This study reports on the development of a novel serum protein panel of three prostate cancer biomarkers, Filamin A, Filamin B and Keratin-19 (FLNA, FLNB and KRT19) using multivariate models for disease screening and prognosis. ELISA and IPMRM (LC-MS/MS) based assays were developed and analytically validated by quantitative measurements of the biomarkers in serum. Retrospectively collected and clinically annotated serum samples with PSA values and Gleason scores were analyzed from subjects who underwent prostate biopsy, and showed no evidence of cancer with or without indication of prostatic hyperplasia, or had a definitive pathology diagnosis of prostatic adenocarcinoma. Probit linear regression models were used to combine the analytes into score functions to address the following clinical questions: does the biomarker test augment PSA for population screening? Can aggressive disease be differentiated from lower risk disease, and can the panel discriminate between prostate cancer and benign prostate hyperplasia? Modelling of the data showed that the new prostate biomarkers and PSA in combination were better than PSA alone in identifying prostate cancer, improved the prediction of high and low risk disease, and improved prediction of cancer versus benign prostate hyperplasia.

Prostate-specific antigen (PSA) screening for prostate cancer (PCa) is limited by the lack of specificity but is further complicated in the benign prostatic hyperplasia (BPH) population which also exhibit elevated PSA, representing a clear unmet need to distinguish BPH from PCa. Herein, we evaluated the utility of FLNA IP-MRM, age, and prostate volume to stratify men with BPH from those with PCa. Diagnostic performance of the biomarker panel was better than PSA alone in discriminating patients with negative biopsy from those with PCa, as well as those who have had multiple prior biopsies (AUC 0.75 and 0.87 compared to AUC of PSA alone 0.55 and 0.57 for patients who have had single compared to multiple negative biopsies, respectively). Of interest, in patients with PCa, the panel demonstrated improved performance than PSA alone in those with Gleason scores of 5–7 (AUC 0.76 vs. 0.56) and Gleason scores of 8–10 (AUC 0.74 vs. 0.47). With Gleason scores (8–10), the negative predictive value of the panel is 0.97, indicating potential to limit false negatives in aggressive cancers. Together, these data demonstrate the ability of the biomarker panel to perform better than PSA alone in men with BPH, thus preventing unnecessary biopsies.

Parkinson’s disease is a progressive neurodegenerative disorder in which loss of dopaminergic neurons in the substantia nigra results in a clinically heterogeneous group with variable motor and non-motor symptoms with a degree of misdiagnosis. Only 3-5% of sporadic Parkinson’s patients present with genetic abnormalities, thus environmental, metabolic, and other unknown causes contribute to the pathogenesis of Parkinson’s disease, which highlights the critical need for biomarkers. There could be a significant clinical benefit to treating Parkinson’s disease at the earliest stage and identify at-risk populations once disease-modifying treatments are available. In the present study, we prospectively collected and analyzed plasma samples from 201 Parkinson’s disease patients and 199 age-matched non-diseased controls. Multiomic and Bayesian artificial intelligence analysis of molecular and clinical data identified the diagnostic utility of N-acetyl putrescine (NAP) in combination with smell (B-SIT), depression/anxiety (HADS), and acting out dreams (RBD1Q) clinical measurements. The clinical and biomarker panel demonstrated an area under the curve, AUC = 0.9, positive predictive value, PPV=0.91, and negative predictive value, NPV=0.66 utilizing all four variables. The assessed diagnostic panel demonstrates combinatorial utility in diagnosing Parkinson’s disease, allowing for an integrated interpretation of disease pathophysiology and highlighting the use of multi-tiered panels in neurological disease diagnosis.

Background: Prostate cancer (PrCa) is a leading cause of cancer deaths in males in the US. Current tests of prostate-specific antigen (PSA) screening and the diagnostic prostate biopsy are often inconclusive. Many patients with a PSA positive blood test often undergo invasive repeat biopsy procedures. Additionally, there is a need for diagnostic tests that differentiate between low and high-risk cancers. This study reports on the development of a novel serum protein panel of three PrCa biomarkers, Filamin A, Filamin B and Keratin-19 (FLNA, FLNB and KRT19) using multivariate models for disease screening and prognosis. Methods: ELISA and IPMRM (LC-MS/MS) based assays were developed and analytically validated by quantitative measurements of the biomarkers in serum. Retrospectively collected and clinically annotated serum samples with PSA values and Gleason scores (GS) were analyzed from 503 subjects who underwent prostate biopsy, and showed no evidence of cancer with or without indication of prostatic hyperplasia, or had a definitive pathology diagnosis of prostatic adenocarcinoma. Probit linear regression models were used to combine the analytes into score functions to address the following clinical questions: does the biomarker test augment PSA for population screening? Can aggressive disease be differentiated from lower risk disease, and can the panel discriminate between benign prostate hyperplasia (BPH) and PrCa? Results: Table 1: Berg PrCa Panel AUC summary for the four clinical indications. Conclusion: As shown in Table 1, modelling of the data demonstrated that the new PrCa biomarkers and PSA in combination were better than PSA alone in identifying PrCa, improved the prediction of high and low risk disease, and improved prediction of BPH versus PrCa. Citation Format: Shobha Ravipaty, Wenfang Wu, Aditee Dalvi, Nikunj Tanna, Joe Andreazi, Tracey Friss, Allison Klotz, Chenchen Liao, Jeonifer Garren, Sally Schofield, Eleftherios P. Diamandis, Eric A. Klein, Albert Dobi, Shiv Srivastava, Poornima Tekumalla, Michael A. Kiebish, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain, Viatcheslav Akmaev. Clinical validation of a serum protein panel (FLNA, FLNB and KRT19) for diagnosis and prognosis of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3826. doi:10.1158/1538-7445.AM2017-3826

Background: Prostate-specific antigen (PSA) based screening tests have been considered as a benchmark for PCa diagnosis (PSA >4 ng/mL), however, in recent years their use has been widely debated due to various limitations. In particular, increased PSA levels are also observed in patients with benign prostatic hyperplasia (BPH) thus generating a false positive. These patients are often subjected to unnecessary prostate biopsies and have to endure both physical and mental anguish. Thus, there is a clear unmet need to develop molecular diagnostics that stratifies men with BPH from those that have PCa and prevent unwarranted prostate biopsies in symptomatic, DRE negative men. Here in, we demonstrate clinical utility of a validated biomarker panel (FLNA, KRT 19) in combination with age and prostate volume in stratifying BPH from PCa patients. Methods: This study was conducted using retrospectively collected and clinically annotated serum samples from 203 BPH patients and 333 PCa patients with PSA values ranging from 4-10ng/mL. These samples included BPH patients with negative Digital Rectum Exam, single biopsy and repeat biopsies, and prostate cancer patients undergoing radical prostatectomy. Validated bioanalytical assays (FLNA ELISA, FLNA IPMRM and KRT19 ELISA) were used to quantitate the serum biomarkers. Regression models were built and compared for their ability to distinguish patients with BPH from those with PCa. Results: Table 1: Summary of predictive power analysis of PCa panel (49 characters) BERG TestPSAAUC0.80.54Sensitivity0.8n/aSpecificity0.62n/aPPV0.78n/aNPV0.65n/aOR (CI)6.67 (4.49,9.90)n/a Conclusion: The data demonstrates that these PCa biomarkers in combination with age, and prostatic volume were significantly better than (0.8) PSA (0.54 AUC in this population) in identifying men with BPH rather than PCa thus preventing unnecessary biopsies for this population. Moreover, this panel may be used in clinical decision support to physicians to fill a clinical unmet need. Citation Format: Michael A. Kiebish, Poornima Tekmulla, Shobha Ravipaty, Wenfang Wu, Tracey Friss, Chenchen Liao, Allison Klotz, Joe Andreazi, Elisabeth Hutchins, Albert Dobi, Shiv Srivastava, Jennifer Cullen, Amina Ali, Stephen Freedland, Kagan Griffin, Sandra Laszlo, Michele Petrovic, Neil Fleshner, Jeonifer Garren, Leonardo Rodrigues, Mark D. Kellog, Viatcheslav R. Akmaev, Rangaprasad Sarangarajan, Niven R. Narain. Clinical utility of a serum protein biomarker panel (FLNA, KRT19) in stratification of prostate cancer from benign prostate hyperplasia patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-219.