Faculty Bibliography

Importance/UNASSIGNED:The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown. Objective/UNASSIGNED:To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population. Design, Setting, and Participants/UNASSIGNED:In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018. Main Outcomes and Measures/UNASSIGNED:Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immunohistochemistry for MMR protein expression were performed in select cases. Results/UNASSIGNED:Among the 1033 patients who had adequate tumor quality for MSIsensor analysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome-associated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received anti-PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks. Conclusions and Relevance/UNASSIGNED:The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti-PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR phenotype respond, further studies should explore mechanisms of resistance.

Human cancers represent complex structures, which display substantial inter- and intratumor heterogeneity in their genetic expression and phenotypic features. However, cancers usually exhibit characteristic structural, physiologic, and molecular features and display specific biological capabilities named hallmarks. Many of these tumor traits are imageable through different imaging techniques. Imaging is able to spatially map key cancer features and tumor heterogeneity improving tumor diagnosis, characterization, and management. This paper aims to summarize the current and emerging applications of imaging in tumor biology assessment.

Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3×9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention.

OBJECTIVES:To evaluate the diagnostic performance and interobserver agreement of PI-RADS v2. MATERIALS AND METHODS:In this Institutional Review Board approved single-center retrospective study, 98 patients with clinically suspected PCa who underwent 3-T multiparametric MRI followed by MRI/TRUS fusion-guided prostate biopsy were included from June 2013 to February 2015. Two radiologists (R1 and R2) with 8 and 1 years of experience in abdominal radiology reviewed the MRI scans and assigned PI-RADS v2 scores in all prostate zones. PI-RADS v2 were compared to MRI/TRUS fusion-guided biopsy results, which were classified as negative, PCa, and significant PCa (sPCa). RESULTS:Sensitivity, specificity, NPV, PPV and accuracy for PCa was 85.7% (same for all metrics) for R1 and 81.6%, 79.6%, 81.2%, 80.0% and 80.6% for R2. For detecting sPCa, the corresponding values were 95.3%, 85.4%, 95.9%, 83.7% and 89.8% for R1 and 93.0%, 81.8%, 93.7%, 86.7% and 86.7% for R2. There was substantial interobserver agreement in assigning PI-RADS v2 score as negative (1, 2, 3) or positive (4, 5) (Kappa=0.78). On multivariate analysis, PI-RADS v2 (p <0.001) was the only independent predictor of sPCa compared with age, abnormal DRE, prostate volume, PSA and PSA density. CONCLUSIONS:Our study population demonstrated that PI-RADS v2 had high diagnostic accuracy, substantial interobserver agreement, and it was the only independent predictor of sPCa.

Pelvic masses can present a diagnostic challenge owing to the difficulty in assessing their origin and the overlap in imaging features. The majority of pelvic tumors arise from gastrointestinal or genitourinary organs, with less common sites of origin including the connective tissues, nerves, and lymphovascular structures. Lesion evaluation usually starts with clinical assessment followed by imaging, or the lesion may be an incidental finding at imaging performed for other clinical indications. Since accurate diagnosis is essential for optimal management, imaging is useful for suggesting the correct diagnosis or narrowing the differential possibilities and distinguishing tumors from their mimics. Some masses may require histologic confirmation of the diagnosis with biopsy and/or up-front surgical resection. In this case, imaging is essential for presurgical planning to assess mass size and location, evaluate the relationship to adjacent pelvic structures, and narrow differential possibilities. Pelvic US is often the first imaging modality performed in women with pelvic symptoms. While US is often useful to detect a pelvic mass, it has significant limitations in assessing masses located deep in the pelvis or near gas-filled organs. CT also has limited value in the pelvis owing to its inferior soft-tissue contrast. MRI is frequently the optimal imaging modality, as it offers both multiplanar capability and excellent soft-tissue contrast. This article highlights the normal anatomy of the pelvic spaces in the female pelvis and focuses on MRI features of common tumors and tumor mimics that arise in these spaces. It provides an interpretative algorithm for approaching an unknown pelvic lesion at MRI. It also discusses surgical management, emphasizing the value of MRI as a road map to surgery and highlighting anatomic locations where surgical resection may present a challenge. ^©RSNA, 2019.

PURPOSE/OBJECTIVE:To determine if radiomic measures of tumor heterogeneity derived from baseline contrast-enhanced computed tomography (CE-CT) are associated with durable clinical benefit and time to off-treatment in patients with recurrent ovarian cancer (OC) enrolled in prospective immunotherapeutic trials. MATERIALS AND METHODS/METHODS:This retrospective study included 75 patients with recurrent OC who were enrolled in prospective immunotherapeutic trials (n = 74) or treated off-label (n = 1) and had baseline CE-CT scans. Disease burden (total tumor volume, number of disease sites), radiomic measures of intertumor heterogeneity (cluster-site entropy, cluster-site dissimilarity), and intratumor heterogeneity of the largest lesion (Haralick texture features) were computed. Associations of clinical, conventional imaging, and radiomic measures with durable clinical benefit and time to off-treatment were examined. RESULTS:= .004; hazard ratio, 1.19; C-index, 0.6). CONCLUSION/CONCLUSIONS:Fewer disease sites and lower intra- and intertumor heterogeneity modeled from the baseline CE-CT may indicate better response of OC to immunotherapy.

Rapid developments in imaging and treatment with radiopharmaceuticals targeting prostate cancer pose issues for the development of guidelines for their appropriate use. To tackle this problem, international experts representing medical oncologists, urologists, radiation oncologists, radiologists, and nuclear medicine specialists convened at the European Association of Nuclear Medicine Focus 1 meeting to deliver a balanced perspective on available data and clinical experience of imaging in prostate cancer, which had been supported by a systematic review of the literature and a modified Delphi process. Relevant conclusions included the following: diphosphonate bone scanning and contrast-enhanced CT are mentioned but rarely recommended for most patients in clinical guidelines; MRI (whole-body or multiparametric) and prostate cancer-targeted PET are frequently suggested, but the specific contexts in which these methods affect practice are not established; sodium fluoride-18 for PET-CT bone scanning is not widely advocated, whereas gallium-68 or fluorine-18 prostate-specific membrane antigen gain acceptance; and, palliative treatment with bone targeting radiopharmaceuticals (rhenium-186, samarium-153, or strontium-89) have largely been replaced by radium-223 on the basis of the survival benefit that was reported in prospective trials, and by other systemic therapies with proven survival benefits. Although the advances in MRI and PET-CT have improved the accuracy of imaging, the effects of these new methods on clinical outcomes remains to be established. Improved communication between imagers and clinicians and more multidisciplinary input in clinical trial design are essential to encourage imaging insights into clinical decision making.

Pelvic pain is common in both reproductive age and postmenopausal women, and the major etiologies change throughout the life cycle. Chronic pain is defined as lasting for at least 6 months. There are many gastrointestinal and urinary disorders associated with chronic pain in this age group, which are not discussed in this guideline. Pain may be localized to the deep pelvis, with potential causes including pelvic congestion syndrome, intraperitoneal adhesions, hydrosalpinx, chronic inflammatory disease, or cervical stenosis. Ultrasound is the initial imaging modality of choice, while CT and MRI may be appropriate for further characterization of sonographic findings. Alternatively, pain may be localized to the vagina, vulva, or perineum, with potential causes including vaginal atrophy, vaginismus, vaginal or vulvar cysts, vulvodynia, or pelvic myofascial pain. Imaging is primarily indicated in context of an abnormal physical exam and ultrasound is the initial modality of choice, while MRI may be appropriate for further characterization in select cases. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.