Filamin A Is a Prognostic Serum Biomarker for Differentiating Benign Prostatic Hyperplasia from Prostate Cancer in Caucasian and African American Men.

Prostate cancer represents a significant health risk to aging men, in which diagnostic challenges to the identification of aggressive cancers remain unmet. Prostate cancer screening is driven by the prostate-specific antigen (PSA); however, in men with benign prostatic hyperplasia (BPH) due to an enlarged prostate and elevated PSA, PSA's screening utility is diminished, resulting in many unnecessary biopsies. To address this issue, we previously identified a cleaved fragment of Filamin A (FLNA) protein (as measured with IP-MRM mass spectrometry assessment as a prognostic biomarker for stratifying BPH from prostate cancer and subsequently evaluated its expanded utility in Caucasian (CA) and African American (AA) men. All men had a negative digital rectal examination (DRE) and PSA between 4 and 10 ng/mL and underwent prostate biopsy. In AA men, FLNA serum levels exhibited diagnostic utility for stratifying BPH from patients with aggressive prostate cancer (0.71 AUC and 12.2 OR in 48 men with BPH and 60 men with PCa) and outperformed PSA (0.50 AUC, 2.2 OR). In CA men, FLNA serum levels also exhibited diagnostic utility for stratifying BPH from patients with aggressive prostate cancer (0.74 AUC and 19.4 OR in 191 men with BPH and 109 men with PCa) and outperformed PSA (0.46 AUC, 0.32 OR). Herein, we established FLNA alone as a serum biomarker for stratifying men with BPH vs. those with high Gleason (7-10) prostate cancers compared to the current diagnostic paradigm of using PSA. This approach demonstrates clinical actionability of FLNA alone without the requirement of prostate volume measurement as a test with utility in AA and CA men and represents a significant opportunity to decrease the number of unnecessary biopsies in aggressive prostate cancer diagnoses.

Impact of hemolysis on multi-OMIC pancreatic biomarker discovery to derisk biomarker development in precision medicine studies.

Cancer biomarker discovery is critically dependent on the integrity of biofluid and tissue samples acquired from study participants. Multi-omic profiling of candidate protein, lipid, and metabolite biomarkers is confounded by timing and fasting status of sample collection, participant demographics and treatment exposures of the study population. Contamination by hemoglobin, whether caused by hemolysis during sample preparation or underlying red cell fragility, contributes 0-10 g/L of extraneous protein to plasma, serum, and Buffy coat samples and may interfere with biomarker detection and validation. We analyzed 617 plasma, 701 serum, and 657 buffy coat samples from a 7-year longitudinal multi-omic biomarker discovery program evaluating 400+ participants with or at risk for pancreatic cancer, known as Project Survival. Hemolysis was undetectable in 93.1% of plasma and 95.0% of serum samples, whereas only 37.1% of buffy coat samples were free of contamination by hemoglobin. Regression analysis of multi-omic data demonstrated a statistically significant correlation between hemoglobin concentration and the resulting pattern of analyte detection and concentration. Although hemolysis had the greatest impact on identification and quantitation of the proteome, distinct differentials in metabolomics and lipidomics were also observed and correlated with severity. We conclude that quality control is vital to accurate detection of informative molecular differentials using OMIC technologies and that caution must be exercised to minimize the impact of hemolysis as a factor driving false discovery in large cancer biomarker studies.

Clinical utility of a serum biomarker panel in distinguishing prostate cancer from 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.

Elevated levels of mitochondrial CoQ10 induce ROS-mediated apoptosis in pancreatic cancer.

Reactive oxygen species (ROS) are implicated in triggering cell signalling events and pathways to promote and maintain tumorigenicity. Chemotherapy and radiation can induce ROS to elicit cell death allows for targeting ROS pathways for effective anti-cancer therapeutics. Coenzyme Q10 is a critical cofactor in the electron transport chain with complex biological functions that extend beyond mitochondrial respiration. This study demonstrates that delivery of oxidized Coenzyme Q10 (ubidecarenone) to increase mitochondrial Q-pool is associated with an increase in ROS generation, effectuating anti-cancer effects in a pancreatic cancer model. Consequent activation of cell death was observed in vitro in pancreatic cancer cells, and both human patient-derived organoids and tumour xenografts. The study is a first to demonstrate the effectiveness of oxidized ubidecarenone in targeting mitochondrial function resulting in an anti-cancer effect. Furthermore, these findings support the clinical development of proprietary formulation, BPM31510, for treatment of cancers with high ROS burden with potential sensitivity to ubidecarenone.

A phase I safety study of topical calcitriol (BPM31543) for the prevention of chemotherapy-induced alopecia.

PURPOSE: Chemotherapy-induced alopecia (CIA) negatively affects psychosocial health and quality of life (QoL). Currently, there are no approved pharmacologic agents to prevent CIA. Here, we evaluated the safety, tolerability, and potential signal of efficacy of topical calcitriol (BPM31543) on CIA prevention. MATERIALS AND METHODS: This Phase 1 trial included 23 female patients with breast cancer, gynecologic cancer, or sarcomas receiving a taxane-based chemotherapy. Patients received a 3 + 3 dose-escalation regimen at 5, 10, 20, 40, 60, and 80 µg/mL, with 3-6 patients per group. Patients applied topical BPM31543 to the scalp twice a day for 2 weeks prior to chemotherapy and continued until chemotherapy treatment was completed. The maximum tolerated dose (MTD) during first 28 day application was determined. Adverse event (AE) monitoring, pharmacokinetics, blinded photographic assessments, and patient self-assessment were evaluated. RESULTS: Out of 23 patients treated with BPM31543, 8 patients experienced at least 1 treatment-related adverse event (AE). The majority of AEs were mild to moderate in severity. Only 1 patient experienced SAEs (vomiting, nausea, fever, and flank pain) considered treatment related. Alopecia < 50% from baseline was observed in 8 patients at Week 7, and, of which 2 patients had < 50% alopecia maintained at Week 15. There were no detectable effects of topical BPM31543 on serum levels of calcitriol. CONCLUSIONS: BPM31543 applied topically twice daily to the scalp is safe and well tolerated in patients receiving taxane-based chemotherapy. No DLT was observed at up to 80 µg/mL, and MTD was not reached. Based on the data from this trial, BPM31543 represents a promising therapy and warrants further investigation in Phase 2/3 trials.

Multi-omic serum biomarkers for prognosis of disease progression in prostate cancer.

BACKGROUND: Predicting the clinical course of prostate cancer is challenging due to the wide biological spectrum of the disease. The objective of our study was to identify prostate cancer prognostic markers in patients 'sera using a multi-omics discovery platform. METHODS: Pre-surgical serum samples collected from a longitudinal, racially diverse, prostate cancer patient cohort (N = 382) were examined. Linear Regression and Bayesian computational approaches integrated with multi-omics, were used to select markers to predict biochemical recurrence (BCR). BCR-free survival was modeled using unadjusted Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis, adjusted for key pathologic variables. Receiver operating characteristic (ROC) curve statistics were used to examine the predictive value of markers in discriminating BCR events from non-events. The findings were further validated by creating a training set (N = 267) and testing set (N = 115) from the cohort. RESULTS: Among 382 patients, 72 (19%) experienced a BCR event in a median follow-up time of 6.9 years. Two proteins-Tenascin C (TNC) and Apolipoprotein A1V (Apo-AIV), one metabolite-1-Methyladenosine (1-MA) and one phospholipid molecular species phosphatidic acid (PA) 18:0-22:0 showed a cumulative predictive performance of AUC = 0.78 [OR (95% CI) = 6.56 (2.98-14.40), P < 0.05], in differentiating patients with and without BCR event. In the validation set all four metabolites consistently reproduced an equivalent performance with high negative predictive value (NPV; > 80%) for BCR. The combination of pTstage and Gleason score with the analytes, further increased the sensitivity [AUC = 0.89, 95% (CI) = 4.45-32.05, P < 0.05], with an increased NPV (0.96) and OR (12.4) for BCR. The panel of markers combined with the pathological parameters demonstrated a more accurate prediction of BCR than the pathological parameters alone in prostate cancer. CONCLUSIONS: In this study, a panel of serum analytes were identified that complemented pathologic patient features in predicting prostate cancer progression. This panel offers a new opportunity to complement current prognostic markers and to monitor the potential impact of primary treatment versus surveillance on patient oncological outcome.

Return-to-Duty Rates Following Minimally Invasive Spine Surgery Performed on Active Duty Military Patients in an Ambulatory Surgery Center.

BACKGROUND: Low back pain is a primary health care utilization driver in the US population. Health care evaluation visits for low back pain are as common as medical evaluation for the common cold. Low back pain is the most common reason for reductions in activities of daily living and work activity in the general population. Although these statistics are compelling, in the military population, there is arguably a significantly greater economic impact on the military population, as the cost to train, retain, and deploy a service member is a tremendous cost. METHODS: The current study retrospectively examines surgical outcomes, return to duty, and patient-centric outcomes among 82 active duty or reserve military patients who underwent an outpatient minimally invasive spine surgery Laminotomy Foraminotomy Decompression for the treatment of lumbar spinal stenosis in an ambulatory surgery center. FINDINGS: Overall, our results indicate that within the 82 active duty military service members, 100% of the service members return to duty within 3 mo. Additionally, there was a significant reduction in self-reported pain and disability 12 mo postoperative, whereas the average length of surgery was 62 min with an average estimated blood loss of 30.64 mL. DISCUSSION: The current study indicates that minimally invasive procedures for the treatment of lumbar spinal stenosis in an ambulatory surgery center setting are an effective option for active duty servicemen to reduce return-to-duty rates and symptomatic back-related pain and disability.

Cancer incidence in the U.S. military population: comparison with rates from the SEER program.

The U.S. active-duty military population may differ from the U.S. general population in its exposure to cancer risk factors and access to medical care. Yet, it is not known if cancer incidence rates differ between these two populations. We therefore compared the incidence of four cancers common in U.S. adults (lung, colorectal, prostate, and breast cancers) and two cancers more common in U.S. young adults (testicular and cervical cancers) in the military and general populations. Data from the Automated Central Tumor Registry (ACTUR) of the Department of Defense and the nine cancer registries of the Surveillance, Epidemiology and End Results (SEER) of the National Cancer Institute for the years 1990 to 2004 for persons with ages 20 to 59 years were analyzed. Incidence rates were significantly lower in the military population for colorectal cancer in White men, lung cancer in White and Black men and White women, and cervical cancer in Black women. In contrast, incidence rates of breast and prostate cancers were significantly higher in the military among Whites and Blacks. Incidence rates of testicular cancer did not differ between ACTUR and SEER. Although the numbers of diagnoses among military personnel were relatively small for temporal trend analysis, we found a more prominent increase in prostate cancer in ACTUR than in SEER. Overall, these results suggest that cancer patterns may differ between military and nonmilitary populations. Further studies are needed to confirm these findings and explore contributing factors.

Use of six clinical preventive services in TRICARE Prime compared to insured, managed care, and all U.S. populations and Healthy People 2010.

OBJECTIVES: Timely preventive healthcare services are important to troop readiness and the health of Military Health System (MHS) beneficiaries. Prior studies have reported on use of preventive care among select MHS subgroups, but broader performance is undocumented. This study addresses that gap by comparing TRICARE Prime beneficiaries to select U.S. populations. METHODS: Rates of prenatal care in the first trimester, flu shots, and screening for breast cancer, cervical cancer, cholesterol, and blood pressure were estimated from the 2004 Health Care Survey of Department of Defense (DoD) Beneficiaries. Rates for U.S. populations were estimated from several national health surveys. Healthy People 2010 goals provided a comparison benchmark. RESULTS: Utilization rates of TRICARE Prime enrollees significantly exceeded the U.S. population for all services examined and exceeded the insured U.S. population for flu shots, prenatal care, and screening for breast cancer and cervical cancer. Two Healthy People 2010 goals were met but three were not. CONCLUSIONS: TRICARE Prime enrollees had similar rates of six clinical preventive care services as insured U.S. populations in 2004, but failed to meet several Healthy People 2010 guidelines. Increased emphasis on these services will be required in order to meet such objectives and reduce long-term health and financial pressures on the MHS.