Ovarian cancer mutational processes drive site-specific immune evasion.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1-4 patterned by distinct mutational processes5,6, tumour heterogeneity7-9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11-13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFß signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.

Synoptic Reporting for Pretreatment CT Examination in Patients With Advanced Ovarian Cancer: Impact on Documentation of Disease Sites and Physician Satisfaction.

BACKGROUND. Imaging reports that consistently document all disease sites with a potential to increase surgical complexity or morbidity can facilitate ovarian cancer treatment planning. OBJECTIVE. The aims of this study were to compare simple structured reports and synoptic reports from pretreatment CT examinations in patients with advanced ovarian cancer in terms of completeness of documenting involvement of clinically relevant anatomic sites as well as to evaluate physician satisfaction with synoptic reports. METHODS. This retrospective study included 205 patients (median age, 65 years) who underwent contrast-enhanced abdominopelvic CT before primary treatment of advanced ovarian cancer from June 1, 2018, to January 31, 2022. A total of 128 reports generated on or before March 31, 2020, used a simple structured report (free text organized into sections); 77 reports generated on or after April 1, 2020, used a synoptic report (a list of 45 anatomic sites relevant to ovarian cancer management, each of which was classified in terms of disease absence versus presence). Reports were reviewed for completeness of documentation of involvement of the 45 sites. For patients who underwent neoadjuvant chemotherapy based on diagnostic laparoscopy findings or underwent primary debulking surgery with suboptimal resection, the EMR was reviewed to identify surgically established sites of disease that were unresectable or challenging to resect. Gynecologic oncology surgeons were electronically surveyed. RESULTS. The mean report turnaround time was 29.8 minutes for simple structured reports versus 54.5 minutes for synoptic reports (p < .001). A mean of 17.6 of 45 sites (range, four to 43 sites) were mentioned by simple structured reports versus 44.5 of 45 sites (range, 39-45) for synoptic reports (p < .001). Forty-three patients had surgically established unresectable or challenging-to-resect disease; involvement of anatomic site(s) with such disease was mentioned in 37% (11/30) of simple structured reports versus 100% (13/13) of synoptic reports (p < .001). All eight surveyed gynecologic oncology surgeons completed the survey. CONCLUSION. A synoptic report improved completeness of pretreatment CT reports in patients with advanced ovarian cancer, including for established sites of unresectable or challenging-to-resect disease. CLINICAL IMPACT. The findings indicate the role of disease-specific synoptic reports in facilitating referrer communication and potentially guiding clinical decision-making.

CT of Ovarian Cancer for Primary Treatment Planning: What the Surgeon Needs to Know-Radiology In Training.

A 60-year-old woman presented with intermittent abdominal pain, an elevated serum CA-125 level, and an abnormal CT examination and was ultimately diagnosed with advanced-stage high-grade serous ovarian cancer. Key tumor locations on CT scans that should be highlighted by the radiologist to guide treatment selection are discussed.

Local Extent of Prostate Cancer at MRI versus Prostatectomy Histopathology: Associations with Long-term Oncologic Outcomes.

Background It is unknown how the imperfect accuracy of MRI for local staging of prostate cancer relates to oncologic outcomes. Purpose To analyze how staging discordances between MRI and histopathologic evaluation relate to recurrence and survival after radical prostatectomy. Materials and Methods Health Insurance Portability and Accountability Act-compliant retrospective analysis of preprostatectomy T2-weighted prostate MRI (January 2001 to December 2006). Extraprostatic extension and seminal vesicle invasion were assessed by using five-point Likert scales; scores of 4 or higher were classified as positive. Biochemical recurrence (BCR), metastases, and prostate cancer-specific mortality rates were estimated with Kaplan-Meier and Cox models. Results A total of 2160 patients (median age, 60 years; interquartile range, 55-64 years) were evaluated. Among patients with histopathologic extraprostatic (pT3) disease (683 of 2160; 32%), those with organ-confined disease at MRI (384 of 683; 56%) experienced better outcomes than those with concordant extraprostatic disease at MRI and pathologic analysis: 15-year risk for BCR, 30% (95% CI: 22, 40) versus 68% (95% CI: 60, 75); risk for metastases, 14% (95% CI: 8.4, 24) versus 32% (95% CI: 26, 39); risk for prostate cancer-specific mortality, 3% (95% CI: 1, 6) versus 15% (95% CI: 9.5, 23) (P < .001 for all comparisons). Among patients with histopathologic organ-confined disease (pT2) (1477 of 2160; 68%), those with extraprostatic disease at MRI (102 of 1477; 7%) were at higher risk for BCR (27% [95% CI: 19, 37] vs 10% [95% CI: 8, 14]; P < .001), metastases (19% [95% CI: 6, 48] vs 3% [95% CI: 1, 6]; P < .001), and prostate cancer-specific mortality (2% [95% CI: 1, 9] vs 1% [95% CI: 0, 5]; P = .009) than those with concordant organ-confined disease at MRI and pathologic analysis. At multivariable analyses, tumor extent at MRI (hazard ratio range, 4.1-5.2) and histopathologic evaluation (hazard ratio range, 3.6-6.7) was associated with the risk for BCR, metastases, and prostate cancer-specific mortality (P < .001 for all analyses). Conclusion The local extent of prostate cancer at MRI is associated with oncologic outcomes after prostatectomy, independent of pathologic tumor stage. This might inform a strategy on how to integrate MRI into a clinical staging algorithm. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Gottlieb in this issue.

Oncologic Outcomes after Localized Prostate Cancer Treatment: Associations with Pretreatment Prostate Magnetic Resonance Imaging Findings.

PURPOSE: We investigated whether T2-weighted magnetic resonance imaging findings could improve upon established prognostic indicators of metastatic disease and prostate cancer specific survival. MATERIALS AND METHODS: For a cohort of 3,406 consecutive men who underwent prostate magnetic resonance imaging before prostatectomy (2,160) or radiotherapy (1,246) between 2001 and 2006, T2-weighted magnetic resonance imaging exams were retrospectively interpreted and categorized as I) no focal suspicious lesion, II) organ confined focal lesion, III) focal lesion with extraprostatic extension or IV) focal lesion with seminal vesicle invasion. Clinical risk was recorded based on European Association of Urology (EAU) guidelines and the Cancer of the Prostate Risk Assessment (CAPRA) scoring system. Survival probabilities and c-indices were estimated using Cox models and inverse probability censoring weights, respectively. RESULTS: The median followup was 10.8 years (IQR 8.6-13.0). Higher magnetic resonance imaging categories were associated with a higher likelihood of developing metastases (HR 3.5-18.1, p <0.001 for all magnetic resonance imaging categories) and prostate cancer death (HR 3.1-29.7, p <0.001-0.025); these associations were statistically independent of EAU risk categories, CAPRA scores and treatment type (surgery vs radiation). Combining EAU risk or CAPRA scores with magnetic resonance imaging categories significantly improved prognostication of metastases (c-indices: EAU: 0.798, EAU + magnetic resonance imaging: 0.872; CAPRA: 0.808, CAPRA + magnetic resonance imaging: 0.877) and prostate cancer death (c-indices: EAU 0.813, EAU + magnetic resonance imaging: 0.889; CAPRA: 0.814, CAPRA + magnetic resonance imaging: 0.892; p <0.001 for all). CONCLUSION: Magnetic resonance imaging findings of localized prostate cancer are associated with clinically relevant long-term oncologic outcomes. Combining magnetic resonance imaging and clinicopathological data results in more accurate prognostication, which could facilitate individualized patient management.

A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers.

PURPOSE: Selinexor, a selective inhibitor of nuclear export, monotherapy causes nuclear accumulation of tumor-suppressor proteins and has anti-tumor activity in ovarian and endometrial cancers. The safety and tolerability of oral selinexor plus intravenous carboplatin and paclitaxel chemotherapy (selinexor + CP) was evaluated in this population. PATIENTS AND METHODS: This phase I, 3 + 3 dose-escalation study assessed 4 selinexor + CP regimens. Patients in cohorts of 3, regardless of disease type, were administered 1 of 4 alternating regimens (selinexor at 30 mg/m2 or 60 mg plus CP at AUC 5 and 175 mg/m2 or 80 mg/m2, respectively) for 6-10 cycles (1 cycle = 21 days), followed by selinexor maintenance. Enrolled patients with ovarian cancer had received 1 prior platinum-based therapy. Patients with endometrial cancer were chemotherapy-naive or had received 1 prior platinum-based therapy. Response was evaluated every 9 weeks. RESULTS: Twenty-three patients were treated (5 serous ovarian cancer; 18 endometrial cancer, including 6 carcinosarcomas). The most common treatment-related adverse events (TRAEs) were thrombocytopenia (100%), leukopenia (91%), and hyperglycemia (87%). The most common grade 3/4 TRAEs were leukopenia (70%), neutropenia (70%), lymphopenia (61%), anemia (57%), and alanine transaminase increase (43%). One treatment-related dose-limiting toxicity (grade 3 syncope) occurred. Twelve patients achieved a partial response and 1 achieved a complete response. Responses to all four regimens were observed in ovarian and endometrial cancers. CONCLUSIONS: Combination selinexor + CP was safe and tolerated in advanced ovarian and endometrial cancers.

NRF2 Dysregulation in Hepatocellular Carcinoma and Ischemia: A Cohort Study and Laboratory Investigation.

Background Intermediate stage hepatocellular carcinomas (HCCs) are treated by inducing ischemic cell death with transarterial embolization (TAE) or transarterial chemoembolization (TACE). A subset of HCCs harbor nuclear factor E2-related factor 2 (NRF2), a major regulator of the oxidative stress response implicated in cell survival after ischemia. NRF2-mutated HCC response to TAE and/or TACE is unknown. Purpose To test whether ischemia resistance is present in individuals with NRF2-mutated HCC and if this resistance can be overcome by means of NRF2 inhibition in HCC cell lines. Materials and Methods This was a combined retrospective review of an institutional database (from January 2011 to December 2018) and prospective study (from January 2014 to December 2018) of participants with HCC who underwent TAE and a laboratory investigation of HCC cell lines. Imaging follow-up included liver CT or MRI at 1 month after the procedure followed by 3-month interval scans. Tumor radiologic response was assessed on the basis of follow-up imaging. The time to local progression after TAE for individuals with and individuals without NRF2 pathway alterations was estimated by using competing risk analysis (Gray test). The in vitro response to ischemia in four HCC cell lines with and without NRF2 overexpression was evaluated, and the combination of ischemia with NRF2 knockdown by means of short hairpin RNA or an NRF2 inhibitor was tested. Doubling time estimates, dose response curve regression, and comparison analyses were performed. Results Sixty-five individuals (median age, 69 years [range, 19-84 years]; 53 men) were evaluated. HCCs with NRF2 pathway mutation had a shorter time to local progression after TAE compared to those without mutation (6-month cumulative incidence of local progression, 56% [range, 19%-91%] vs 22% [range, 12%-34%], respectively; P < .001) and confirmed ischemia resistance in NRF2-overexpressing HCC cell lines. However, ischemia and NRF2 knock-down worked synergistically to decrease proliferation of NRF2-overexpressing HCC cell lines. Dose response curves of ML385, an NRF2 inhibitor, showed that ischemia induces addiction to NRF2 in cells with NRF2 alterations. Conclusion Hepatocellular carcinoma with nuclear factor E2-related factor 2 (NRF2) alterations showed resistance to ischemia, but ischemia simultaneously induced sensitivity to NRF2 inhibition. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Weiss and Nezami in this issue.

A multimodality triage algorithm to improve cytoreductive outcomes in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center team ovary initiative.

OBJECTIVE: To describe outcomes using a multimodal algorithm to triage patients with advanced epithelial ovarian cancer (EOC) to primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT). METHODS: All patients with EOC treated at our institution from 04/2015-08/2018 were identified. We included patients without contraindication to PDS who underwent prospective calculation of a Resectability (R)-score. A low risk score for suboptimal cytoreduction was defined as ≤6, and a high risk score ≥7. Patients were triaged to laparotomy/PDS, laparoscopic evaluation of resectability (LSC), or NACT depending on R-score. RESULTS: Among 299 participants, 226 (76%) had a low risk score and 73 (24%) a high risk score. For patients with a low risk score, management included laparotomy/PDS, 181 (80%); LSC, 43 (19%) (with subsequent triage: PDS, 31; NACT, 12); and NACT, 2 (1%). For patients with a high risk score, management included laparotomy/PDS, 9 (12%); LSC, 51 (70%) (with subsequent triage: PDS, 28; NACT, 23); and NACT, 13 (18%). Overall, 83% underwent PDS, with a 75% CGR rate and 94% optimal cytoreduction rate. Use of the algorithm resulted in a 31% LSC rate and a 6% rate of suboptimal PDS. CONCLUSIONS: The multimodal algorithm led to excellent surgical results; 94% of patients achieved an optimal resection, with a very low rate of suboptimal cytoreduction.

Does the method of primary treatment affect the pattern of first recurrence in high-grade serous ovarian cancer?

PURPOSE: To determine if the primary treatment approach (primary debulking surgery (PDS) versus neoadjuvant chemotherapy and interval debulking surgery (NACT-IDS)) influences the pattern of first recurrence in patients with completely cytoreduced advanced high-grade serous ovarian carcinoma (HGSOC). MATERIALS AND METHODS: This retrospective study included 178 patients with newly diagnosed stage IIIC-IV HGSOC, complete gross resection during PDS (n = 124) or IDS (n = 54) from January 2008-March 2013, and baseline and first recurrence contrast-enhanced computed tomography scans. Clinical characteristics and number of disease sites at baseline were analyzed for associations with time to recurrence. In 135 patients who experienced recurrence, the overlap in disease locations between baseline and recurrence and the number of new disease locations at recurrence were analyzed according to the primary treatment approach. RESULTS: At univariate and multivariate analyses, NACT-IDS was associated with more overlapping locations between baseline and first recurrence (p ≤ 0.003) and fewer recurrences in new anatomic locations (p ≤ 0.043) compared with PDS. The same results were found in a subgroup that received intra-peritoneal adjuvant chemotherapy after either treatment approach. At univariate analysis, patient age, primary treatment approach, adjuvant chemotherapy route, and number of disease locations at baseline were associated with time to recurrence (p ≤ 0.009). At multivariate analysis, older patient age, NACT-IDS, and greater disease locations at baseline remained significant (p ≤ 0.018). CONCLUSION: The distribution of disease at the time of first recurrence varied with the choice of primary treatment. Compared to patients treated with PDS, patients who underwent NACT-IDS experienced recurrence more often in the same locations as the original disease.

Models to predict outcomes after primary debulking surgery: Independent validation of models to predict suboptimal cytoreduction and gross residual disease.

OBJECTIVE: Treatment planning requires accurate estimation of surgical complexity (SC) and residual disease (RD) at primary debulking surgery (PDS) for advanced ovarian cancer (OC). We sought to independently validate two published computed tomography (CT) prediction models. METHODS: We included stage IIIC/IV OC patients who underwent PDS from 2003 to 2011. Two prediction models which included imaging and clinical variables to predict RD > 1 and any gross RD, respectively, were applied to our cohort. Two radiologists scored CTs. Discrimination was estimated using the c-index and calibration were assessed by comparing the observed and predicted estimates. RESULTS: The validation cohort consisted of 276 patients; median age of the cohort was 64 years old and majority had serous histology. The validation and model development cohorts were similar in terms of baseline characteristics, however the RD rates differed between cohorts (9.4% vs 25.4% had RD >1 cm; 50.7% vs. 66.6% had gross RD). Model 1, the model to predict RD >1 cm, did not validate well. The c-index of 0.653 for the validation cohort was lower than reported in the development cohort (0.758) and the model over-predicted the proportion with RD >1 cm. The second model to predict gross RD had excellent discrimination with a c-index of 0.762. CONCLUSIONS: We are able to validate a CT model to predict presence of gross RD in an independent center; the separate model to predict RD >1 cm did not validate. Application of the model to predict gross RD can help with clinical decision making in advanced ovarian cancer.

Imaging of Small Renal Masses before and after Thermal Ablation.

Thermal ablation of small renal masses is increasingly accepted as an alternative to partial nephrectomy, particularly in patients with multiple comorbidities. Many professional societies support this alternate treatment with updated guidelines. Before performing thermal ablation, it is important to stratify risk and assess technical feasibility by evaluating tumor imaging features such as size, location, and centrality. Routine postablation imaging with CT or MRI is necessary for assessment of residual or recurrent tumor, evidence of complications, or new renal masses outside the ablation zone. The normal spectrum and evolution of findings at CT and MRI include a halo appearance of the ablation zone, ablation zone contraction, and ablation zone calcifications. Tumor recurrence frequently manifests at CT or MRI as new nodular enhancement at the periphery of an expanding ablation zone, although it is normal for the ablation zone to enlarge within the first few months. Recognizing early tumor recurrence is important, as small renal masses are often easily treated with repeat ablations. Potential complications of thermal ablation include vascular injury, urine leak, ureteral stricture, nerve injury, and bowel perforation. The risk of these complications may be related to tumor size and location.©RSNA, 2019.

MRI of Tumors and Tumor Mimics in the Female Pelvis: Anatomic Pelvic Space-based Approach.

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.

The Prevalence and Radiologic Features of Renal Cancers Associated with FLCN, BAP1, SDH, and MET Germline Mutations.

Purpose To investigate the prevalence of FLCN, BAP1, SDH, and MET mutations in an oncologic cohort and determine the prevalence, clinical features, and imaging features of renal cell carcinoma (RCC) associated with these mutations. Secondarily, to determine the prevalence of encountered benign renal lesions. Materials and Methods From 25 220 patients with cancer who prospectively underwent germline analysis with a panel of more than 70 cancer-predisposing genes from 2015 to 2021, patients with FLCN, BAP1, SDH, or MET mutations were retrospectively identified. Clinical records were reviewed for patient age, sex, race/ethnicity, and renal cancer diagnosis. If RCC was present, baseline CT and MRI examinations were independently assessed by two radiologists. Summary statistics were used to summarize continuous and categorical variables by mutation. Results A total of 79 of 25 220 (0.31%) patients had a germline mutation: FLCN, 17 of 25 220 (0.07%); BAP1, 22 of 25 220 (0.09%); SDH, 39 of 25 220 (0.15%); and MET, one of 25 220 (0.004%). Of these 79 patients, 18 (23%) were diagnosed with RCC (FLCN, four of 17 [24%]; BAP1, four of 22 [18%]; SDH, nine of 39 [23%]; MET, one of one [100%]). Most hereditary RCCs demonstrated ill-defined margins, central nonenhancing area (cystic or necrotic), heterogeneous enhancement, and various other CT and MR radiologic features, overlapping with the radiologic appearance of nonhereditary RCCs. The prevalence of other benign solid renal lesions (other than complex cysts) in patients was up to 11%. Conclusion FLCN, BAP1, SDH, and MET mutations were present in less than 1% of this oncologic cohort. Within the study sample size limits, imaging findings for hereditary RCC overlapped with those of nonhereditary RCC, and the prevalence of other associated benign solid renal lesions (other than complex cysts) was up to 11%. Keywords: Familial Renal Cell Carcinoma, Birt-Hogg-Dubé Syndrome, Carcinoma, Renal Cell, Paragangliomas, Urinary, Kidney © RSNA, 2024.

MRI-Detectability of Clinically Significant Prostate Cancer Relates to Oncologic Outcomes After Prostatectomy.

INTRODUCTION/BACKGROUND: Magnetic resonance imaging (MRI) misses a proportion of "clinically significant" prostate cancers (csPC) as defined by histopathology criteria. The aim of this study was to analyze whether long-term oncologic outcomes differ between MRI-detectable and MRI-occult csPC. PATIENTS AND METHODS: Retrospective analysis of 1449 patients with pre-prostatectomy MRI and csPC on prostatectomy specimens (ie, Grade group ≥2 or extraprostatic spread) between 2001-2006. T2-weighted MRIs were classified according to the Prostate Imaging Reporting and Data System into MRI-occult (categories 1, 2), MRI-equivocal (category 3), and MRI-detectable (categories 4, 5). Cumulative incidence of biochemical recurrence (BCR), metastatic disease, and cancer-specific mortality, estimated with competing risk models. The median follow-up in survivors was 11.0 years (IQR: 8.9-13.1). RESULTS: In 188 (13%) cases, csPC was MRI-occult, 435 (30%) MRIs were equivocal, and 826 (57%) csPC were MRI-detectable. The 15-year cumulative incidence [95% CI] of BCR was 8.3% [2.2, 19.5] for MRI-occult cases, 17.4% [11.1, 24.8] for MRI-equivocal cases, and 43.3% [38.7, 47.8] for MRI-detectable cases (P < .001). The cumulative incidences of metastases were 0.61% [0.06, 3.1], 3.5% [1.5, 6.9], and 19.6% [15.4, 24.2] for MRI-occult, MRI-equivocal, and MRI-detectable cases, respectively (P < .001). There were no deaths from prostate cancer observed in patients with MRI-occult csPC, compared to an estimated 1.9% [0.54, 4.9], and 7.1 % [4.5, 10.6] for patients with MRI-equivocal and MRI-detectable cancer, respectively (P < .001). CONCLUSION: Oncologic outcomes after prostatectomy for csPC differ between MRI-occult and MRI-detectable lesions. Judging the clinical significance of a negative prostate MRI based on histopathologic surrogates alone might be misleading. MICROABSTRACT: Among 1449 patients with pre-prostatectomy MRI and clinically significant prostate cancer on prostatectomy histopathology, MRI-occult cancers (n = 188, 13%) were less likely to recur biochemically (8% vs. 43%, P < .001), metastasize (0.6% vs. 20%, P < .001), or lead to prostate cancer mortality (0% vs. 7%, P < .001) than MRI-detectable cancers (n = 826, 57%). MRI-occult cancers constitute a prognostically distinct subgroup among higher-grade prostate cancers.

Multimodal data integration using machine learning improves risk stratification of high-grade serous ovarian cancer.

Patients with high-grade serous ovarian cancer suffer poor prognosis and variable response to treatment. Known prognostic factors for this disease include homologous recombination deficiency status, age, pathological stage and residual disease status after debulking surgery. Recent work has highlighted important prognostic information captured in computed tomography and histopathological specimens, which can be exploited through machine learning. However, little is known about the capacity of combining features from these disparate sources to improve prediction of treatment response. Here, we assembled a multimodal dataset of 444 patients with primarily late-stage high-grade serous ovarian cancer and discovered quantitative features, such as tumor nuclear size on staining with hematoxylin and eosin and omental texture on contrast-enhanced computed tomography, associated with prognosis. We found that these features contributed complementary prognostic information relative to one another and clinicogenomic features. By fusing histopathological, radiologic and clinicogenomic machine-learning models, we demonstrate a promising path toward improved risk stratification of patients with cancer through multimodal data integration.

Imaging features of fumarate hydratase-deficient renal cell carcinomas: a retrospective study.

BACKGOUND: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a subtype of RCC that is increasingly recognized pathologically. The aim of this study was to evaluate the imaging features of FH-RCC on computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG PET), and to determine the pre-operative diagnostic potential of imaging. METHODS: This single-site retrospective study included patients with histologically confirmed FH-RCC or with a renal cancer and known germline FH mutation; imaging of the renal mass before treatment with contrast-enhanced CT, contrast-enhanced MRI, or FDG PET/CT between October 2007 and May 2019. Clinical information, pathological data, and imaging features were analyzed and reported descriptively. RESULTS: Sixteen patients with sixteen tumors were included (median age 46 years, interquartile range 38-53 years; 31 % female). Almost all tumors were unifocal (15/16, 94 %). Most tumors had infiltrative margins (14/16, 88 %); few were circumscribed (2/16, 12 %). A large cystic tumor component (> 75 % of tumor volume) was seen in 8/16 (50 %) of tumors. Involvement of renal sinus fat was seen in 13/16 (81 %) of tumors, involvement of the hilar collecting system in 8/16 (50 %), and renal vein tumor thrombus in 6/16 (38 %). All 12 tumors (100 %) imaged with MRI had heterogenous tumor enhancement and heterogenous T2 signal. Of those patients that had diffusion-weighted imaging, 11/11 (100 %) of tumors had diffusion restriction in the solid portions of the tumor. Of the patients who had PET, 3/3 (100 %) tumors showed high metabolic activity with mean maximum standardized uptake value (SUVmax) of 16.4 (range 9.6-21.9). Patients presented with retroperitoneal nodal metastases in 69 % of cases and distant metastases in 75 %. Of those four patients without metastatic disease at presentation, three (75 %) developed metastases within 4 years of diagnosis. CONCLUSIONS: In our study, the majority of tumors (≥ 75 %) were unifocal, had an infiltrative margin, invaded the renal sinus fat, and presented with distant metastases. On MRI, most tumors had heterogenous T2 signal and diffusion restriction in their solid components. The small number of cases that had PET imaging showed high metabolic activity.

Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking. EXPERIMENTAL DESIGN: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included. RESULTS: A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n = 18, ORR 44%), VEGF monotherapy (n = 15, ORR 20%), checkpoint inhibitor therapy (n = 8, ORR 0%), and mTOR monotherapy (n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3-33.8] and 8.7 months (95% CI: 4.8-12.3), respectively. CONCLUSIONS: Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.

Machine learning-based prediction of microsatellite instability and high tumor mutation burden from contrast-enhanced computed tomography in endometrial cancers.

To evaluate whether radiomic features from contrast-enhanced computed tomography (CE-CT) can identify DNA mismatch repair deficient (MMR-D) and/or tumor mutational burden-high (TMB-H) endometrial cancers (ECs). Patients who underwent targeted massively parallel sequencing of primary ECs between 2014 and 2018 and preoperative CE-CT were included (n = 150). Molecular subtypes of EC were assigned using DNA polymerase epsilon (POLE) hotspot mutations and immunohistochemistry-based p53 and MMR protein expression. TMB was derived from sequencing, with > 15.5 mutations-per-megabase as a cut-point to define TMB-H tumors. After radiomic feature extraction and selection, radiomic features and clinical variables were processed with the recursive feature elimination random forest classifier. Classification models constructed using the training dataset (n = 105) were then validated on the holdout test dataset (n = 45). Integrated radiomic-clinical classification distinguished MMR-D from copy number (CN)-low-like and CN-high-like ECs with an area under the receiver operating characteristic curve (AUROC) of 0.78 (95% CI 0.58-0.91). The model further differentiated TMB-H from TMB-low (TMB-L) tumors with an AUROC of 0.87 (95% CI 0.73-0.95). Peritumoral-rim radiomic features were most relevant to both classifications (p ≤ 0.044). Radiomic analysis achieved moderate accuracy in identifying MMR-D and TMB-H ECs directly from CE-CT. Radiomics may provide an adjunct tool to molecular profiling, especially given its potential advantage in the setting of intratumor heterogeneity.

Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy.

In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.

Imaging features of hepatocellular carcinoma compared to intrahepatic cholangiocarcinoma and combined tumor on MRI using liver imaging and data system (LI-RADS) version 2014.

PURPOSE: To evaluate the prevalence of major and ancillary imaging features from liver imaging reporting and data systems (LI-RADS) version 2014 and their interreader agreement when comparing hepatocellular carcinoma (HCC) to intrahepatic cholangiocarcinoma (ICC) and combined tumor (cHCC-CC). METHODS: The Institutional Review Board approved this HIPAA-compliant retrospective study and waived the requirement for patients' informed consent. Patients with resected HCC (n = 51), ICC (n = 40), and cHCC-CC (n = 11) and available pre-operative contrast-enhanced MRI were included from 2000 to 2015. Imaging features and final LI-RADS category were evaluated by four radiologists. Imaging features were compared by Fisher's exact test and interreader agreements were assessed by κ statistics. RESULTS: None of the features were unique to either HCC or non-HCC. Imaging features that were significantly more common among HCC compared to ICC and cHCC-CC included washout (76%-78% vs. 10%-35%, p < 0.001), capsule (55%-71% vs. 16%-49%, p < 0.05), and intralesional fat (27%-52% vs. 2%-12%, p < 0.002). Features that were more common among ICC and cHCC-CC included peripheral arterial phase hyperenhancement (40%-64% vs. 10%-14%, p < 0.001) and progressive central enhancement (65%-82% vs. 14%-25%, p < 0.001). The interreader agreement was moderate for each of these imaging features (κ = 0.41-0.55). Moderate agreement was also achieved in the assignment of LR-M (κ = 0.53), with an overall sensitivity and specificity for non-HCC malignancy of 86.3% and 78.4%, respectively. CONCLUSION: HCC and non-HCC show significant differences in the prevalence of imaging features defined by LI-RADS, and are identified by radiologists with moderate interreader agreement. Using LI-RADS, radiologists also achieved moderate interreader agreement in the assignment of the LR-M category.