Impact of PSMA PET on Prostate Cancer Management.

OPINION STATEMENT: PSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET radiotracers in many contexts. With multiple approved PSMA-targeting radiotracers, PSMA PET will become even more available in clinical practice. Its increased use requires an understanding of the prospective data available and caution when extrapolating from prior trial data that utilized other imaging modalities. Future trials leveraging PSMA PET for treatment optimization and management decision-making will ultimately drive its clinical utility.

MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.

Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.

Anatomic location of colorectal cancer presents a new paradigm for its prognosis in African American patients.

Among all racial groups in the U.S., African Americans (AA) have the highest incidence of and mortality from colorectal cancer (CRC). Although socioeconomic factors, as the major contributors to racial disparity of CRC, have been widely investigated, there is a dearth of information germane to understanding its biological basis. To better elucidate the clinicopathologic features we extracted demographic, clinical, pathologic and molecular features of 500 consecutive cases of CRC diagnosed at our institution which has an AA-predominant patient population (75% of all patients). We compared data from our AA patients with those of white patients both from our institution and from SEER and the published literature for meaningful comparison. AA patients were more likely to be at an advanced disease stage (25.9% vs. 20.8%, p = 0.041), have low grade tumors (89.2% vs. 77.5%, p<0.001) in cecum (18.7% vs. 16.2%, p<0.001) and <60-years-old than white patients (31.8% vs. 26.3%, p = 0.015). The frequency of KRAS mutation was higher in AA patients than in white patients (56.8% vs. 20.7%, p<0.001). Amongst subtypes of KRAS tested in CRC, codon 12 mutation is more common in AA than white patients (85.2% vs. 68.9%, p = 0.020). Compared with other racial groups, we found AA patients to have worse disease-free survival (HR = 3.682, p = 0.035). Also, AA patients with CRC in distal (sigmoid and rectum) or proximal (cecum) colon have worse overall survival than those with CRC in middle colon (HR = 2.926, p = 0.014), a finding not observed in white patients. In both racial groups, advanced stage, perforation, and hypertension were independent prognostic factors for overall survival (p<0.05). Similarly, low body-mass index at presentation, mucinous adenocarcinoma, lymphovascular invasion, perineural invasion and KRAS mutations were independent factors significantly associated with poor disease-free survival. Collectively, our data provide new insights into the roles of clinicopathologic features, especially anatomic distribution, in predicting outcomes of CRC in AA population.

Mixed and nonvaccine high risk HPV types are associated with higher mortality in Black women with cervical cancer.

We studied the incidence of HPV genotypes in mostly Black women with cervical carcinoma and correlated histopathologic tumor characteristics, immune markers and clinical data with survival. Disease-free survival (DFS) and overall survival (OS) were recorded for 60 months post-diagnosis. Fifty four of the 60 (90%) patients were Black and 36 (60%) were < 55 years of age. Of the 40 patients with typeable HPV genotypes, 10 (25%) had 16/18 HPV genotypes, 30 (75%) had one of the non-16/18 HPV genotypes, and 20 (50%) had one of the 7 genotypes (35, 39, 51, 53, 56, 59 and 68) that are not included in the nonavalent vaccine. Mixed HPV infections (≥ 2 types) were found in 11/40 (27.5%) patients. Patients infected with non-16/18 genotypes, including the most common genotype, HPV 35, had significantly shorter DFS and OS. PD-L1 (p = 0.003), MMR expression (p = 0.01), clinical stage (p = 0.048), histologic grade (p = 0.015) and mixed HPV infection (p = 0.026) were independent predictors of DFS. A remarkably high proportion of cervical cancer cells in our patients expressed PD-L1 which opens the possibility of the use of immune checkpoint inhibitors to treat these cancers. Exclusion of the common HPV genotypes from the vaccine exacerbates mortality from cervical cancer in underserved Black patients.

Big data in digital healthcare: lessons learnt and recommendations for general practice.

Big Data will be an integral part of the next generation of technological developments-allowing us to gain new insights from the vast quantities of data being produced by modern life. There is significant potential for the application of Big Data to healthcare, but there are still some impediments to overcome, such as fragmentation, high costs, and questions around data ownership. Envisioning a future role for Big Data within the digital healthcare context means balancing the benefits of improving patient outcomes with the potential pitfalls of increasing physician burnout due to poor implementation leading to added complexity. Oncology, the field where Big Data collection and utilization got a heard start with programs like TCGA and the Cancer Moon Shot, provides an instructive example as we see different perspectives provided by the United States (US), the United Kingdom (UK) and other nations in the implementation of Big Data in patient care with regards to their centralization and regulatory approach to data. By drawing upon global approaches, we propose recommendations for guidelines and regulations of data use in healthcare centering on the creation of a unique global patient ID that can integrate data from a variety of healthcare providers. In addition, we expand upon the topic by discussing potential pitfalls to Big Data such as the lack of diversity in Big Data research, and the security and transparency risks posed by machine learning algorithms.

EZH2 Downregulation Augments the Effect of Irradiation in Reducing Pancreatic Cancer Cell Proliferation in vitro.

OBJECTIVE: Pancreatic ductal carcinoma has a 5-year survival rate of 9%. This makes it the 4th leading cause of cancer-related death in the United States. Advanced-stage diagnosis and limited treatment options contribute to poor prognosis. Thus, there is an urgent need for new approaches to treatment. Enhancer of Zeste 2 (EZH2), a catalytic subunit of the multi-protein histone methyltransferase, known as the polycomb repressive complex, has been implicated in carcinogenesis. E2H2's downregulation has been shown to have a therapeutic effect in B cell lymphomas. MATERIALS AND METHODS: We examined the effect of EZH2 downregulation in combination with irradiation on the proliferation and apoptosis of pancreatic cancer cells (PANC-1 and MIA PaCa-2) in vitro. EZH2 downregulation was accomplished by treatment of cells with small interfering RNA (siRNA) or EPZ. To do this, cell survival was assessed over a 96 hr (short-term) by ATP measurement and immunohistochemical assessment of Phosphohistone 3 (PHH3), Ki-67 and CC3 over two weeks (long-term) by clonogenic assay. RESULTS: EZH2 downregulation resulted in the decreased proliferation of PANC-1 and MIA PaCa-2 cells within short-term assays with maximal reduction at 72 hr. Irradiation reduced cell proliferation beginning at 96 hr and continued over the long-term. Irradiation with EZH2 downregulation reduced cell proliferation between 48 and 72 hr. This combined treatment reduced cell proliferation by 3 to 14% as compared to those treated with irradiation alone at two weeks. PANC-1 and MIA PaCa-2 cells exhibited similar responses to EZH2 downregulation and irradiation, but to different degrees. siRNA or EPZ were equally effective in EZH2 downregulation. CONCLUSIONS: EZH2 downregulation in combination with irradiation reduces PANC-1 and MIA PaCa-2 cell proliferation more than irradiation alone. This study affirms the role of EZH2 downregulation for radiosensitization in pancreatic cancer treatment.

Diagnosis of Liver Neoplasms by Computational and Statistical Image Analysis.

BACKGROUND: Distinguishing well-differentiated hepatocellular carcinoma (WD-HCC), hepatocellular adenoma (HA) and non-neoplastic liver tissue (NNLT) solely on morphology is often challenging. The purpose of this study was to evaluate the use of computational image analysis to distinguish WD-HCC, HA and NNLT. METHODS: Seventy-seven cases comprising of WD-HCC (n = 26), HA (n = 23) and NNLT (n = 28) were retrieved and reviewed. A total of 485 hematoxylin and eosin (H&E) photomicrographs (× 400, 0.09 µm2) of WD-HCC (n = 183), HA (n = 173), NNLT (n = 129) and nine whole-slide scans (three of each diagnosis) were obtained, color deconvoluted and digitally transformed. Quantitative data including nuclear density, nuclear sphericity, nuclear perimeter, and nuclear eccentricity from each image were acquired. The data were analyzed by one-way analysis of variance (ANOVA) with Tukey post hoc test, followed by unsupervised and supervised (Chi-square automatic interaction detection (CHAID)) cluster analysis. RESULTS: Unsupervised cluster analysis identified three well defined clusters of WD-HCC, HA and NNLT. Employing the four most discriminating nuclear features, supervised analysis was performed on a training set of 383 images, and validated on the remaining 102 test images. The analysis identified WD-HCC (sensitivity 100%, specificity 98%), HA (sensitivity 71%, specificity 85%) and NNLT (sensitivity 70%, specificity 86%). An analysis of whole-slide images identified WD-HCC with sensitivity and specificity of 100%. CONCLUSIONS: We have successfully demonstrated that computational image analysis of nuclear features can differentiate WD-HCC from non-malignant liver with high accuracy, and can be used to assist in the histopathological diagnosis of hepatocellular carcinoma.

Reduced [14C]-methionine uptake and fecundity in Schistosoma mansoni females treated with recombinant tumor necrosis factor α in vitro.

Recombinant human TNFα (rhTNFα) has previously been shown to reduce fecundity in Schistosoma mansoni adult females maintained in vitro without males, and adversely affect the uptake of [14C]-tyrosine, an amino acid required for schistosome vitellogenesis. Here we report on the effect of rhTNFα on [14C]-methionine uptake in both separated and paired females, and the effect of three different preparations of rTNFα on schistosome oviposition in vitro. In the absence of rhTNFa, separated females incorporated only 30% of the [14C]-methionine incorporated by paired females in a dose and time-dependent manner, suggesting low metabolic activity of females in the absence of males. Separated females and worm-pairs were treated with increasing doses of rhTNFα for 2 or 4 hr and then incubated in RPMI 1640 containing 10% fetal calf serum (FCS) and 5 µCi ml-1[14C]-methionine for 1 hr. Separated females treated with rhTNFa for 4 hr incorporated less methionine than those treated for 2 hr. In contrast, paired females treated with rhTNFa incorporated significantly smaller amounts of [14C]-methionine in a TNFa dose-dependent but time-independent manner [2 hr (P = 0.001) or 4 hr (P = 0.027) One-Way ANOVA]. Worm-pairs maintained in RPMI 1640 containing 10% FCS and 100 ng ml-1 of any of the three rTNFa preparations laid significantly fewer eggs than the worms cultured without rTNFα(P = 0.001; Kruskal-Wallis Test). We also observed that among rTNFα-treated worm-pairs, females were sluggish and tended to separate from their male partners. These observations suggest that TNFa inhibits [14C]-methionine uptake and reduces fecundity in females paired with males. Since paired females incorporate substantially greater amounts of [14C]-methionine, the role of males in stimulating metabolic activity in females is affirmed. Reduced amino acid uptake, and possibly other nutrients, may contribute to the diminished fecundity observed in TNFa-treated females.