 and 12.53, 22.13, and 8.0, respectively. Significant differences in the percent change in MTV for MET, FLT, and FMISO in the first-line group, the percent change in MTV for FDG and MET, the percent change in FDG TNR and FMISO TBR in the recurrent group, and the percent change in MTV for MET and FLT in the neoadjuvant group were shown in the Cox proportional hazards model. Conclusion Neoadjuvant treatment with Bev prolonged PFS and OS. The decrease in MET MTV change rate and FMISO TBR.

Accuracy and Safety of Scout Dose Resin Yttrium-90 Microspheres for Radioembolization Therapy Treatment Planning: A Prospective Single-Arm Clinical Trial

PurposeTo compare the accuracy and safety of 0.56 GBq resin yttrium-90 (90Y) (scout90Y) microspheres with those of technetium-99m macroaggregated albumin (MAA) in predicting the therapeutic 90Y (Rx90Y) dose for patients with hepatocellular carcinoma (HCC). Materials and MethodsThis prospective single-arm clinical trial (Clinicaltrials.gov: NCT04172714) recruited patients with HCC. Patients underwent same-day mapping with MAA and scout90Y. Rx90Y activity was administered 3 days after mapping. Using paired t test and Pearson correlation, the tumor-to-normal ratio (TNR), lung shunt fraction (LSF), predicted mean tumor dose (TD), and nontumoral liver dose (NTLD) by MAA and scout90Y were compared with those by Rx90Y. Bland-Altman plots compared the level of agreement between the TNR and LSF of scout90Y and MAA with that of Rx90Y. The safety of scout90Y was evaluated by examining the discrepancy in extrahepatic activity between MAA and scout90Y. ResultsThirty patients were treated using 19 segmental and 14 nonsegmental (ie, 2 contiguous segments or nonsegmental) therapies. MAA had weak LSF, moderate TNR, and moderate TD linear correlation with Rx90Y. Scout90Y had a moderate LSF, strong TNR, strong TD, and very strong NTLD in correlation with those of Rx90Y. Furthermore, the TNR and LSF of scout90Y had a stronger agreement with those of Rx90Y than with those of MAA. In the nonsegmental subgroup, MAA had no significant correlation with the TD and NTLD of Rx90Y, whereas scout90Y had a very strong correlation with both of these factors. In the segmental subgroup, both MAA and scout90Y had a strong linear correlation with the TD and NTLD of Rx90Y. ConclusionsCompared with MAA, scout90Y is a more accurate surrogate for Rx90Y biodistribution for nonsegmental therapies.

Abstract No. 200 Correlation between tumor-to-normal ratio in pre-treatment MRI and technetium-99 macroaggregated albumin in patients with hepatocellular carcinoma treated with yttrium-90

To quantify the relationship between tumor-to-normal ratio (TNR) attained from the pre-treatment multi-phase liver MRI compared with that from planning technetium-99m macroaggregated albumin (MAA) SPECT/CT in patients with hepatocellular carcinoma (HCC) undergoing Yttrium-90 radioembolization (Y-90-RE) treatment planning

Fluorescence Imaging-Guided Identification of Thymic Masses Using Low-Dose Indocyanine Green.

Indocyanine green (ICG) fluorescence imaging has been used to detect many types of tumors during surgery; however, there are few studies on thymic masses and the dose and time of ICG injection have not been optimized. We aimed to evaluate the optimal ICG injection dose and timing for detecting thymic masses during surgery. Forty-nine consecutive patients diagnosed with thymic masses on preoperative computed tomography (CT) and scheduled to undergo thymic cystectomy or thymectomy were included. Patients were administered 1, 2, or 5mg/kg of ICG at different times. Thymic masses were observed during and after surgery using a near-infrared fluorescence imaging system, and the fluorescence signal tumor-to-normal ratio (TNR) was analyzed. Among the 49 patients, 14 patients with thymic cysts showed negative fluorescence signals, 33 patients with thymoma or thymic carcinoma showed positive fluorescence signals, and 2 patients showed insufficient fluorescence signals. The diagnosis of thymic masses based on CT was correct in 32 (65%) of 49 cases; however, the differential diagnosis of thymic masses based on NIR signals was correct in 47 of 49 cases (96%), including 14 cases of thymic cysts (100%) and 33 cases of thymomas or thymic carcinomas (94%). In addition, TNR was not affected by the time or dose of ICG injection, histological type, stage, or tumor size. Low-dose intravenous injection of ICG at flexible time can detect thymic tumors. In addition, thymic cysts can be distinguished from thymomas or thymic carcinomas during surgery by the absence of ICG fluorescence signals.

Near-infrared fluorescent imaging with indocyanine green in rabbit and patient specimens of esophageal cancer.

BackgroundWe aimed to assess the possibility of detecting esophageal cancer after intravenous injection of indocyanine green (ICG) in preclinical and clinical models.MethodsForty-five rabbits were surgically implanted with VX2 tumors into the esophageal muscular layer 2 weeks before esophagectomy. The rabbits received intravenous injection of ICG at doses of 1, 2, or 5 mg/kg at 3, 6, 12, 24, or 48 h before surgical removal of esophagus. Twelve patients scheduled to undergo esophagectomy were also enrolled, and all received 2 mg/kg of ICG intravenously at 3, 6, 12, or 24 h before surgical removal of esophagus. The fluorescence intensity was measured in all resected specimens from the rabbits and patients using a near-infrared (NIR) fluorescence imaging system after surgery.ResultsEsophageal tumors were successfully established in all rabbits, and fluorescent signals were detected in all animal and patient specimens. Tumor-to-normal ratio (TNR) analysis showed that higher doses resulted in a greater TNR. Injection of at least 2 mg/kg of ICG was required for clear visualization of the tumor, and the TNR was highest at 12 h after injection. The TNR in patients was also highest at 12 h (P=0.0004), with 2 mg/kg of ICG. None of the patients had major complications following ICG injection.ConclusionsNIR fluorescence imaging can be used to visualize esophageal cancer after systemic injection of ICG. ICG at 2 mg/kg at 12 h is optimal for tumor detection. However, since the clinical trials were conducted in a small number of patients, further studies are needed in larger populations.

Hypoxia and glucose metabolism assessed by FMISO and FDG PET for predicting IDH1 mutation and 1p/19q codeletion status in newly diagnosed malignant gliomas

BackgroundTumor hypoxia and glycolysis have been recognized as determinant factors characterizing tumor aggressiveness in malignant gliomas. To clarify in vivo hypoxia and glucose metabolism in relation to isocitrate dehydrogenase (IDH) mutation and chromosome 1p and 19q (1p/19q) codeletion status, we retrospectively analyzed hypoxia as assessed by positron emission tomography (PET) with [18F]-fluoromisonidazole (FMISO) and glucose metabolism as assessed by PET with [18F]-fluoro-2-deoxy-d-glucose (FDG) in newly diagnosed malignant gliomas.MethodsIn total, 87 patients with newly diagnosed supratentorial malignant (WHO grade III and IV) gliomas were enrolled in this study. They underwent PET studies with FMISO and FDG before surgery. The molecular features and histopathological diagnoses based on the 2016 WHO classification were determined using surgical specimens. Maximal tumor-to-normal ratio (TNR) was calculated for FDG PET, and maximal tumor-to-blood SUV ratio (TBR) was calculated for FMISO PET. The PET uptake values in relation to IDH mutation and 1p/19q codeletion status were statistically analyzed.ResultsIn all tumors and malignant astrocytomas, the median FMISO TBR in IDH-wildtype tumors was significantly higher than that in IDH-mutant tumors (P < 0.001 and P < 0.01, respectively). In receiver operating characteristic (ROC) analysis, the area under the curve showed that the sensitivity for the discrimination was moderate (0.7–0.8) and the specificity was low (0.65–0.68). In the same population, the median FDG TNR in IDH-wildtype tumors tended to be higher than that in IDH-mutant tumors, but the difference was not statistically significant. In WHO grade III anaplastic astrocytomas, there were no significant differences in median FMISO TBR or FDG TNR between IDH-mutant and IDH-wildtype tumors. In IDH-mutant WHO grade III anaplastic gliomas, there were no significant differences in median FMISO TBR or FDG TNR between anaplastic astrocytomas and anaplastic oligodendrogliomas.ConclusionsTumor hypoxia as assessed by FMISO PET was informative for prediction of the IDH mutation status in newly diagnosed malignant gliomas. However, the accuracy of the discrimination was not satisfactory for clinical application. On the other hand, glucose metabolism as assessed by FDG PET could not differentiate the IDH-mutant status. Moreover, PET studies using FMISO and FDG could not predict IDH mutation and 1p/19q codeletion status in WHO grade III tumors.

BIMG-06. RESPONSE ASSESSMENT OF BEVACIZUMAB THERAPY FOR GLIOBLASTOMA BY USING MULTIPLE PET TRACERS

OBJECTIVEUse of the positron emission tomography (PET), such as 18F-fluorodeoxyglucose (FDG), 11C-Methionine (MET), 18F- Fluorothymidine (FLT), and 18F-Fluoromisonidazole (FMISO), is expected to lead the way for novel applications aimed at achieving efficient malignancy grading and treatment of gliomas. The aim of this study was to assess FDG, MET, FLT, and FMISO PET studies to evaluate the biological effects induced by bevacizumab (BEV) therapy in glioblastoma patients.METHODSSeventy-one patients with glioblastoma were treated biweekly with BEV from July 2013 to November 2020. FDG, MET, FLT, and FMISO PET scans were obtained at baseline and at follow-up (4 weeks after treatment onset). Measures of FDG, MET, FLT, and FMISO avidity were recorded; the measures were SUVmax, metabolic tumor volume (MTV; volume of tumor with SUV>42% of SUVmax), SUVmean (within the MTV), tumor-to-normal ratio (TNR), tumor-to blood ratio (TBR), and total lesion avidity (TLA; calculated as MTV x SUVmean). The prognostic analysis was performed in relation to the response assessment by multiple PET tracers using progression-free survival (PFS) and overall survival (OS).RESULTSUnder the assessment of the Cox proportional hazard model, increased changes of FDG SUVmax, MET TLA at follow-up, FLT TLA at follow up, increased changes of FLT TLA, increased changes of FMISO TBR and FMISO MTV were significant prognostic factor of PFS. Increase changes of FDG TLA and FLT TLA and increased changes of FMISO TBR were significant prognostic factor of OS.CONCLUSIONIncreased changes in FLT TLA and FMISO-PET after BEV therapy may be a useful biomarker for predicting PFS and OS in glioblastoma.

Tumor-to-Normal Ratio Relationship between Planning Technetium-99 Macroaggregated Albumin and Posttherapy Yttrium-90 Bremsstrahlung SPECT/CT

PurposeTo quantify the relationship of the tumor-to-normal ratio (TNR) attained from the technetium-99m macroaggregated albumin (MAA) and posttreatment yttrium-90 bremsstrahlung (Y90-Brem) single-photon emission computerized tomography (SPECT)/computer tomography (CT) studies in patients with hepatocellular carcinoma (HCC) treated with glass microspheres. Materials and MethodsRetrospectively, a total of 190 consecutive patients with HCC who underwent 204 MAA and Y90-Brem SPECT/CT for glass microsphere Y90 radiation segmentectomy (Y90-RS) or lobar treatment (Y90-RLT) between 2013 and 2018 were included. Semi-automated regions-of-interests were drawn around the targeted tumor and nontumoral liver tissue on the SPECT/CT studies. TNR values from MAA and Y90-Brem SPECT/CT were compared using paired t-tests, Pearson correlation, and median with interquartile ranges (IQR). ResultsThe mean TNR for MAA and Y90-Brem SPECT/CT was 2.96 ± 1.86 (median, 2.64; IQR, 2.50) and 2.29 ± 1.10 (median, 2.06; IQR, 1.05), respectively (P < .0001). The mean Y90-RLT TNR was 2.88 ± 1.67 (median, 2.59; IQR, 0.83) and 2.17 ± 0.89 (median, 1.98; IQR, 0.81) for MAA and Y90-Brem SPECT/CT, respectively (P < .0001). The mean Y90-RS TNR was 3.02 ± 2.01 (median, 2.87; IQR, 3.01) and 2.39 ± 1.25 (median, 2.11; IQR, 1.28) for MAA and Y90-Brem SPECT/CT, respectively (P = .0003). TNR attained from MAA and Y90 SPECT/CT studies showed a moderate correlation in a positive linear fashion for the overall (r = 0.54; P < .001), Y90-RLT (r = 0.66, P < .001), and Y90-RS cohorts (r = 0.48, P < .001). ConclusionsThe TNR attained from Y90-Brem SPECT/CT is often underestimated, positively correlated, and less variable than that attained from MAA SPECT/CT.

Tuning the Brightness and Photostability of Organic Dots for Multivalent Targeted Cancer Imaging and Surgery.

Specific labeling of biomarkers with bright and high photostable fluorophores is vital in fluorescent imaging applications. Here, we report a general strategy to develop single-molecule dendritic nanodots with finely tunable optical properties for in vivo fluorescent imaging. The well-defined nanodots are based on the divergent growth of biodegradable polylysine dendrimers with a fluorophore as the core. By tuning the size and surface chemistry, we obtained fluorescent nanodots with excellent brightness and photostability, favorable pharmacokinetics, and multivalent tumor-targeting capability. The nanodots provided robust, stable, long-lasting, and specific fluorescence enhancement in tumor tissue with an in situ tumor-to-normal ratio (TNR) of ∼3 and lasting over 5 days and an ex vivo TNR up to ∼17, holding considerable promise for cancer imaging and image-guided surgery. This strategy significantly improves the in vivo performance of fluorophores and can be applied to other modality imaging probes.

Influence of the scan time point when assessing hypoxia in 18F-fluoromisonidazole PET: 2 vs. 4h.

18F-fluoromisonidazole (18F-FMISO) is the most widely used positron emission tomography (PET) tracer for imaging tumor hypoxia. Previous reports suggested that the time from injection to the scan may affect the assessment of 18F-FMISO uptake. Herein, we directly compared the images at 2h and 4h after a single injection of 18F-FMISO. Twenty-three patients with or suspected of having a brain tumor were scanned twice at 2 and 4h following an intravenous injection of 18F-FMISO. We estimated the mean standardized uptake value (SUV) of the gray matter and white matter and the gray-to-white matter ratio in the background brain tissue from the two scans. We also performed a semi-quantitative analysis using the SUVmax and maximum tumor-to-normal ratio (TNR) for the tumor. At 2h, the SUVmean of gray matter was significantly higher than that of white matter (median 1.23, interquartile range (IQR) 1.10-1.32 vs. 1.04, IQR 0.95-1.16, p < 0.0001), whereas at 4h, it significantly decreased to approach that of the white matter (1.10, IQR 1.00-1.23 vs. 1.02, IQR 0.93-1.13, p = NS). The gray-to-white matter ratio thus significantly declined from 1.17 (IQR 1.14-1.19) to 1.09 (IQR 1.07-1.10) (p < 0.0001). All 7 patients with glioblastoma showed significant increases in the SUVmax (2.20, IQR 1.67-3.32 at 2h vs. 2.65, IQR 1.74-4.41 at 4h, p = 0.016) and the TNR (1.75, IQR 1.40-2.38 at 2h vs. 2.34, IQR 1.67-3.60 at 4h, p = 0.016). In the assessment of hypoxic tumors, 18F-FMISO PET for hypoxia imaging should be obtained at 4h rather than 2h after the injection.

SURG-09. AGENTS FOR FLUORESCENCE GUIDED GLIOMA SURGERY: REVIEW OF PRECLINICAL AND CLINICAL RESULTS

Gross total resection (GTR) of gliomas is associated with improved survival. Fluorescence guided surgery (FGS) is a technique used to enhance visualization of tumor margins in order to increase the extent of tumor resection. The aim of this paper was to systematically review all pre-clinical and clinical studies that investigated fluorescent agents for application in FGS of gliomas. We searched Pubmed and Embase databases for all potentially relevant studies up to march 2016. We compared the usefulness of the fluorescent agents by assessing the following outcomes: GTR rate, overall and progression free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio (TNR) of fluorescent signal and incidence of adverse events. The search strategy resulted in 1696 articles that were screened by titles and abstracts. After full-text screening, 98 articles fulfilled the inclusion criteria. Clinically, forty-four studies, including two randomized control trails (RCTs), tested 5-ALA, eleven studies tested fluorescein, two studies tested indocyanine green, one study tested hypericin and five studies tested endogenous fluorophores in FGS of gliomas. Twenty-four other fluorescent agents were identified that have only been tested pre-clinically. Overall, 5-ALA and fluorescein offer the best improvement in GTR and survival of all clinically tested agents. Molecular targeting agents (e.g. fluorophore labeled anti-EGFR antibodies) offer promising results on histological accuracy but are still in the pre-clinical phase. For FGS in glioma surgery, 5-ALA and fluorescein offer the best improvement in GTR rate and survival. However, several pre-clinically tested agents may be interesting future alternatives.