Cells often alter metabolic strategies under nutrient-deprived conditions to support their survival and growth. Characterizing metabolic reprogramming in the tumor microenvironment (TME) is of ...emerging importance in cancer research and patient care. However, recent technologies only measure a subset of metabolites and cannot provide in situ measurements. Computational methods such as flux balance analysis (FBA) have been developed to estimate metabolic flux from bulk RNA-seq data and can potentially be extended to single-cell RNA-seq (scRNA-seq) data. However, it is unclear how reliable current methods are, particularly in TME characterization. Here, we present a computational framework METAFlux (METAbolic Flux balance analysis) to infer metabolic fluxes from bulk or single-cell transcriptomic data. Large-scale experiments using cell-lines, the cancer genome atlas (TCGA), and scRNA-seq data obtained from diverse cancer and immunotherapeutic contexts, including CAR-NK cell therapy, have validated METAFlux's capability to characterize metabolic heterogeneity and metabolic interaction amongst cell types.
Hepatocellular carcinomas (HCC) are adapted to survive extreme genomic stress conditions imposed by hyperactive DNA replication and genotoxic drug treatment. The underlying mechanisms remain unclear, ...but may involve intensified DNA damage response/repair programs. Here, we investigate a new role of nucleostemin (NS) in allowing HCC to survive its own malignancy, as NS was previously shown to promote liver regeneration via a damage repair mechanism. We first established that a higher NS transcript level correlates with high-HCC grades and poor prognostic signatures, and is an independent predictor of shorter overall and progression-free survival specifically for HCC and kidney cancer but not for others. Immunostaining confirmed that NS is most abundantly expressed in high-grade and metastatic HCCs. Genome-wide analyses revealed that NS is coenriched with MYC target and homologous recombination (HR) repair genes in human HCC samples and functionally intersects with those involved in replication stress response and HR repair in yeasts. In support, NS-high HCCs are more reliant on the replicative/oxidative stress response pathways, whereas NS-low HCCs depend more on the mTOR pathway. Perturbation studies showed NS function in protecting human HCC cells from replication- and drug-induced DNA damage. Notably, NS depletion in HCC cells increases the amounts of physical DNA damage and cytosolic double-stranded DNA, leading to a reactive increase of cytokines and PD-L1. This study shows that NS provides an essential mechanism for HCC to adapt to high genomic stress for oncogenic maintenance and propagation. NS deficiency sensitizes HCC cells to chemotherapy but also triggers tumor immune responses. IMPLICATIONS: HCC employs a novel, nucleostemin (NS)-mediated-mediated adaptive mechanism to survive high genomic stress conditions, a deficiency of which sensitizes HCC cells to chemotherapy but also triggers tumor immune responses.
Background
Despite consensus guidelines, many men with low‐grade prostate cancer are not managed with active surveillance. Patient perception of the nomenclature used to describe low‐grade prostate ...cancers may partly explain this discrepancy.
Methods
A randomized online survey was administered to men without a history of prostate cancer, presenting a hypothetical clinical scenario in which they are given a new diagnosis of low‐grade prostate cancer. The authors determined whether diagnosis nomenclature was associated with management preference and diagnosis‐related anxiety using ratings given on a scale from 1 to 100, adjusting for participant characteristics through multivariable linear regression.
Results
The survey was completed by 718 men. Compared with Gleason 6 out of 10 prostate cancer, the term grade group 1 out of 5 prostate cancer was associated with lower preference for immediate treatment versus active surveillance (β = −9.3; 95% CI, −14.4, −4.2; P < .001), lower diagnosis‐related anxiety (β = −8.3; 95% CI, −12.8, −3.8; P < .001), and lower perceived disease severity (β = −12.3; 95% CI, −16.5, −8.1; P < .001) at the time of initial diagnosis. Differences decreased as participants received more disease‐specific education. Indolent lesion of epithelial origin, a suggested alternative term for indolent tumors, was not associated with differences in anxiety or preference for active surveillance.
Conclusions
Within a hypothetical clinical scenario, nomenclature for low‐grade prostate cancer affects initial perception of the disease and may alter subsequent decision making, including preference for active surveillance. Disease‐specific education reduces the differential impact of nomenclature use, reaffirming the importance of comprehensive counseling and clear communication between the clinician and patient.
Online survey participants are randomized to 1 of 3 hypothetical prostate cancer diagnosis scenarios, in which a different term is used in each scenario to describe the disease. They associated the term grade group 1 out of 5 prostate cancer with greater preference for active surveillance, the recommended strategy for managing low‐grade prostate cancers, and less diagnosis‐related anxiety compared with Gleason 6 out of 10 prostate cancer.
To assess the reliability of peer-review of TURBT videos as a means to evaluate surgeon skill and its relationship to detrusor sampling.
Urologists from an academic health system submitted TURBT ...videos in 2019. Ten blinded peers evaluated each surgeon's performance using a 10-item scoring instrument to quantify surgeon skill. Normalized composite skill scores for each surgeon were calculated using peer ratings. For surgeons submitting videos, we retrospectively reviewed all TURBT pathology results (2018-2019) to assess surgeon-specific detrusor sampling. A hierarchical logistic regression model was fit to evaluate the association between skill and detrusor sampling, adjusting for patient and surgeon factors.
Surgeon skill scores and detrusor sampling rates were determined for 13 surgeons performing 245 TURBTs. Skill scores varied from -6.0 to 5.1 mean: 0; standard deviation (SD): 2.40. Muscle was sampled in 72% of cases, varying considerably across surgeons (mean: 64.5%; SD: 30.7%). Among 8 surgeons performing >5 TURBTs during the study period, adjusted detrusor sampling rate was associated with sending separate deep specimens (odds ratio OR: 1.97; 95% confidence interval CI: 1.02-3.81, P = .045) but not skill (OR: 0.81; 95% CI: 0.57-1.17, P = .191).
Surgeon skill was not associated with detrusor sampling, suggesting there may be other drivers of variability of detrusor sampling in TURBT.
To assess willingness of adults to undergo home screening for urologic cancers via urine dipstick and determine the effect of an educational pamphlet on hematuria on screening willingness and ...knowledge of hematuria.
We performed an online survey of adult volunteers throughout the United States from September 25, 2018 to October 15, 2018. The primary outcome was pretest willingness to undergo home screening for hematuria with urine dipstick (4 or 5 out of 5-point Likert). Secondary outcomes included changes in willingness to screen and knowledge on hematuria after exposure to an educational pamphlet.
Of 1442 participants, 54% were male and 87% were White. Median age was 48. Pretest willingness to home screen was high (90%). Older age was associated with an increased willingness to screen (per 10-year increase: odds ratio 1.47, 95% confidence interval 1.28-1.68, P <.001). Participants who had not previously discussed hematuria with a health care provider were less willing to screen (odds ratio 0.50, 95% confidence interval 0.27-0.94, P = .033). Patients with risk factors for urologic cancers (ie, smoking and occupational exposures) were equally willing to screen. After pamphlet exposure hematuria knowledge increased (P <.001) while willingness to screen did not change (P = .15).
Willingness to perform home-based screening for urologic cancers by assessing for hematuria is high in an adult population, including those with risk factors. Knowledge of hematuria improves significantly after exposure to an educational pamphlet.
Shared decision making is recommended in regard to prostate cancer screening. Decision aids may facilitate this process but the impact of decision aids on screening preferences is poorly understood.
...In an online survey we randomized a national sample of adults to the online decision aids of 1 of 6 professional societies. We compared survey responses before and after decision aid exposure. The primary outcome was the change in participant likelihood of undergoing or recommending prostate cancer screening on a scale of 1—unlikely to 100—extremely likely. Secondary outcomes included change in participant comfort with prostate cancer screening based on the average of 6, 5-point Likert-scale questions.
Median age was 53 years in the 1,336 participants and 50% were men. The randomized groups did not differ significantly by race, age, gender, income, marital status or education level. The likelihood of undergoing or recommending prostate cancer screening decreased from 83 to 78 following decision aid exposure (p <0.001). Reviewing the decision aid from the Centers for Disease Control or the American Academy of Family Physicians did not alter the likelihood (each p >0.2). However, the decision aid from the United States Preventive Services Task Force was associated with the largest decrease in screening preference (–16.0, p <0.001). Participants reported increased comfort (from 3.5 to 4.1 of 5) with the decision making process of prostate cancer screening following exposure to a decision aid (p <0.001).
Exposure to a decision aid decreased the participant likelihood of undergoing or recommending prostate cancer screening and increased comfort with the screening process.
Abstract Introduction and Objectives Prostate magnetic resonance imaging (MRI) is used for prostate cancer (PCa) screening and risk stratification and is helpful for surgical planning for patients ...undergoing holmium laser enucleation of the prostate (HoLEP). There are few studies investigating the correlation between MRI Prostate Imaging‐Reporting and Data System (PIRADS) lesion characteristics and HoLEP pathology and outcomes. Methods We performed retrospective review of patients who underwent HoLEP between January 2021 and August 2023 by a single surgeon. Preoperative, intraoperative, and postoperative characteristics and outcomes were analyzed for all patients who had a documented preoperative prostate MRI. Results There were 334 patients without a pre‐existing diagnosis of PCa and with a preoperative prostate MRI, of which 140 (42%) had at least one PIRADS lesion. There was a total of 203 PIRADS lesions: 91 (45%) in the peripheral zone (PZ), 106 (52%) in the transition zone (TZ), and 6 (2%) not specified. Incidental PCa was noted in 44 (13%) patients at time of HoLEP. Presence or location of lesion was not significantly associated with rate or grade of incidental PCa on pathology. Greater number of lesions and lesion size correlated with longer procedure times. Lesion number, size, or grade were not found to correlate with cancer grade or rate of cancer. Conclusions Grade, presence, location, size, and number of PIRADS lesions on preoperative prostate MRI for patients with an appropriate prior PCa workup were not significantly associated with incidental PCa or higher PCa grade on HoLEP pathology.
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