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Systemic immunotherapies have led to tremendous progress across the cancer landscape. However, several challenges exist, potentially limiting their efficacy in the treatment of solid tumors. Direct intratumoral injection can increase the therapeutic index of immunotherapies while overcoming many of the barriers associated with systemic administration, including limited bioavailability to tumors and potential systemic safety concerns. However, challenges remain, including the lack of standardized approaches for administration, issues relating to effective drug delivery, logistical hurdles, and safety concerns specific to this mode of administration. This article reviews the biologic rationale for the localized injection of immunotherapeutic agents into tumors. It also addresses the existing limitations and practical considerations for safe and effective implementation and provide recommendations for optimizing logistics and treatment workflows. It also highlights the critical role that radiologists, interventional radiologists, and medical physicists play in intratumoral immunotherapy with respect to target selection, image-guided administration, and response assessment., (© RSNA, 2024.)

Purpose: To examine the natural history of splenic artery aneurysms (SAAs) at a single institution and assess the effect of patient factors and aneurysm characteristics on aneurysm growth., Materials and Methods: This single-center retrospective study included patients with SAAs who underwent serial imaging over 30 years (1990-2020). Data regarding patient demographics and aneurysm characteristics were collected. The variables contributing to aneurysm growth were assessed using nonparametric tests for continuous variables and chi-square test for categorical variables. Multivariable linear regression was performed using aneurysm growth rate as a continuous dependent variable., Results: A total of 132 patients were included in this study. The median maximum diameter of the SAAs was 15.8 mm (range, 4.0-50.0 mm). Growth over time was observed in 39% of the aneurysms, whereas the remaining 61% were stable in size. Of aneurysms that increased in size, the median aneurysm growth rate was 0.60 mm/y (range, 0.03-5.00 mm/y). Maximum aneurysm diameter of >2 cm and the presence of >50% mural thrombus were significant positive predictors for aneurysm growth (P = .020 and P = .022, respectively). Greater than 50% rim calcification was a significant negative predictor for aneurysm growth (P = .009) in multivariate analysis., Conclusions: A larger baseline SAA size, presence of mural thrombus, and lack of rim calcification are associated with increased aneurysm growth rate., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Percutaneous cryoablation is a common clinical therapy for metastatic and primary cancer. There are rare clinical reports of cryoablation inducing regression of distant metastases, known as the "abscopal" effect. Intratumoral immunoadjuvants may be able to augment the abscopal rate of cryoablation, but existing intratumoral therapies suffer from the need for frequent injections and inability to confirm target delivery, leading to poor clinical trial outcomes. To address these shortcomings, an injectable thermoresponsive gel-based controlled release formulation is developed for the FDA-approved Toll-like-receptor 7 (TLR7) agonist imiquimod ("Imigel") that forms a tumor-resident depot upon injection and contains a contrast agent for visualization under computed tomography (CT). The poly-lactic-co-glycolic acid-polyethylene glycol-poly-lactic-co-glycolic acid (PLGA-PEG-PLGA)-based amphiphilic copolymer gel's underlying micellar nature enables high drug concentration and a logarithmic release profile that is additive with the neo-antigen release from cryoablation, requiring only a single injection. Rheological testing demonstrated the thermoresponsive increase in viscosity at body temperature and radio-opacity via microCT. Its ability to significantly augment the abscopal rate of cryoablation is demonstrated in otherwise immunotherapy resistant metastatic tumors in two aggressive colorectal and breast cancer dual tumor models with an all or nothing response, responders generally demonstrating complete regression of bilateral tumors in 90-day survival studies., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Thermal ablation modalities (cryoablation, radiofrequency ablation, and microwave ablation) have long been noted to occasionally induce a systemic antitumoral response. With the widespread use of checkpoint inhibitors, there is a significant interest in whether thermal ablation can promote immune system tumor recognition and increase checkpoint inhibitor response rates. In this review, we examine the current state of preclinical and clinical evidence examining the combination of checkpoint inhibitor therapies and thermal ablation modalities as well as discuss remaining the unanswered questions and directions for future research., (Copyright © 2023 SIR. Published by Elsevier Inc. All rights reserved.)

Background: The aim was to investigate the role of pre-ablation tumor radiomics in predicting pathologic treatment response in patients with early-stage hepatocellular carcinoma (HCC) who underwent liver transplant., Methods: Using data collected from 2005-2015, we included adult patients who (1) had a contrast-enhanced MRI within 3 months prior to ablation therapy and (2) underwent liver transplantation. Demographics were obtained for each patient. The treated hepatic tumor volume was manually segmented on the arterial phase T1 MRI images. A vector with 112 radiomic features (shape, first-order, and texture) was extracted from each tumor. Feature selection was employed through minimum redundancy and maximum relevance using a training set. A random forest model was developed based on top radiomic and demographic features. Model performance was evaluated by ROC analysis. SHAP plots were constructed in order to visualize feature importance in model predictions., Results: Ninety-seven patients (117 tumors, 31 (32%) microwave ablation, 66 (68%) radiofrequency ablation) were included. The mean model for end-stage liver disease (MELD) score was 10.5 ± 3. The mean follow-up time was 336.2 ± 179 days. Complete response on pathology review was achieved in 62% of patients at the time of transplant. Incomplete pathologic response was associated with four features: two first-order and two GLRM features using univariate logistic regression analysis ( p < 0.05). The random forest model included two radiomic features (diagnostics maximum and first-order maximum) and four clinical features (pre-procedure creatinine, pre-procedure albumin, age, and gender) achieving an AUC of 0.83, a sensitivity of 82%, a specificity of 67%, a PPV of 69%, and an NPV of 80%., Conclusions: Pre-ablation MRI radiomics could act as a valuable imaging biomarker for the prediction of tumor pathologic response in patients with HCC.

Purpose: During catheter directed intraarterial therapy for liver lesions, challenging hepatic vascular anatomy can sometimes prevent selective administration of treatment delivery to liver tumors leading to increased toxicity to normal liver parenchyma. The objective of this study is to describe a variation of the double balloon technique that isolates the feeding artery to liver tumors proximally and distally to provide treatment delivery in lesions that cannot be otherwise selected., Materials and Methods: An IRB-approved retrospective review of 7 patients who had undergone either radioembolization, chemoembolization, or bland embolization and the double balloon technique was employed. The devices used for flow augmentation were two 2.1 French balloon microcatheters (Sniper™, Embolx). One balloon was inflated distal to target vessel and the second was inflated proximal to protect from reflux., Results: DEB-TACE was performed in 3 cases, 90 Y was performed in 4, and bland embolization was performed in the last patient. There were no adverse effects from the procedure or clinically evident effects from non-target embolization. Mean follow up time was 286.4 +/- 200.1 days. Six of the 7 patients are alive. One patient passed away on post-procedure day 121 from septic shock unrelated to the procedure. One patient was bridged to transplant with an additional TACE of a separate lesion., Conclusion: Double-balloon technique for patients undergoing 90 Y or chemoembolization is a safe adjunctive technique for super selective treatment of hepatic lesions where direct selection via catheter is not feasible. This may increase the range of lesions that can be both safely and effectively treated by catheter directed therapies., (© 2023. The Author(s).)

Immunotherapy has revolutionized the contemporary oncology landscape, with durable responses possible across a range of cancer types. However, the majority of cancer patients do not respond to immunotherapy due to numerous immunosuppressive barriers. Efforts to overcome these barriers and increase systemic immunotherapy efficacy have sparked interest in the local intratumoral delivery of immune stimulants to activate the local immune response and subsequently drive systemic tumor immunity. While clinical evaluation of many therapeutic candidates is ongoing, development is hindered by a lack of imaging confirmation of local delivery, insufficient intratumoral drug distribution, and a need for repeated injections. The use of polymeric drug delivery systems, which have been widely used as platforms for both image guidance and controlled drug release, holds promise for delivery of intratumoral immunoadjuvants and the development of an in situ cancer vaccine for patients with metastatic cancer. In this review, we explore the current state of the field for intratumoral delivery and methods for optimizing controlled drug release, as well as practical considerations for drug delivery design to be optimized for clinical image guided delivery particularly by CT and ultrasound., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Although immune checkpoint inhibitors (ICI) have revolutionized cancer management, patient response can be heterogeneous, and the development of ICI resistance is increasingly reported. Novel treatment strategies are necessary not only to expand the use of ICI to previously unresponsive tumor types but also to overcome resistance. Targeted radionuclide therapy may synergize well with ICIs since it can promote a pro-inflammatory tumor microenvironment. We investigated the use of a granzyme B targeted peptide (GZP) as a cancer theranostic agent, radiolabeled with 68 Ga ( 68 Ga-GZP) as a PET imaging agent and radiolabeled with 90 Y ( 90 Y-GZP) as a targeted radionuclide therapy agent for combinational therapy with ICI in murine models of colon cancer. Our results demonstrate that GZP increasingly accumulates in tumor tissue after ICI and that the combination of ICI with 90 Y-GZP promotes a dose-dependent response, achieving curative response in some settings and increased overall survival.

Objective . To evaluate the pre-treatment and post-treatment imaging-based dosimetry of patients treated with 90Y-microspheres, including accurate estimations of dose to tumor, healthy liver and lung. To do so, the Monte Carlo (MC) TOPAS platform is in this work extended towards its utilization in radionuclide therapy. Approach . Five patients treated at the Massachusetts General Hospital were selected for this study. All patients had data for both pre-treatment SPECT-CT imaging using 99mTc-MAA as a surrogate of the 90Y-microspheres treatment and SPECT-CT imaging immediately after the 90Y activity administration. Pre- and post-treatment doses were computed with TOPAS using the SPECT images to localize the source positions and the CT images to account for tissue inhomoegeneities. We compared our results with analytical calculations following the voxel-based MIRD scheme. Main results . TOPAS results largely agreed with the MIRD-based calculations in soft tissue regions: the average difference in mean dose to the liver was 0.14 Gy GBq -1 (2.6%). However, dose distributions in the lung differed considerably: absolute differences in mean doses to the lung ranged from 1.2 to 6.3 Gy GBq -1 and relative differences from 153% to 231%. We also found large differences in the intra-hepatic dose distributions between pre- and post-treatment imaging, but only limited differences in the pulmonary dose. Significance . Doses to lung were found to be higher using TOPAS with respect to analytical calculations which may significantly underestimate dose to the lung, suggesting the use of MC methods for 90Y dosimetry. According to our results, pre-treatment imaging may still be representative of dose to lung in these treatments., (© 2021 Institute of Physics and Engineering in Medicine.)

Competing Interests: EW-K reports research funding (to their institution) from Boston Scientific and Sirtex, and for acting on a scientific advisory board from Cytosite Bio; consulting fees from Sirtex, Boston Scientific, and Embolx; payment or honoraria for lectures, presentations, or speakers bureau, from Sirtex and Embolx; patents pending, issued, or planned for Cytosite; participation on data safety monitoring boards or advisory boards for Eisai and Replimmune; stock or stock options with Embolx and Cytosite; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Boston Scientific. LG reports research funding (to their institution) from Adaptimmune, Bayer, Merck, Macrogenics, Genentech, Novartis, Incyte, Loxo Oncology, Relay Therapeutics, QED, Taiho Oncology, Leap Therapeutics, Bristol Myers Squibb, Nucana, and Servier and for acting on scientific advisory committees from Alentis Therapeutics AG, Basilea, H3Biomedicine, Incyte Corporation, QED Therapeutics, Sirtex Medical Ltd, and Taiho Oncology; consulting fees from Alentis Therapeutics, Genentech, Exelixis, Incyte Corporation, QED Therapeutics, The Servier Groups, Sirtex Medical Ltd, Taiho Oncology Inc; Black Diamond, and Basilea; and participation on data safety monitoring boards or advisory boards for AstraZeneca.

Purpose: Standard therapy for HER2+ breast cancers includes HER2 inhibition. While HER2 inhibitors have significantly improved therapeutic outcomes, many patients remain resistant to therapy. An important intrinsic resistance mechanism to HER2 inhibition in some breast cancers is dynamic upregulation of HER3. Increase in HER3 expression that occurs in response to HER2 inhibition allows for continued growth signaling through HER2/HER3 heterodimers, promoting tumor escape. We hypothesized that a non-invasive method to image changes in HER3 expression would be valuable to identify those breast cancers that dynamically upregulate HER3 in response to HER2 inhibition. We further hypothesized that this imaging method could identify those tumors that would benefit by additional HER3 knockdown., Procedures: In a panel of HER2+ breast cancer cell lines treated with the HER2 inhibitor lapatinib, we evaluate changes in HER3 expression and viability. Mouse HER2+ breast cancer models treated with lapatinib were imaged with a peptide-based HER3-specific PET imaging agent [ 68 Ga]HER3P1 to assess for dynamic changes in tumoral HER3 expression and uptake confirmed by biodistribution. Subsequently, HER2+ cell lines were treated with the HER2 inhibitor lapatinib as well HER3-specific siRNA to assess for changes in viability and correlate with HER3 expression upregulation. For all statistical comparisons, P<0.05 was considered statistically significant., Results: Lapatinib treatment of a panel of HER2+ breast cancer cell lines increased HER3 expression in the lapatinib-resistant cell line MDA-MB 453 but not the lapatinib-resistant cell-line HCC-1569. Evaluation of [ 68 Ga]HER3P1 uptake in mice implanted with the HER2+ breast cancer cell lines MDA-MB453 or HCC-1569 prior to and after treatment with lapatinib demonstrated a significant increase in MDA-MB453 tumors only, consistent with in vitro findings. The additional knockdown of HER3 increased therapeutic efficacy of lapatinib only in MDA-MB453 cells, but not in HCC-1569 cells., Conclusion: HER3 PET imaging can be used to visualize dynamic changes in HER3 expression that occur in HER2+ breast cancers with HER2 inhibitor treatment and identify those likely to benefit by the addition of combination HER3 and HER2 inhibition., (© 2021. World Molecular Imaging Society.)

Purpose: To determine the pathologic response of computed tomography-guided percutaneous microwave ablation as bridging therapy for patients with hepatocellular carcinoma awaiting liver transplant, and its subsequent effect on survival., Materials and Methods: A single-center retrospective analysis was conducted on 62 patients (M:F = 50:12) with mean age of 59.6 years ± 7.2 months (SD). Sixty-four total MWA procedures were performed for hepatocellular carcinomas within Milan criteria as bridging therapy to subsequent orthotopic liver transplant between August 2014 and September 2018. The pathology reports of the explanted livers were reviewed to assess for residual disease. Residual disease was categorized as complete or incomplete necrosis. Patient demographics, tumor/procedural characteristics, and laboratory values were evaluated. Survival from time of ablation and time of transplantation were recorded and compared between cohorts using log rank tests., Results: The mean tumor size was 2.4 cm ± 0.7 cm (SD), (range = 1-4.6 cm). 32 (50%) cases required hydrodissection. Histopathologic necrosis was seen in 66% of cases at time of liver transplantation. Median time to liver transplant post-MWA was 12.6 months. [IQR = 8.6-14.8 months]. The median survival from ablation was 60.8 months [IQR = 45.5-73.7 months], and the median survival from transplant was 49.3 months [IQR = 33.7-60.1 months]. There was no significant difference in survival for patients with complete versus incomplete necrosis from ablation or liver transplant (p = 0.49, p = 0.46, respectively)., Conclusions: Computed tomography-guided percutaneous microwave ablation is an effective bridge to orthotopic liver transplantation for patients with hepatocellular carcinoma., Cebm Level of Evidence: Level 3, non-randomized controlled cohort study/follow-up study., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Purpose: Cancer immunotherapy has markedly improved the prognosis of patients with a broad variety of malignancies. However, benefits are weighed against unique toxicities, with immune-related adverse events (irAE) that are frequent and potentially life-threatening. The diagnosis and management of these events are challenging due to heterogeneity of timing onset, multiplicity of affected organs, and lack of non-invasive monitoring techniques. We demonstrate the use of a granzyme B-targeted PET imaging agent (GZP) for irAE identification in a murine model., Experimental Design: We generated a model of immunotherapy-induced adverse events in Foxp3-DTR-GFP mice bearing MC38 tumors. GZP PET imaging was performed to evaluate organs non-invasively. We validated imaging with ex vivo analysis, correlating the establishment of these events with the presence of immune infiltrates and granzyme B upregulation in tissue. To demonstrate the clinical relevance of our findings, the presence of granzyme B was identified through immunofluorescence staining in tissue samples of patients with confirmed checkpoint inhibitor-associated adverse events., Results: GZP PET imaging revealed differential uptake in organs affected by irAEs, such as colon, spleen, and kidney, which significantly diminished after administration of the immunosuppressor dexamethasone. The presence of granzyme B and immune infiltrates were confirmed histologically and correlated with significantly higher uptake in PET imaging. The presence of granzyme B was also confirmed in samples from patients that presented with clinical irAEs., Conclusions: We demonstrate an interconnection between the establishment of irAEs and granzyme B presence and, for the first time, the visualization of those events through PET imaging., (©2021 American Association for Cancer Research.)

Purpose: To evaluate whether the recalculation of lung shunt fraction (LSF) is necessary prior to next-stage or same lobe repeat radioembolization., Materials and Methods: Retrospective chart review was performed for patients who underwent radioembolization between February 2008 and December 2018. Eighty of 312 patients had repeat mapping angiograms and LSF calculations. A total of 160 LSF calculations were made using planar imaging (155, [97%]) and single-photon emission computed tomography (5 [3%]) technetium-99m macroaggregated albumin hepatic arterial injection imaging. The mean patient age was 61.8 years ± 12.7; 69 (86%) patients had metastatic disease and 11 (14%) had hepatocellular carcinoma., Results: Patients had a median LSF of 5% (interquartile range [IQR] 3%-9%) with a median absolute difference of 1.25 (IQR 0.65-3.4) and a median of 76 days (IQR 42.5-120 days) between repeat LSF calculations. There was a median change in LSF of 0.2% between mapping studies (P = .11). There was no statistical significance between the repeat LSFs regardless of the arterial distribution (P = .79) or between tumor types (P = .75). No patients exceeded lung dose limits using actual or predicted prescribed dose amounts. The actual median lung dose was 2.6 Gy (IQR 1.8-4.4 Gy, maximum = 20.5) for the first radioembolization and 2.0 Gy (IQR 1.3-3.7 Gy, maximum = 10.1) for the second radioembolization., Conclusions: No significant difference in LSF was identified between different time points and arterial distributions within the same patient undergoing repeat radioembolization. In patients who receive well under 30-Gy lung dose for the initial treatment and a 50-Gy cumulative lung dose, repeat radioembolization treatments in the same patient may not require a repeat LSF calculation., (Copyright © 2020 SIR. Published by Elsevier Inc. All rights reserved.)

Treatment options in locally advanced hepatocellular carcinoma (HCC) have evolved considerably over the past few years with the recent approval of multiple systemic therapies and significant advances in locoregional therapy. Given the poor prognosis for patients with unresectable HCC, there is significant interest in rationally designed combination therapies. This article reviews the treatment options available to patients with locally advanced HCC and discusses the rationale, ongoing trials, and future prospects for combining locoregional and systemic therapy in both the definitive and neoadjuvant settings.

Background: Cancer immunotherapy research is expanding to include a more robust understanding of the mechanisms of treatment response and resistance. Identification of drivers of pro-tumor and anti-tumor immunity during treatment offers new strategies for effective alternative or combination immunotherapies. Currently, tissue or blood samples are collected and analyzed, then dichotomized based on clinical end points that may occur months or years after tissue is collected. While overall survival is ultimately the desired clinical outcome, this dichotomization fails to incorporate the nuances that may occur during an anti-tumor response. By failing to directly measure immune activation at the time of sampling, tumors may be misclassified and potentially obscure important biological information. Non-invasive techniques, such as positron emission tomography (PET), allow for global and quantitative measurements of cancer specific processes and are widely used clinically to help manage disease., Methods: We have previously developed a novel PET agent that can non-invasively quantify granzyme B release in tumors and have demonstrated its ability to predict response to checkpoint inhibitor therapy in multiple murine models of cancer. Here, we used the quantitative measurement of granzyme B release as a direct and time-matched marker of immune cell activation in order to determine immune cell types and cytokines that correlate with effective checkpoint inhibitor therapy in both tumors and tumor-draining lymph nodes., Results: Through PET imaging, we were able to successfully distinguish distinct microenvironments, based on tumor type, which influenced immune cell subpopulations and cytokine release. Although each tumor was marked by functionally distinct pathways of immune cell activation and inflammation, they also shared commonalities that ultimately resulted in granzyme B release and tumor killing., Conclusions: These results suggest that discrete tumor immune microenvironments can be identified in both responsive and non-responsive tumors and offers strategic targets for intervention to overcome checkpoint inhibitor resistance., Competing Interests: Competing interests: BL, EWK and UM are consultants and shareholders of Cytosite Biopharma., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Y90 radioembolization is an alternative to transarterial chemoembolization for the intra-arterial treatment of hepatocellular carcinoma (HCC). However, the optimal treatment of HCC varies by tumor stage, underlying liver function and functional status, and local expertise. Therefore, the appropriate selection of patients for Y90 radioembolization is of paramount importance for optimal outcomes. Data on the role of Y90 radioembolization for HCC are most robust in the palliative treatment of inoperable, liver-confined disease. However, data are also present on the role of Y90 radioembolization as a bridge to or to downstage patients for transplant. Outcomes for radiation segmentectomy (ablative radiation doses) with curative intent or prior to resection are also discussed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the feasibility of a same-day yttrium-90 ( 90 Y) radioembolization protocol with resin microspheres (including pretreatment angiography, lung shunt fraction [LSF] determination, and radioembolization) for the treatment of hepatocellular carcinoma (HCC) and liver metastases., Materials and Methods: All same-day radioembolization procedures performed over 1 y (February 2017 to January 2018) were included in this single-institutional retrospective analysis, in which 34 procedures were performed in 26 patients (median age, 63 y; 13 women), 19 with liver metastases and 7 with HCC. Yttrium-90 treatment activities were calculated by body surface area method. Tumor imaging response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for liver metastases and modified RECIST for HCC. Clinical side effects and adverse events were graded per Common Terminology Criteria for Adverse Events version 4.0., Results: All planned cases were technically successful, and no cases were canceled for elevated LSF or vascular anatomic reasons. Pretreatment angiography modified the planned 90 Y treatment activity in 1 case in which vascular anatomy required a lobar-dose split into 2 for segmental infusions. In 18% of cases, patients were briefly admitted after the procedure for observation or symptom management. Imaging evaluation of initial efficacy at 1 month demonstrated partial response in 25% and stable disease in 67% of patients with liver metastases and partial/complete response in 43% and stable disease in 14% of patients with HCC. Grade ≥ 3 adverse events occurred in 6% of cases, with no systemic therapy-limiting toxicities. The mean total procedure time was 4.2 hours., Conclusions: A same-day 90 Y radioembolization protocol with resin microspheres is feasible in select patients, which can expedite cancer therapy., (Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: The lack of a timely and reliable measure of response to cancer immunotherapy has confounded understanding of mechanisms of resistance and subsequent therapeutic advancement. We hypothesized that PET imaging of granzyme B using a targeted peptide, GZP, could be utilized for early response assessment across many checkpoint inhibitor combinations, and that GZP uptake could be compared between therapeutic regimens and dosing schedules as an early biomarker of relative efficacy., Experimental Design: Two models, MC38 and CT26, were treated with a series of checkpoint inhibitors. GZP PET imaging was performed to assess tumoral GZP uptake, and tumor volume changes were subsequently monitored to determine response. The average GZP PET uptake and response of each treatment group were correlated to evaluate the utility of GZP PET for comparing therapeutic efficacy., Results: In both tumor models, GZP PET imaging was highly accurate for predicting response, with 93% sensitivity and 94% negative predictive value. Mean tumoral GZP signal intensity of treatment groups linearly correlated with percent response across all therapies and schedules. Moreover, GZP PET correctly predicted that sequential dose scheduling of PD-1 and CTLA-4 targeted therapies demonstrates comparative efficacy to concurrent administration., Conclusions: Granzyme B quantification is a highly sensitive and specific early measure of therapeutic efficacy for checkpoint inhibitor regimens. This work provides evidence that GZP PET imaging may be useful for rapid assessment of therapeutic efficacy in the context of clinical trials for both novel drugs as well as dosing regimens., (©2018 American Association for Cancer Research.)

Nivolumab has recently received approval by the Food and Drug Administration for treatment of advanced hepatocellular carcinoma (HCC) in patients previously treated with sorafenib. Nivolumabs' overall response rate of 20% (El-Khoueiry et al. in Lancet 389:2492-2502, 2017) is a step forward for these patients, but there is significant room for improvement. We describe a case of combining Y-90 radioembolization with nivolumab for treatment of angioinvasive HCC, which successfully bridged patient to partial hepatectomy. Surgical pathology showed negative margins with complete pathological response. With the introduction of immunotherapy for HCC, combining Y-90 radioembolization with immunotherapy may enhance the anti-tumoral immune response of checkpoint inhibitors.

Purpose: To assess the technical success rate, diagnostic yield, and clinical value of computed tomography (CT)-guided percutaneous needle biopsy (PNB) for retroperitoneal and pelvic lymphadenopathy., Materials and Methods: This retrospective study included 344 patients evaluated for safety and technique and 334 patients evaluated for diagnostic yield and clinical analyses. PNBs were performed with fine-needle aspiration (FNA) in 315 patients and with core biopsy in 333 patients. Follow-up analyses, including repeat biopsy, open surgery, imaging, and clinical indicators, were conducted for 94 patients who had nonspecific malignant or benign results. Diagnostic yields were calculated based on biopsy and follow-up results. Factors associated with final diagnoses were compared and modeled by multivariate analysis., Results: Technical success rate was 99.7%. Thirty-nine patients (11.3%) had minor complications. From biopsy results and follow-up analyses, final malignant diagnoses were determined for 281 patients (84.1%). Overall sensitivity, specificity, and accuracy rates of PNB were 91.5%, 100%, and 92.8%, respectively. For patients with a history of malignancy, the likelihood of nodal involvement was 84.6% and that of a new, different malignancy was 3.7%. Older age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.00-1.05), history of malignancy (OR, 3.44; 95% CI, 1.71-6.92), multiple lymph nodes (LNs; OR, 2.65; 95% CI, 1.38-5.09), and new or enlarging LNs (OR, 2.62; 95% CI, 1.25-5.48) were independent risk factors for malignancy diagnosis., Conclusions: CT-guided PNB is a safe, effective procedure that can achieve high diagnostic yields for patients with retroperitoneal and pelvic lymphadenopathy., (Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: HER3 (ERBB3) is a receptor tyrosine kinase that is implicated in treatment resistance across multiple cancers, including those of the breast, lung, and prostate. Overexpression of HER3 following targeted therapy can occur rapidly and heterogeneously both within a single lesion and across sites of metastasis, making protein quantification by biopsy highly challenging. A global, non-invasive methodology such as positron emission tomography (PET) imaging can permit serial quantification of HER3, providing a useful approach to monitor HER3 expression across the entire tumor burden both prior to and following treatment. PET imaging of HER3 expression may permit a more personalized approach to targeted therapy by allowing for detection of HER3-mediated resistance, in addition to informing clinical trial patient selection for novel therapies targeting HER3., Procedures: Phage display selection targeting the HER3 extracellular domain was performed in order to develop a peptide with optimal blood clearance and highly accurate HER3 quantification., Results: The selection converged to a consensus peptide sequence that was subsequently found to bind HER3 with an affinity of 270 ± 151 nM. The peptide, termed HER3P1, was bound with high selectivity to HER3 over other similar receptor tyrosine kinases such as EGFR and HER2. Furthermore, HER3P1 was able to distinguish between high and low HER3-expressing cells in vitro. The peptide was radiolabeled with Ga-68 and demonstrated to specifically bind HER3 by in vivo PET imaging. Uptake of [ 68 Ga]HER3P1 was highly specific for HER3-positive tumors, with tumor-to-background ratios ranging from 1.59-3.32, compared to those of HER3-negative tumors, ranging from 0.84-0.93. The uptake of [ 68 Ga]HER3P1 also demonstrated high (P < 0.001) correlation with protein expression as quantified by Western blot and confirmed by biodistribution., Conclusions: HER3P1 accurately quantifies expression of HER3 by PET imaging and has potential utility as a clinical imaging agent.

While cancer immunotherapy can produce dramatic responses, only a minority of patients respond to treatment. Reliable response biomarkers are needed to identify responders, and conventional imaging modalities have not proved adequate. Here, we provide a preclinical proof of concept for the use of granzyme B, a downstream effector of tumoral cytotoxic T cells, as an early biomarker for tumors responding to immunotherapy. We designed novel PET imaging probes for the murine and human granzyme B isoforms that specifically and quantitatively bind granzyme B. Immunotherapy-treated mice were imaged prior to therapy-induced tumor volume reduction. Imaging distinguished treated responders from nonresponders with excellent predictive ability. To assess the clinical value of a granzyme B imaging paradigm, biopsy specimens from melanoma patients on checkpoint inhibitor therapy were analyzed. A marked differential in granzyme B expression was observed between treated responders and nonresponders. Additionally, our human probe was able to specifically detect granzyme B expression in human samples, providing a clear candidate for clinical application. Overall, our results suggest granzyme B PET imaging can serve as a quantitatively useful predictive biomarker for efficacious responses to cancer immunotherapy. Cancer Res; 77(9); 2318-27. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Immune checkpoint inhibitors have made rapid advances, resulting in multiple Food and Drug Administration-approved therapeutics that have markedly improved survival. However, these benefits are limited to a minority subpopulation that achieves a response. Predicting which patients are most likely to benefit would be valuable for individual therapy optimization. T-cell markers such as CD3-by examining active recruitment of the T cells responsible for cancer-cell death-represent a more direct approach to monitoring tumor immune response than pretreatment biopsy or genetic screening. This approach could be especially effective as numerous different therapeutic strategies emerge, decreasing the need for drug-specific biomarkers and instead focusing on T-cell infiltration, which has been previously correlated with treatment response., Methods: A CD3 PET imaging agent targeting T cells was synthesized to test the role of such imaging as a predictive marker. The 89 Zr-p-isothiocyanatobenzyl-deferoxamine-CD3 PET probe was assessed in a murine tumor xenograft model of anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) immunotherapy of colon cancer., Results: Imaging on day 14 revealed 2 distinct groups of mice stratified by PET signal intensity. Although there was no significant difference in tumor volume on the day of imaging, in the high-uptake group subsequent measurements revealed significantly smaller tumors than in either the low-uptake group or the untreated controls. In contrast, there was no significant difference in the size of tumors between the low-uptake and untreated control mice., Conclusion: These findings indicate that high CD3 PET uptake in the anti-CTLA-4-treated mice correlated with subsequent reduced tumor volume and was a predictive biomarker of response., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: Inhibitors of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway hold promise for the treatment of breast cancer, but resistance to these treatments can arise via feedback loops that increase surface expression of the receptor tyrosine kinases (RTK) epidermal growth factor receptor 1 (EGFR) and human epidermal growth factor receptor 3 (HER3), leading to persistent growth pathway signaling. We developed PET probes that provide a method of imaging this response in vivo, determining which tumors may use this escape pathway while avoiding the need for repeated biopsies., Methods: Anti-EGFR-F(ab')2 and anti-HER3-F(ab')2 were generated from monoclonal antibodies by enzymatic digestion, conjugated to DOTA, and labeled with (64)Cu. A panel of breast cancer cell lines was treated with increasing concentrations of the AKT inhibitor GDC-0068 or the PI3K inhibitor GDC-0941. Pre- and posttreatment expression of EGFR and HER3 was compared using Western blot and correlated to probe accumulation with binding studies. Nude mice xenografts of HCC-70 or MDA-MB-468 were treated with either AKT inhibitor or PI3K inhibitor and imaged with either EGFR or HER3 PET probe., Results: Changes in HER3 and EGFR PET probe accumulation correlate to RTK expression change as assessed by Western blot (R(2) of 0.85-0.98). EGFR PET probe PET/CT imaging of HCC70 tumors shows an SUV of 0.32 ± 0.03 for vehicle-, 0.50 ± 0.01 for GDC-0941-, and 0.62 ± 0.01 for GDC-0068-treated tumors, respectively (P < 0.01 for both comparisons to vehicle). HER3 PET probe PET/CT imaging of MDAMB468 tumors shows an SUV of 0.35 ± 0.02 for vehicle- and 0.73 ± 0.05 for GDC-0068-treated tumors (P < 0.01)., Conclusion: Our imaging studies, using PET probes specific to EGFR and HER3, show that changes in RTK expression indicative of resistance to PI3K and AKT inhibitors can be seen within days of therapy initiation and are of sufficient magnitude as to allow reliable clinical interpretation. Noninvasive PET monitoring of these RTK feedback loops should help to rapidly assess resistance to PI3K and AKT inhibitors and guide selection of an appropriate combinatorial therapeutic regimen on an individual patient basis., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

After initial therapy and total resection of glioblastoma multiforme (GBM), 80-90% of recurrences occur at the surgical margins. Insufficient sensitivity and specificity of current imaging techniques based on non-specific vascular imaging agents lead to delay in diagnosis of residual and/or recurrent disease. A tumor-specific imaging agent for GBM may improve detection of small residual disease in the post-operative period, and improve ability to distinguish tumor recurrence from its imaging mimics that can delay diagnosis. To this end, we developed an EGFR-targeted PET probe and assessed its ability to image EGFR WT (U87) and EGFRvIII (Gli36vIII) expressing GBMs in both murine intra-cranial xenografts and in a surgical-resection model. The developed imaging probe, (64)Cu-DOTAcetuximab-F(ab´)2, binds with a Kd of 11.2 nM to EGFR expressing GBM. (64)Cu-DOTA-cetuximab-F(ab´)2 specifically localized to intra-cranial tumor with a significant difference in SUVmean between tumor and contralateral brain for both Gli36vIII and U87 tumors (P<0.01 for both comparisons), with mean TBR of 22.5±0.7 for Gli36vIII tumors and 28.9±2.1 for U87 tumors (TBR±SEM). Tracer uptake by tumor was significantly inhibited by pre-injection with cetuximab (P<0.01 for both), with SUVmean reduced by 68% and 58% for Gli36vIII and U87 tumors, respectively. Surgical resection model PET-CT imaging demonstrates residual tumor and low nonspecific uptake in the resection site. We conclude that (64)Cu-DOTA-cetuximab-F(ab´)2 binds specifically to intracranial EGFR WT and EGFRvIII expressing GBM, demonstrates excellent TBR, and specifically images small residual tumor in a surgical model, suggesting future clinical utility in identifying true tumor recurrence.

Somatostatin receptors (SSTR) are highly expressed in well-differentiated neuroendocrine tumors (NET). Octreotide, an SSTR agonist, has been used to suppress the production of vasoactive hormones and relieve symptoms of hormone hypersecretion with functional NETs. In a clinical trial, an empiric dose of octreotide treatment prolonged time to tumor progression in patients with small bowel neuroendocrine (carcinoid) tumors, irrespective of symptom status. However, there has yet to be a dose optimization study across the patient population, and methods are currently lacking to optimize dosing of octreotide therapy on an individual basis. Multiple factors such as total tumor burden, receptor expression levels, and nontarget organ metabolism/excretion may contribute to a variation in SSTR octreotide occupancy with a given dose among different patients. In this study, we report the development of an imaging method to measure surface SSTR expression and occupancy level using the PET radiotracer (68)Ga-DOTATOC. In an animal model, SSTR occupancy by octreotide was assessed quantitatively with (68)Ga-DOTATOC PET, with the finding that increased occupancy resulted in decreased tumor proliferation rate. The results suggested that quantitative SSTR imaging during octreotide therapy has the potential to determine the fractional receptor occupancy in NETs, thereby allowing octreotide dosing to be optimized readily in individual patients. Clinical trials validating this approach are warranted.

Purpose: To compare the amount of sedation medication administered during radiofrequency (RF) ablation versus cryoablation of small renal masses., Materials and Methods: Records were retrospectively reviewed in patients who underwent percutaneous computed tomography-guided RF ablation and cryoablation of small renal masses from January 2002 to June 2011 for patient and tumor characteristics, amount of medications used for moderate sedation, and complications. Sedation was performed by giving patients titrated doses of midazolam and fentanyl. Additional medications were given if the desired level of sedation was not achieved., Results: There were 116 patients who underwent 136 ablation procedures; 71 patients underwent RF ablation, and 65 patients underwent cryoablation. RF ablation was associated with a significantly higher mean dose of fentanyl (mean dose for RF ablation, 236.43 μg; mean dose for cryoablation, 172.27 μg; P<.001). RF ablation was also associated with a higher mean dose of midazolam (mean dose for RF ablation, 4.5 mg; mean dose for cryoablation, 3.27 mg; P<.001). In the RF ablation group, two patients required additional sedation with droperidol. As a result of oversedation, two patients in the RF ablation cohort required sedation reversal with naloxone and flumazenil. None of the patients who underwent cryoablation required sedation reversal. No other sedation-related complications occurred., Conclusions: Cryoablation of small renal masses was performed with less sedation medication than RF ablation. This finding suggests renal cryoablation is less painful than RF ablation; however, prospective studies with validated pain scales are needed to confirm these results., (Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.)