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Background: Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers., Methods: We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically relevant genetic interactions and uses them to predict a patient's response to a variety of therapies in multiple cancer types without training on previous treatment response data. We study ENLIGHT in two translationally oriented scenarios: personalized oncology (PO), aimed at prioritizing treatments for a single patient, and clinical trial design (CTD), selecting the most likely responders in a patient cohort., Findings: Evaluating ENLIGHT's performance on 21 blinded clinical trial datasets in the PO setting, we show that it can effectively predict a patient's treatment response across multiple therapies and cancer types. Its prediction accuracy is better than previously published transcriptomics-based signatures and is comparable with that of supervised predictors developed for specific indications and drugs. In combination with the interferon-γ signature, ENLIGHT achieves an odds ratio larger than 4 in predicting response to immune checkpoint therapy. In the CTD scenario, ENLIGHT can potentially enhance clinical trial success for immunotherapies and other monoclonal antibodies by excluding non-responders while overall achieving more than 90% of the response rate attainable under an optimal exclusion strategy., Conclusions: ENLIGHT demonstrably enhances the ability to predict therapeutic response across multiple cancer types from the bulk tumor transcriptome., Funding: This research was supported in part by the Intramural Research Program, NIH and by the Israeli Innovation Authority., Competing Interests: Declaration of interests G.D., E.D.S., E. Elis, D.S.B.-Z., O.T., E.M., E. Elalouf, B.T., P.V., T.B., and R.A. are employees of Pangea Biomed. I.M. is a paid consultant of Pangea Biomed. E.S. is the Chairman of the Board of Pangea Biomed. E.R. is a co-founder of MedAware, Metabomed, and Pangea Biomed (divested) and an unpaid member of Pangea Biomed’s scientific advisory board. Z.R. is a co-founder of Pangea Biomed and an unpaid member of its scientific advisory board. R.B. is a member of Pangea Biomed’s scientific advisory board., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patients treated with immune checkpoint inhibitors (ICIs) may experience pseudoprogression, which can be classified as progressive disease (PD) by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and could lead to inappropriate treatment discontinuation. Immune-response criteria were developed to better capture novel response patterns seen with ICIs., Methods: We pooled data from 1765 patients with 12 types of advanced solid tumors treated with avelumab (an anti-programmed death ligand 1 (PD-L1) monoclonal antibody) monotherapy in the JAVELIN Solid Tumor and JAVELIN Merkel 200 trials, conducted a comparative analysis of tumor assessments by investigators according to RECIST 1.1 and immune-related RECIST (irRECIST), and evaluated the correlation between progression-free survival (PFS) and overall survival (OS)., Results: In total, 147 patients (8.3%) had a best overall response (BOR) of PD by RECIST 1.1 but had immune-related disease control by irRECIST (defined as immune-related BOR (irBOR) of immune-related stable disease or better). This discordance was seen irrespective of PD-L1 status and observed across all tumor types. Overall, PFS and immune-related PFS showed similar imputed rank correlations with OS., Conclusions: The use of irRECIST identified a subset of patients with a BOR of PD by RECIST 1.1 but an irBOR of immune-related disease control by irRECIST with a distinctive survival curve, thereby providing more clinically relevant information than RECIST 1.1 alone. However, as a surrogate endpoint for OS in the whole population, immune-related PFS by irRECIST did not show improved predictive value compared with PFS by RECIST 1.1., Competing Interests: Competing interests: JLG has received research funding from Astellas Medivation, Bavarian Nordic, Bristol Myers Squibb, EMD Serono, an affiliate of Merck KGaA, NantBioScience, and Pfizer. SPD has provided consultancy or advisory services for Amgen, GlaxoSmithKline, Immune Design, Incyte, EMD Serono, an affiliate of Merck KGaA, and Nektar Therapeutics, and received travel expenses from Adaptimmune, EMD Serono, an affiliate of Merck KGaA, and Nektar Therapeutics. JM is an employee of EMD Serono Research & Development Institute, Billerica, Massachusetts, USA, an affiliate of Merck KGaA. SPE is an employee of Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA. MB is an employee of Merck. All other authors report no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Purpose To compare Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with volumetric measurement in the setting of target lymph nodes that split into two or more nodes or merge into one conglomerate node. Materials and Methods In this retrospective study, target lymph nodes were evaluated on CT scans from 166 patients with different types of cancer; 158 of the scans came from The Cancer Imaging Archive. Each target node was measured using RECIST 1.1 criteria before and after merging or splitting, followed by volumetric segmentation. To compare RECIST 1.1 with volume, a single-dimension hypothetical diameter (HD) was determined from the nodal volume. The nodes were divided into three groups: (a) one-target merged (one target node merged with other nodes); (b) two-target merged (two neighboring target nodes merged); and (c) split node (a conglomerate node cleaved into smaller fragments). Bland-Altman analysis and t test were applied to compare RECIST 1.1 with HD. On the basis of the RECIST 1.1 concept, we compared response category changes between RECIST 1.1 and HD. Results The data set consisted of 30 merged nodes (19 one-target merged and 11 two-target merged) and 20 split nodes (mean age for all 50 included patients, 50 years ± 7 [standard deviation]; 38 men). RECIST 1.1, volumetric, and HD measurements indicated an increase in size in all one-target merged nodes. While volume and HD indicated an increase in size for nodes in the two-target merged group, RECIST 1.1 showed a decrease in size in all two-target merged nodes. Although volume and HD demonstrated a decrease in size of all split nodes, RECIST 1.1 indicated an increase in size in 60% (12 of 20) of the nodes. Discrepancy of the response categories between RECIST 1.1 and HD was observed in 5% (one of 19) in one-target merged, 82% (nine of 11) in two-target merged, and 55% (11 of 20) in split nodes. Conclusion RECIST 1.1 does not optimally reflect size changes when lymph nodes merge or split. Keywords: CT, Lymphatic, Tumor Response Supplemental material is available for this article. © RSNA, 2021.

Purpose: To report the clinical features, severity, and management of ocular immune-related adverse events (irAEs) in the setting of immune checkpoint inhibitor therapy for metastatic malignancies., Methods: Retrospective chart review at three tertiary ophthalmology clinics. Electronic medical records were reviewed between 2000 and 2017 for patients with new ocular symptoms while undergoing checkpoint inhibition therapy., Results: Eleven patients were identified. Ocular irAEs ranged from keratoconjunctivitis sicca to Vogt-Koyanagi-Harada-like findings. Average timing of irAEs from starting checkpoint inhibitor therapy was 15.7 weeks. Ocular inflammation was successfully controlled with corticosteroids in most cases, however three patients discontinue treatment as a result of ocular inflammation with decreased visual acuity, two discontinued due to progression of metastatic disease, and one discontinued due to severe systemic irAEs., Conclusion: We found a wide spectrum of ocular irAEs associated with immune checkpoint inhibitors. In most cases, ocular AEs did not limit ongoing cancer treatment.

Importance: Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for an ever-increasing number of cancers. However, their use has also led to the emergence of immune-related adverse events, such as ICI-induced inflammatory arthritis. A reproducible, reliable, and accessible modality is needed to assess and distinguish early ICI-induced inflammatory arthritis and help in management. Magnetic resonance imaging (MRI) of joints may be helpful for early diagnosis, guiding therapeutic decision-making, and identifying patients at high risk for erosive disease., Objective: To assess the role of MRI of joints in patients with ICI-induced inflammatory arthritis., Design, Setting, and Participants: This retrospective case series included patients enrolled at the National Institutes of Health Clinical Center in Bethesda, Maryland. Patients were evaluated by the rheumatology consultation service between December 27, 2016, and May 28, 2019. A retrospective health record review was performed to determine demographic characteristics, clinical characteristics of inflammatory arthritis and malignant tumors, and imaging findings. Inclusion criteria were patients who were enrolled on various institutional review board-approved protocols of ICIs, developed joint-related symptoms, and had MRI data for at least 1 joint. Data were analyzed from June 1, 2019, to September 1, 2019., Exposures: Undergoing MRI of at least 1 joint., Main Outcomes and Measures: All MRIs were reviewed for synovitis, tenosynovitis, bone marrow edema, and soft tissue conditions., Results: A total of 8 patients (mean [SD] age, 58.8 [5.2] years; 6 women and 2 men) between the ages of 50 and 65 years who were undergoing ICI therapy for a variety of malignant tumors were included in this study. Only 1 patient was receiving combined ICI therapy. The results of 13 separate MRI examinations were reviewed. The most commonly performed MRIs were of the hands and wrists (9 MRIs), followed by knee examinations (3 MRIs). Tenosynovitis and synovitis were frequently seen in the hands and wrists. Bone marrow edema and erosions were also found in 3 patients, suggesting early damage. In larger joints (ie, knees and ankles), joint effusions and synovial thickening were characteristic. Most patients (5 patients) were treated with corticosteroids and had good responses. In patients with high-risk features on MRI imaging (eg, bone marrow edema, erosions), disease-modifying antirheumatic drug therapy was also discussed as a treatment option., Conclusions and Relevance: These findings suggest that advanced imaging may help to distinguish ICI-induced inflammatory arthritis from other causes of joint pain, aid in identifying patients at increased risk of joint damage, and provide utility in monitoring inflammatory arthritis treatment response in patients receiving ICI therapy.

Oncologists evaluate therapeutic response in cancer trials based on tumor quantification following selected "target" lesions over time. At our cancer center, a majority of oncologists use Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 quantifying tumor progression based on lesion measurements on imaging. Currently, our oncologists handwrite tumor measurements, followed by multiple manual data transfers; however, our Picture Archiving Communication System (PACS) (Carestream Health, Rochester, NY) has the ability to export tumor measurements, making it possible to manage tumor metadata digitally. We developed an interface, "Exportable Notation and Bookmark List Engine" (ENABLE), which produces prepopulated RECIST v1.1 worksheets and compiles cohort data and data models from PACS measurement data, thus eliminating handwriting and manual data transcription. We compared RECIST v1.1 data from eight patients (16 computed tomography exams) enrolled in an IRB-approved therapeutic trial with ENABLE outputs: 10 data fields with a total of 194 data points. All data in ENABLE's output matched with the existing data. Seven staff were taught how to use the interface with a 5-min explanatory instructional video. All were able to use ENABLE successfully without additional guidance. We additionally assessed 42 metastatic genitourinary cancer patients with available RECIST data within PACS to produce a best response waterfall plot. ENABLE manages tumor measurements and associated metadata exported from PACS, producing forms and data models compatible with cancer databases, obviating handwriting and the manual re-entry of data. Automation should reduce transcription errors and improve efficiency and the auditing process.

Objective: The purpose of this study was to evaluate the success, consistency, and efficiency of a semiautomated lesion management application within a PACS in the analysis of metastatic lesions in serial CT examinations of cancer patients., Materials and Methods: Two observers using baseline and follow-up CT data independently reviewed 93 target lesions (17 lung, five liver, 71 lymph node) in 50 patients with either metastatic bladder or prostate cancer. The observers measured the longest axis (or short axis for lymph nodes) of each lesion and made Response Evaluation Criteria in Solid Tumors (RECIST) determinations using manual and lesion management application methods. The times required for examination review, RECIST calculations, and data input were recorded. The Wilcoxon signed rank test was used to assess time differences, and Bland-Altman analysis was used to assess interobserver agreement within the manual and lesion management application methods. Percentage success rates were also reported., Results: With the lesion management application, most lung and liver lesions were semiautomatically segmented. Comparison of the lesion management application and manual methods for all lesions showed a median time saving of 45% for observer 1 (p<0.05) and 28% for observer 2 (p=0.05) on follow-up scans versus 28% for observer 1 (p<0.05) and 9% for observer 2 (p=0.087) on baseline scans. Variability of measurements showed mean percentage change differences of only 8.9% for the lesion management application versus 26.4% for manual measurements., Conclusion: With the lesion management application method, most lung and liver lesions were successfully segmented semiautomatically; the results were more consistent between observers; and assessment of tumor size was faster than with the manual method.

In 1994 the first heat shock protein 90 (Hsp90) inhibitor was identified and Hsp90 was reported to be a target for anticancer therapeutics. In the past 18 years there have been 17 distinct Hsp90 inhibitors entered into clinical trial, and the small molecule Hsp90 inhibitors have been highly valuable as probes of the role of Hsp90 and its client proteins in cancer. Although no Hsp90 inhibitor has achieved regulatory approval, recently there has been significant progress in Hsp90 inhibitor clinical development, and in the past year RECIST responses have been documented in HER2-positive breast cancer and EML4-ALK-positive non-small cell lung cancer. All of the clinical Hsp90 inhibitors studied to date are specific in their target, i.e. they bind exclusively to Hsp90 and two related heat shock proteins. However, Hsp90 inhibitors are markedly pleiotropic, causing degradation of over 200 client proteins and impacting critical multiprotein complexes. Furthermore, it has only recently been appreciated that Hsp90 inhibitors can, paradoxically, cause transient activation of the protein kinase clients they are chaperoning, resulting in initiation of signal transduction and significant physiological events in both tumor and tumor microenvironment. An additional area of recent progress in Hsp90 research is in studies of the posttranslational modifications of Hsp90 itself and Hsp90 co-chaperone proteins. Together, a picture is emerging in which the impact of Hsp90 inhibitors is shaped by the tumor intracellular and extracellular milieu, and in which Hsp90 inhibitors impact tumor and host on a microenvironmental and systems level. Here we review the tumor intrinsic and extrinsic factors that impact the efficacy of small molecules engaging the Hsp90 chaperone machine.

Unlabelled: We evaluated the kinetics of (18)F-sodium fluoride (NaF) and reassessed the recommended dose, optimal uptake period, and reproducibility using a current-generation PET/CT scanner., Methods: In this prospective study, 73 patients (31 patients with multiple myeloma or myeloma precursor disease and 42 with prostate cancer) were injected with a mean administered dose of 141 MBq of (18)F-NaF. Sixty patients underwent 3 sequential sessions of 3-dimensional PET/CT of the torso beginning approximately 15 min after (18)F-NaF injection, followed by whole-body 3-dimensional PET/CT at 2 h. The remaining 13 prostate cancer patients were imaged only at 2 and 3 h after injection. Twenty-one prostate cancer patients underwent repeated baseline studies (mean interval, 5.9 d) to evaluate reproducibility., Results: The measured effective dose was 0.017 mSv/MBq, with the urinary bladder, osteogenic cells, and red marrow receiving the highest doses at 0.080, 0.077, and 0.028 mGy/MBq, respectively. Visual analysis showed that uptake in both normal and abnormal bone increased with time; however, the rate of increase decreased with time. A semiautomated workflow provided objective uptake parameters, including the mean standardized uptake value of all pixels within bone with SUVs greater than 10 and the average of the mean SUV of all malignant lesions identified by the algorithm. The values of these parameters for the images beginning at approximately 15 min and approximately 35 min were significantly different (0.3% change per minute). Differences between the later imaging time points were not significant (P < 0.01). Repeated baseline studies showed high intraclass correlations (>0.9) and relatively low critical percentage change (the value above which a change can be considered real) for these parameters. The tumor-to-normal bone ratio, based on the maximum SUV of identified malignant lesions, decreased with time; however, this difference was small, estimated at approximately 0.16%/min in the first hour., Conclusion: (18)F-NaF PET/CT images obtained with modest radiation exposures can result in highly reproducible imaging parameters. Although the tumor-to-normal bone ratio decreases slightly with time, the high temporal dependence during uptake periods less than 30 min may limit accurate quantitation. An uptake period of 60 ± 30 min has limited temporal dependence while maintaining a high tumor-to-normal bone ratio.