Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

Polo-like kinase 1 (Plk1) plays an important role in cell-cycle regulation. Recent work has suggested that Plk1 could be a biomarker of gemcitabine response in pancreatic ductal adenocarcinoma (PDAC). Although targeting Plk1 to treat PDAC has been attempted in clinical trials, the results were not promising, and the mechanisms of resistance to Plk1 inhibition is poorly understood. In addition, the role of Plk1 in PDAC progression requires further elucidation. Here, we showed that Plk1 was associated with poor outcomes in patients with PDAC. In an inducible transgenic mouse line with specific expression of Plk1 in the pancreas, Plk1 overexpression significantly inhibited caerulein-induced acute pancreatitis and delayed development of acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Bioinformatics analyses identified the regulatory networks in which Plk1 is involved in PDAC disease progression, including multiple inflammation-related pathways. Unexpectedly, inhibition or depletion of Plk1 resulted in upregulation of PD-L1 via activation of the NF-κB pathway. Mechanistically, Plk1-mediated phosphorylation of RB at S758 inhibited the translocation of NF-κB to nucleus, inactivating the pathway. Inhibition of Plk1 sensitized PDAC to immune checkpoint blockade therapy through activation of an antitumor immune response. Together, Plk1 suppresses PDAC progression and inhibits NF-κB activity, and targeting Plk1 can potentiate the efficacy of immunotherapy in PDAC. Significance: Inhibition of Plk1 induces upregulation of PD-L1 expression in pancreatic ductal adenocarcinoma, stimulating antitumor immunity and sensitizing tumors to immunotherapy.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) frequently use the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT is strongly correlated with α thalassemia‐mental retardation, X linked (ATRX), and death domain‐associated protein 6 (DAXX) alterations and a poor prognosis in patients with primary PanNET. Because fine‐needle aspiration (FNA) is a noninvasive way to sample tumors, the authors evaluated whether they could accurately detect ALT and loss of ATRX/DAXX in a primary PanNET cohort of FNAs.METHODS: All preoperative FNA cytology cases (2005‐2016) with adequate remnant FNA cell block material were assessed for ALT by telomere‐specific fluorescence in situ hybridization and for ATRX and DAXX protein expression by immunohistochemistry. For 21 patients who underwent tumor resection, the resected specimen also was assessed to determine the concordance between the FNA and surgical specimens.RESULTS: In the primary PanNET cohort of 65 FNAs, ALT was detected in 15 specimens (23%). Although all ATRX‐negative and DAXX‐negative tumors were ALT‐positive, 3 of 14 (21%) ALT‐positive tumors did not exhibit nuclear loss of either ATRX or DAXX. The ALT‐positive tumors were associated with larger radiographic size (4.9 vs 2.4 cm, on average; P < .05) and higher grade (P < .05). Overall, there was 100% concordance in ALT status and ATRX/DAXX immunohistochemistry results between the FNA and surgical specimens.CONCLUSIONS: Both ALT and loss of ATRX/DAXX can be accurately performed on FNA specimens with adequate material. Because ALT is a fundamental mechanism of pathogenesis, the ability to determine ALT in small biospecimens has implications for the design of clinical trials. Cancer Cytopathol 2017;125:544–51. © 2017 American Cancer Society.

BACKGROUND: Nodular fasciitis (NF) is a benign, self‐limited, fibroblastic/myofibroblastic proliferation that is diagnostically challenging, often mimicking a malignant process due to its rapid growth clinically and its high cellularity, mitotic activity, and variable/nonspecific cytomorphologic findings. Herein, the authors report what to their knowledge is the largest and first multi‐institutional study of the cytomorphologic characteristics of NF by fine‐needle aspiration (FNA).METHODS: The pathology archives at The Johns Hopkins Hospital, The Ohio State University Wexner Medical Center, and Emory University Hospital were searched for soft tissue FNA cytology specimens of masses confirmed to be NF. The clinical history, actual FNA diagnosis, and cytomorphologic features were recorded by the authors.RESULTS: A total of 34 patients were identified, 33 of which had material available for review. The mean age of the patients was 40 years (range, 1‐80 years); 18 patients (52.9%) were male. The mean duration of symptoms was 3.75 months. Four cases (11.8%) and 2 cases (5.9%) were signed out as NF and “malignant neoplasm, NOS [not otherwise specified],” respectively. On average, cases were hypercellular (mean, 3.27/4). Thirty cases (90.9%) contained spindled morphology, whereas 30 cases (90.9%) and 28 cases (84.4%) contained cells with unipolar and curved cytoplasmic tails, respectively. Eccentric, ovoid, and spindled/elongated nuclei were observed in 31 cases (93.9%), 30 cases (90.9%), and 29 cases (87.9%), respectively. Nineteen cases (57.6%) lacked atypia.CONCLUSIONS: In the current study, the diagnosis of NF was suggested in nearly 40% of cases. Combining the clinical presentation with the most commonly described cytomorphologic features will appropriately triage the majority of cases, although uncertainty will remain in a significant number of cases. Cancer Cytopathol 2017;125:20‐29. © 2016 American Cancer Society.

Glycogen dysregulation is a hallmark of aging, and aberrant glycogen drives metabolic reprogramming and pathogenesis in multiple diseases. However, glycogen heterogeneity in healthy and diseased tissues remains largely unknown. Herein, we describe a method to define spatial glycogen architecture in mouse and human tissues using matrix‐assisted laser desorption/ionization mass spectrometry imaging. This assay provides robust and sensitive spatial glycogen quantification and architecture characterization in the brain, liver, kidney, testis, lung, bladder, and even the bone. Armed with this tool, we interrogated glycogen spatial distribution and architecture in different types of human cancers. We demonstrate that glycogen stores and architecture are heterogeneous among diseases. Additionally, we observe unique hyperphosphorylated glycogen accumulation in Ewing sarcoma, a pediatric bone cancer. Using preclinical models, we correct glycogen hyperphosphorylation in Ewing sarcoma through genetic and pharmacological interventions that ablate in vivo tumor growth, demonstrating the clinical therapeutic potential of targeting glycogen in Ewing sarcoma.