Fluorine-18 Prostate-Specific Membrane Antigen-1007 PET/CT vs Multiparametric MRI for Locoregional Staging of Prostate Cancer.

Importance: Prostate-specific membrane antigen (PSMA) demonstrates overexpression in prostate cancer and correlates with tumor aggressiveness. PSMA positron emission tomography (PET) is superior to conventional imaging for the metastatic staging of prostate cancer per current research but studies of second-generation PSMA PET radioligands for locoregional staging are limited. Objective: To determine the accuracy of fluorine-18 PSMA-1007 PET/computed tomography (18F-PSMA-1007 PET/CT) compared to multiparametric magnetic resonance imaging (MRI) in the primary locoregional staging of intermediate-risk and high-risk prostate cancers. Design, Setting, and Participants: The Next Generation Trial was a phase 2 prospective validating paired cohort study assessing the accuracy of 18F-PSMA-1007 PET/CT and MRI for locoregional staging of prostate cancer, with results of histopathologic examination as the reference standard comparator. Radiologists, nuclear medicine physicians, and pathologists were blinded to preoperative clinical, pathology, and imaging data. Patients underwent all imaging studies and radical prostatectomies at 2 tertiary care hospitals in Alberta, Canada. Eligible participants included men with intermediate-risk or high-risk prostate cancer who consented to radical prostatectomy. Participants who underwent radical prostatectomy were included in the final analysis. Patients were recruited between March 2022 and June 2023, and data analysis occurred between July 2023 and December 2023. Exposures: All participants underwent both 18F-PSMA-1007 PET/CT and MRI within 2 weeks of one another and before radical prostatectomy. Main Outcomes and Measures: The primary outcome was the correct identification of the prostate cancer tumor stage by each imaging test. The secondary outcomes were correct identification of the dominant nodule, laterality, extracapsular extension, and seminal vesical invasion. Results: Of 150 eligible men with prostate cancer, 134 patients ultimately underwent radical prostatectomy (mean [SD] age at prostatectomy, 62.0 [5.7] years). PSMA PET was superior to MRI for the accurate identification of the final pathological tumor stage (61 [45%] vs 38 [28%]; P = .003). PSMA PET was also superior to MRI for the correct identification of the dominant nodule (126 [94%] vs 112 [83%]; P = .01), laterality (86 [64%] vs 60 [44%]; P = .001), and extracapsular extension (100 [75%] vs 84 [63%]; P = .01), but not for seminal vesicle invasion (122 [91%] vs 115 [85%]; P = .07). Conclusions and Relevance: In this phase 2 prospective validating paired cohort study, 18F-PSMA-1007 PET/CT was superior to MRI for the locoregional staging of prostate cancer. These findings support PSMA PET in the preoperative workflow of intermediate-risk and high-risk tumors.

Prognostic Value of ADAMTS Proteases and Their Substrates in Epithelial Ovarian Cancer.

BACKGROUND: ADAMTS are metalloproteases with disintegrin and thrombospondin motifs. They are secreted proteases playing a role in biological processes such as inflammation, angiogenesis, and urogenital development. ADAMTS have specific substrates, such as the proteoglycans (PG) versican, aggrecan, and brevican. Despite data indicating a role of ADAMTS in tumor invasion and metastases, effects played by these molecules in cancer progression are still controversial. In ovarian cancer, the importance of ADAMTS gene mutations was recently described and related to chemotherapy outcome. OBJECTIVE: To analyze protein levels of ADAMTS-1, -4, and -5, and TIMP-3 in human ovarian cancer classified as benign, borderline, or malignant. We also assessed the expression of the ADAMTS substrates aggrecan, brevican, and versican in these neoplasms. Correlations between overall survival and protein expression were performed. METHODS: Tumors were classified according to the WHO Classification of Tumors of Female Reproductive Organs. Protein and PG expression was studied by immunohistochemistry. Differences in labeling were analyzed by percent measurements of stained areas. RESULTS: ADAMTS-1, ADAMTS-5, and its tissue inhibitor TIMP-3 are increased in borderline and malignant tumors compared to benign neoplasms. Aggrecan and versican levels were increased in malignant subtypes compared to benign ovarian cancer. Higher ADAMTS-1, TIMP-3, and versican expression was associated with a shorter overall survival. CONCLUSIONS: Comparison of protease, TIMP-3, and substrate expression showed that in malignant tumors all ADAMTS and TIMP-3 expression levels were significantly raised compared to the substrates studied.

Integrated Genomic Analysis of Pancreatic Ductal Adenocarcinomas Reveals Genomic Rearrangement Events as Significant Drivers of Disease.

Many somatic mutations have been detected in pancreatic ductal adenocarcinoma (PDAC), leading to the identification of some key drivers of disease progression, but the involvement of large genomic rearrangements has often been overlooked. In this study, we performed mate pair sequencing (MPseq) on genomic DNA from 24 PDAC tumors, including 15 laser-captured microdissected PDAC and 9 patient-derived xenografts, to identify genome-wide rearrangements. Large genomic rearrangements with intragenic breakpoints altering key regulatory genes involved in PDAC progression were detected in all tumors. SMAD4, ZNF521, and FHIT were among the most frequently hit genes. Conversely, commonly reported genes with copy number gains, including MYC and GATA6, were frequently observed in the absence of direct intragenic breakpoints, suggesting a requirement for sustaining oncogenic function during PDAC progression. Integration of data from MPseq, exome sequencing, and transcriptome analysis of primary PDAC cases identified limited overlap in genes affected by both rearrangements and point mutations. However, significant overlap was observed in major PDAC-associated signaling pathways, with all PDAC exhibiting reduced SMAD4 expression, reduced SMAD-dependent TGFß signaling, and increased WNT and Hedgehog signaling. The frequent loss of SMAD4 and FHIT due to genomic rearrangements strongly implicates these genes as key drivers of PDAC, thus highlighting the strengths of an integrated genomic and transcriptomic approach for identifying mechanisms underlying disease initiation and progression.

Genomic rearrangements define lineage relationships between adjacent lepidic and invasive components in lung adenocarcinoma.

The development of adenocarcinoma of the lung is believed to proceed from in situ disease (adenocarcinoma in situ, AIS) to minimally invasive disease with prominent lepidic growth (minimally invasive adenocarcinoma, MIA), then to fully invasive adenocarcinoma (AD), but direct evidence for this model has been lacking. Because some lung adenocarcinomas show prominent lepidic growth (AD-L), we designed a study to address the lineage relationship between the lepidic (noninvasive) component (L) and the adjacent nonlepidic growth component representing invasive disease within individual tumors. Lineage relationships were evaluated by next-generation DNA sequencing to define large genomic rearrangements in microdissected tissue specimens collected by laser capture. We found a strong lineage relationship between the majority of adjacent lepidic and invasive components, supporting a putative AIS-AD transition. Notably, many rearrangements were detected in the less aggressive lepidic component, although the invasive component exhibited an overall higher rate of genomic rearrangement. Furthermore, a significant number of genomic rearrangements were present in histologically normal lung adjacent to tumor, but not in host germline DNA, suggesting field defects restricted to zonal regions near a tumor. Our results offer a perspective on the genetic pathogenesis underlying adenocarcinoma development and its clinical management.

Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor.

BACKGROUND & AIMS: Increasing grade of pancreatic intraepithelial neoplasia (PanIN) has been associated with progression to pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that control progression from PanINs to PDAC are not well understood. We investigated the genetic alterations involved in this process. METHODS: Genomic DNA samples from laser-capture microdissected PDACs and adjacent PanIN2 and PanIN3 lesions from 10 patients with pancreatic cancer were analyzed by exome sequencing. RESULTS: Similar numbers of somatic mutations were identified in PanINs and tumors, but the mutational load varied greatly among cases. Ten of the 15 isolated PanINs shared more than 50% of somatic mutations with associated tumors. Mutations common to tumors and clonally related PanIN2 and PanIN3 lesions were identified as genes that could promote carcinogenesis. KRAS and TP53 frequently were altered in PanINs and tumors, but few other recurrently modified genes were detected. Mutations in DNA damage response genes were prevalent in all samples. Genes that encode proteins involved in gap junctions, the actin cytoskeleton, the mitogen-activated protein kinase signaling pathway, axon guidance, and cell-cycle regulation were among the earliest targets of mutagenesis in PanINs that progressed to PDAC. CONCLUSIONS: Early stage PanIN2 lesions appear to contain many of the somatic gene alterations required for PDAC development.