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Benign prostatic hyperplasia (BPH) may decrease patient quality of life and often leads to acute urinary retention and surgical intervention. While effective treatments are available, many BPH patients do not respond or develop resistance to treatment. To understand molecular determinants of clinical symptom persistence after initiating BPH treatment, we investigated gene expression profiles before and after treatments in the prostate transitional zone of 108 participants in the Medical Therapy of Prostatic Symptoms (MTOPS) Trial. Unsupervised clustering revealed molecular subgroups characterized by expression changes in a large set of genes associated with resistance to finasteride, a 5α-reductase inhibitor. Pathway analyses within this gene cluster found finasteride administration induced changes in fatty acid metabolism, amino acid metabolism, immune response, steroid hormone metabolism, and kinase activity within the transitional zone. We found that patients without this transcriptional response were highly likely to develop clinical progression, which is expected in 13.2% of finasteride-treated patients. Importantly, a patient’s transcriptional response to finasteride was associated with their pre-treatment kinase expression. Further, we identified novel expression signatures of finasteride resistance among the transcriptionally responded patients. These patients showed different gene expression profiles at baseline and increased prostate transitional zone volume compared to the patients who responded to the treatment. Our work suggests molecular mechanisms of clinical resistance to finasteride treatment that could be potentially helpful for personalized BPH treatment as well as new drug development to increase patient drug response.

African American men face a stark prostate cancer (PCa)‐related health disparity, with the highest incidence and mortality rates compared to other races. Additional and innovative measures are warranted to reduce this health disparity. Here, we focused on the identification of a novel serum exosome‐based “protein signature” for potential use in the early detection and better prognosis of PCa in African American men. Nanoparticle tracking analyses showed that compared to healthy individuals, exosome concentration (number/ml) was increased by ~3.2‐fold (P ˂ 0.05) in the sera of African American men with PCa. Mass spectrometry‐based proteomic analysis of serum exosomes identified seven unique and fifty‐five overlapping proteins (up‐ or downregulated) in African Americans with PCa compared to healthy African Americans. Furthermore, ingenuity pathway analyses identified the inflammatory acute‐phase response signaling as the top pathway associated with proteins loaded in exosomes from African American PCa patients. Interestingly, African American PCa E006AA‐hT cells secreted exosomes strongly induced a proinflammatory M2‐phenotype in macrophages and showed calcium response on sensory neurons, suggesting a neuroinflammatory response. Additionally, proteomic analyses showed that the protein Isoform 2 of Filamin A has higher loading (2.6‐fold) in exosomes from African Americans with PCa, but a lesser loading (0.6‐fold) was observed in exosomes from Caucasian men with PCa compared to race‐matched healthy individuals. Interestingly, TCGA and Taylor's dataset as well as IHC analyses of PCa tissue showed a lower Filamin A expression in tissues of PCa patients compared with normal subjects. Overall, these results support the usefulness of serum exosomes to noninvasively detect inflammatory phenotype and to discover novel biomarkers associated with PCa in African American men. In this work, we characterized the proteins loaded in exosomes isolated from the serum of African American prostate cancer patients and identified a novel protein signature.

Background Cancer cachexia is an underrecognized condition characterized by weight loss and muscle wasting resulting from altered metabolism and systemic inflammation. While this comorbid condition is associated with surgical complications and poorer prognosis in other cancer types, its prevalence in epithelial ovarian cancer is not well described. We evaluated the prevalence of cachexia in patients with epithelial ovarian cancer and clinical characteristics associated with cachexia. Methods A retrospective cohort study with longitudinal follow up was performed on 374 patients who underwent cytoreductive surgery for epithelial ovarian cancer. Adult patients, without risk factors for sarcopenia, who underwent surgery from January 2014-June 2024 were evaluated for preoperative weight, skeletal muscle index, demographics, physical and tumor characteristics, oncologic treatment, and outcomes with cancer cachexia. Results Cancer cachexia was common (> 50% of cohort) and more frequently observed in patients who had interval cytoreductive surgery (odds ratio [OR] 3.34, 95% CI 2.16–5.06), required preoperative paracentesis or thoracentesis (OR 4.45, 95% CI 2.73–7.28), had advanced-stage disease (OR 3.76, 95% CI 2.17–6.57), serous histology (OR 1.87, 95% CI 1.12–3.11), and aberrant p53 expression (OR 1.77, 95% CI 1.11–2.78). Median Cancer Antigen 125 (CA-125) was higher in the population of patients with cachexia than among those without ( p  < 0.0001), though discriminatory performance was modest. Cachexia was associated with shorter disease-free survival and overall survival. Median disease-free survival was 19.8 months in patients with cachexia compared with 42.0 months in those without (log-rank p  < 0.0001). Median overall survival was 51.2 months versus 72.0 months, respectively (log-rank p  = 0.02). Conclusions Over half of patients with epithelial ovarian cancer will have cachexia at the time of cytoreductive surgery. Risk factors for cachexia include interval cytoreductive surgery, need for paracentesis, advanced stage, serous histology, and aberrant p53 expression. Disease-free survival and overall survival are worse in patients with cachexia compared to those without. Highlights Specific patient and tumor characteristics increase the risk of cancer cachexia. Gynecologic oncologists must be aware of the implications of cancer cachexia on patient outcomes.

Metastatic breast cancer (mBC) tissue in bone was systematically profiled to define the composition of the tumor microenvironment. Gene expression identified a high myeloid signature of patients with improved survival outcomes. Bone metastases were profiled by spatial proteomics to examine myeloid populations within the stroma that correlated with macrophage functions. Single-cell spatial analysis uncovered macrophage activation in the stroma of mBC bone lesions. Matched BC patient samples of primary breast tumor and bone metastasis tissues were compared for gene expression in the bone, where bone morphogenetic protein 2 ( BMP2 ) was most significantly upregulated. Immune cell changes from breast to bone demonstrated a loss of lymphoid cells but a consistent population of macrophages. BMP-activated macrophages were increased uniquely in bone. Bone marrow–derived macrophage activation coupled with BMP inhibition increased inflammatory responses. Using experimental mouse models of mBC bone metastasis and trained immunity, we found that BMP inhibition restricts progression of metastases early in the macrophage activation state but not after tumors were established in the bone. This study revealed unique myeloid BMP activation states that are distinctly integrated with bone metastases.

Zinc-finger E-box-binding homeobox 1 (ZEB1) is a transcription factor containing two clusters of Kruppel-type zinc-fingers, by which it binds E-box-like sequences on target DNAs. A role for ZEB1 in tumor progression, specifically, epithelial to mesenchymal transitions, has recently been revealed. ZEB1 acts as a master repressor of E-cadherin and other epithelial markers. We previously demonstrated that ZEB1 is confined to the stromal compartment in normal endometrium and low-grade endometrial cancers. Here, we quantify ZEB1 protein expression in endometrial samples from 88 patients and confirm that it is expressed at significantly higher levels in the tumor-associated stroma of low-grade endometrioid adenocarcinomas (type I endometrial cancers) compared to hyperplastic or normal endometrium. In addition, as we previously reported, ZEB1 is aberrantly expressed in the epithelial-derived tumor cells of highly aggressive endometrial cancers, such as FIGO grade 3 endometrioid adenocarcinomas, uterine serous carcinomas, and malignant mixed Müllerian tumors (classified as type II endometrial cancers). We now demonstrate, in both human endometrial cancer specimens and cell lines, that when ZEB1 is inappropriately expressed in epithelial-derived tumor cells, E-cadherin expression is repressed, and that this inverse relationship correlates with increased migratory and invasive potential. Forced expression of ZEB1 in the nonmigratory, low-grade, relatively differentiated Ishikawa cell line renders them migratory. Conversely, reduction of ZEB1 in a highly migratory and aggressive type II cell line, Hec50co, results in reduced migratory capacity. Thus, ZEB1 may be a biomarker of aggressive endometrial cancers at high risk of recurrence. It may help identify women who would most benefit from chemotherapy. Furthermore, if expression of ZEB1 in type II endometrial cancers could be reversed, it might be exploited as therapy for these highly aggressive tumors.

Background: Plant derivatives have been studied as therapies for prostate cancer based on their purported anti-inflammatory and antioxidant properties and low toxicities. The acai berry is an example of a plant rich in phytochemicals, which may slow the growth of prostate cancer. Methods: This was a phase II, Simon 2-stage clinical trial in patients with biochemically recurrent prostate cancer with a primary endpoint of prostate-specific antigen (PSA) response. Patients were asymptomatic, with a rising PSA of at least 0.2 ng/mL, and were treated with twice daily intake of Acai Juice Product until PSA progression, with a primary endpoint of PSA response. Results: Twenty-one patients were enrolled in the first stage of the trial. One of those patients had a PSA response within the study time period. The PSA doubling time was lengthened in 71% of patients (95% confidence interval = 48% to 89%) on the trial, and in a small number of responders, this was sustained over an extended time. Conclusions: This study did not meet its primary endpoint of 50% PSA response. Nevertheless, the overall tolerability and effects on PSA stabilization warrant further exploration in a biochemically recurrent population.

Proper grading of the cribriform prostate cancer pattern has not previously been supported by outcome-based evidence. Among 153 men who underwent radical prostatectomy, 76 with prostate-specific antigen (PSA) failure (≥0.2 ng/mL [0.2 μg/L]) were matched to 77 without failure. Frequencies of high-grade patterns included fused small acini, 83.7%; papillary, 52.3%; large cribriform, 37.9%; small (≤12 lumens) cribriform, 17.0%; and individual cells, 22.9%. A cribriform pattern was present in 61% (46/76) of failures but 16% (12/77) of nonfailures (P < .0001). Multivariate analysis showed the cribriform pattern had the highest odds ratio for PSA failure, 5.89 (95% confidence interval, 2.53-13.70; P < .0001). The presence of both large and small cribriform patterns was significantly linked to failure. The cumulative odds ratio of failure per added square millimeter of cribriform pattern was 1.173 (P = .008), higher than for any other pattern. All 8 men with a cribriform area sum of 25 mm(2) or more had failure (range, 33-930). Regrading cribriform cancer as Gleason 5 improved the grade association with failure, although half of all cases with individual cells also had a cribriform pattern, precluding a precise determination of the independent importance of the latter. The cribriform pattern has particularly adverse implications for outcome.

Some, but not all, epidemiologic studies report an association between vitamin D and prostate cancer risk. The inconsistent findings might be explained in the context of modification by members of the insulin-like growth factor (IGF) axis. Data and specimens for this nested case-control study (n = 1695 cases and n = 1682 controls) are from the Prostate Cancer Prevention Trial (PCPT). Baseline serum samples were assayed for 25(OH)D, IGF-1, IGF-2, IGFBP-2, IGFBP-3, and the ratio of IGF1:BP3, along with insulin-related markers c-peptide and leptin. The presence of prostate cancer was assessed by prostate biopsy. Multivariate logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) for prostate cancer risk. There were no interactions between serum 25(OH)D and IGF analytes in relation to prostate cancer risk when PCPT treatment arms were combined. In the placebo arm, above median serum 25(OH)D levels were associated with increased risk of prostate cancer among men with higher IGF-2 (OR:1.33, 95% CI: 1.00–1.65), with a significant interaction between 25(OH)D and treatment arm (Pinteraction = 0.04). Additionally, there was an interaction between treatment arm and serum IGFBP-3 (Pinteraction = 0.03). Higher serum 25(OH)D may increase risk of prostate cancer in the presence of higher circulating IGF-2.

Members of the p160 steroid receptor cofactor family, including AIB1 (Amplified in Breast Cancer 1) (also known as SRC-3/RAC3/ACTR/pCIP/TRAM-1), are of interest in endometrial carcinoma as they affect the function of estrogen (ER) and progesterone receptors (PR). Since it is feasible that alterations in the expression levels of coregulators can either augment ER activity or reduce the ability of PR to oppose ER action in endometrial cancers, our primary aim was to analyze expression of the AIB1 protein in endometrial carcinoma, carcinoma-associated complex atypical hyperplasia, and carcinoma-associated normal endometrium using immunohistochemistry and tissue microarrays. Expression of AIB1 was compared with other biomarkers and clinicopathologic parameters. We also tested AIB1 expression in non-carcinoma associated hyperplastic, normal secretory and proliferative endometrium to determine baseline AIB1 levels. In endometrial carcinoma, there is a higher expression of AIB1 compared to carcinoma-associated complex atypical hyperplasia (0.007) or carcinoma-associated normal endometrium (<0.001). AIB1 expression correlates with older age (P=0.003), peri- or postmenopausal status (P=0.002) and a higher grade of carcinomas (P=0.04). There were no differences in the expression of additional steroid hormone receptor co-activators (SRC-1 and p300/CBP) and the co-repressor SMRT between histologic categories. AIB1 expression correlated with ER (r=0.30, P=0.006). The strongest correlation was between ER and PR-B isoform nuclear expression (r=0.52, P<0.0001). AIB1 levels were higher in non-carcinoma associated normal and hyperplastic endometrium compared to carcinoma-associated complex atypical hyperplasia and carcinoma-associated normal endometrium, and were the highest in normal secretory endometrium. In conclusion, high AIB1 expression in endometrial carcinoma is associated with parameters of poor prognosis. We propose that when AIB1 is overexpressed in endometrial carcinoma, ER action is augmented, leading to endometrial hyperplasia and progression to malignancy. Future studies correlating expression with response to hormonal therapy may be beneficial.

Multicentricity, heterogeneity, and sampling error complicate the study of the natural history of prostate cancer. Carcinomas previously termed \"latent\" are probably similar to those detected clinically. The diagnosis of carcinoma is only made following biopsy and histologic confirmation. Estimates of grade and stage made at the time of detection are prone to sampling error and are likely to change following examination of radical prostatectomy specimens. In regions with lower life expectancies, the problem of prostate cancer becomes a lower priority due to its association with aging. Access to care, numbers of medical facilities, and differing public health priorities make international rates difficult to compare. However, in view of the high worldwide prevalence of the disease, further epidemiologic studies of prostate cancer are warranted.