Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have ...yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m
on day 1 and cisplatin 35 mg/m
on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to < pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for < pT2N0 89%). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.
Recent molecular characterization of urothelial cancer (UC) has suggested potential pathways in which to direct treatment, leading to a host of targeted therapies in development for UC. In parallel, ...gene expression profiling has demonstrated that high-grade UC is a heterogeneous disease. Prognostic basal-like and luminal-like subtypes have been identified and an accurate transcriptome BASE47 classifier has been developed. However, these phenotypes cannot be broadly investigated due to the lack of a clinically viable diagnostic assay. We sought to develop and evaluate a diagnostic classifier of UC subtype with the goal of accurate classification from clinically available specimens.
Tumor samples from 52 patients with high-grade UC were profiled for BASE47 genes concurrently by RNAseq as well as NanoString. After design and technical validation of a BASE47 NanoString probeset, results from the RNAseq and NanoString were used to translate diagnostic criteria to the Nanostring platform. Evaluation of repeatability and accuracy was performed to derive a final Nanostring based classifier. Diagnostic classification resulting from the NanoString BASE47 classifier was validated on an independent dataset (n = 30). The training and validation datasets accurately classified 87% and 93% of samples, respectively.
Here we have derived a NanoString-platform BASE47 classifier that accurately predicts basal-like and luminal-like subtypes in high grade urothelial cancer. We have further validated our new NanoString BASE47 classifier on an independent dataset and confirmed high accuracy when compared with our original Transcriptome BASE47 classifier.
The NanoString BASE47 classifier provides a faster turnaround time, a lower cost per sample to process, and maintains the accuracy of the original subtype classifier for better clinical implementation.
Urothelial Cancer - Genomic Analysis to Improve Patient Outcomes and Research (NCT02643043), UC-GENOME, is a genomic analysis and biospecimen repository study in 218 patients with metastatic ...urothelial carcinoma. Here we report on the primary outcome of the UC-GENOME-the proportion of subjects who received next generation sequencing (NGS) with treatment options-and present the initial genomic analyses and clinical correlates. 69.3% of subjects had potential treatment options, however only 5.0% received therapy based on NGS. We found an increased frequency of TP53
mutations as compared to non-metastatic cohorts and identified features associated with benefit to chemotherapy and immune checkpoint inhibition, including: Ba/Sq and Stroma-rich subtypes, APOBEC mutational signature (SBS13), and inflamed tumor immune phenotype. Finally, we derive a computational model incorporating both genomic and clinical features predictive of immune checkpoint inhibitor response. Future work will utilize the biospecimens alongside these foundational analyses toward a better understanding of urothelial carcinoma biology.
Artisanal and small-scale gold mining (ASGM) is a major contributor to deforestation and the largest anthropogenic source of atmospheric mercury worldwide. Despite significant information on the ...direct health impacts of mercury to ASGM miners, the impact of mercury contamination on downstream communities has not been well characterized, particularly in Peru's Madre de Dios region. In this area, ASGM has increased significantly since 2000 and has led to substantial political and social controversy. This research examined the spatial distribution and transport of mercury through the Madre de Dios River with distance from ASGM activity. This study also characterized risks for dietary mercury exposure to local residents who depend on fish from the river. River sediment, suspended solids from the water column, and fish samples were collected in 2013 at 62 sites near 17 communities over a 560 km stretch of the Madre de Dios River and its major tributaries. In areas downstream of known ASGM activity, mercury concentrations in sediment, suspended solids, and fish within the Madre de Dios River were elevated relative to locations upstream of mining. Fish tissue mercury concentrations were observed at levels representing a public health threat, with greater than one-third of carnivorous fish exceeding the international health standard of 0.5 mg kg(-1). This study demonstrates that communities located hundreds of kilometers downstream of ASGM activity, including children and indigenous populations who may not be involved in mining, are at risk of dietary mercury exposure that exceed acceptable body burdens. This report represents the first systematic study of the region to aid policy decision-making related to ASGM activities in Peru.
Although immune-checkpoint inhibitors (ICIs) have been a remarkable advancement in bladder cancer treatment, the response rate to single-agent ICIs remains suboptimal. There has been substantial ...interest in the use of epigenetic agents to enhance ICI efficacy, although precisely how these agents potentiate ICI response has not been fully elucidated. We identified entinostat, a selective HDAC1/3 inhibitor, as a potent antitumor agent in our immune-competent bladder cancer mouse models (BBN963 and BBN966). We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment, resulting in a robust antitumor response that was cell autonomous, dependent upon antigen presentation, and associated with increased numbers of neoantigen-specific T cells. Finally, combination treatment with anti-PD-1 and entinostat led to complete responses and conferred long-term immunologic memory. Our work defines a tumor cell-autonomous mechanism of action for entinostat and a strong preclinical rationale for the combined use of entinostat and PD-1 blockade in bladder cancer.
Purpose:
Compressed sensing theory has enabled an accurate, low-dose cone-beam computed tomography (CBCT) reconstruction using a minimal number of noisy projections. However, the reconstruction time ...remains a significant challenge for practical implementation in the clinic. In this work, we propose a novel gradient projection algorithm, based on the Gradient-Projection-Barzilai-Borwein formulation (GP-BB), that handles the total variation (TV)-norm regularization-based least squares problem for the CBCT reconstruction in a highly efficient manner, with speed acceptable for routine use in the clinic.
Methods:
CBCT is reconstructed by minimizing an energy function consisting of a data fidelity term and a TV-norm regularization term. Both terms are simultaneously minimized by calculating the gradient projection of the energy function with the step size determined using an approximate Hessian calculation at each iteration, based on the Barzilai-Borwein formulation. To speed up the process, a multiresolution optimization is used. In addition, the entire algorithm was designed to run with a single graphics processing unit (GPU) card. To evaluate the performance, the Shepp-Logan numerical phantom, the CatPhan 600 physical phantom, and a clinically-treated head-and-neck patient were acquired from the TrueBeam™ system (Varian Medical Systems, Palo Alto, CA). For each scan, in total, 364 projections were acquired in a 200° rotation. The imager has 1024 × 768 pixels with 0.388 × 0.388-mm resolution. This was down-sampled to 512 × 384 pixels with 0.776 × 0.776-mm resolution for reconstruction. Evenly spaced angles were subsampled and used for varying the number of projections for the image reconstruction. To assess the performance of our GP-BB algorithm, we have implemented and compared with three compressed sensing-type algorithms, the two of which are popular and published (forward–backward splitting techniques), and the other one with a basic line-search technique. In addition, the conventional Feldkamp-Davis-Kress (FDK) reconstruction of the clinical patient data is compared as well.
Results:
In comparison with the other compressed sensing-type algorithms, our algorithm showed convergence in ≤30 iterations whereas other published algorithms need at least 50 iterations in order to reconstruct the Shepp-Logan phantom image. With the CatPhan phantom, the GP-BB algorithm achieved a clinically-reasonable image with 40 projections in 12 iterations, in less than 12.6 s. This is at least an order of magnitude faster in reconstruction time compared with the most recent reports utilizing GPU technology given the same input projections. For the head-and-neck clinical scan, clinically-reasonable images were obtained from 120 projections in 34–78 s converging in 12–30 iterations. In this reconstruction range (i.e., 120 projections) the image quality is visually similar to or better than the conventional FDK reconstructed images using 364 projections. This represents a dose reduction of nearly 67% (120/364 projections) while maintaining a reasonable speed in clinical implementation.
Conclusions:
In this paper, we proposed a novel, fast, low-dose CBCT reconstruction algorithm using the Barzilai-Borwein step-size calculation. A clinically viable head-and-neck image can be obtained within ∼34–78 s while simultaneously cutting the dose by approximately 67%. This makes our GP-BB algorithm potentially useful in an on-line image-guided radiation therapy (IGRT).
von Hippel-Lindau (VHL) is a critical tumor suppressor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides ...hypoxia-inducible factor 2α (HIF2α). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degradation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prognosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its oncogenic phenotype. Therefore, the pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC.
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•A genome-wide screen identified SFMBT1 as a pVHL target•Potential Proline hydroxylation of SFMBT1 decreases its protein stability and is regulated by pVHL•SFMBT1 promotes ccRCC tumorigenesis and is upregulated in patients with ccRCC•SFMBT1 increases SPHK1 expression in ccRCC
The pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC.
Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have ...demonstrated promising pathologic response (<pT2) in the neoadjuvant setting. In LCCC1520 (NCT02690558), a phase 2 single-arm trial of neoadjuvant chemo-immunotherapy (gemcitabine and cisplatin plus pembrolizumab; NAC-ICI) for MIBC, 22/39 patients responded (pathologic downstaging as primary outcome), as previously described. Here, we report post-hoc correlative analyses. Treatment was associated with changes in tumor mutational profile, immune gene signatures, and RNA subtype switching. Clinical response was associated with an increase in plasma IL-9 from pre-treatment to initiation of cycle 2 of therapy. Tumors harbored diverse predicted antigen landscapes that change across treatment and are associated with APOBEC, tobacco, and other etiologies. Higher pre-treatment tumor PD-L1 and TIGIT RNA expression were associated with complete response. IL-8 signature and Stroma-rich subtype were associated with improved response to NAC-ICI versus neoadjuvant ICI (ABACUS trial, NCT02662309). Plasma IL-9 represents a potential predictive biomarker of NAC-ICI response, while tumor IL-8 signature and stroma-rich subtype represent potential predictive biomarkers of response benefit of NAC-ICI over neoadjuvant ICI. Future efforts must include additional independent biomarker discovery and validation, ultimately to improve the selection of patients for ICI-related treatments.
Here, we present detailed kinetic analyses of a panel of soluble lipid kinases and phosphatases, as well as Ras activating proteins, acting on their respective membrane surface substrates. The ...results reveal that the mean catalytic rate of such interfacial enzymes can exhibit a strong dependence on the size of the reaction system-in this case membrane area. Experimental measurements and kinetic modeling reveal how stochastic effects stemming from low molecular copy numbers of the enzymes alter reaction kinetics based on mechanistic characteristics of the enzyme, such as positive feedback. For the competitive enzymatic cycles studied here, the final product-consisting of a specific lipid composition or Ras activity state-depends on the size of the reaction system. Furthermore, we demonstrate how these reaction size dependencies can be controlled by engineering feedback mechanisms into the enzymes.
The necessary infrastructure to carry out genomics-driven oncology is now widely available and has resulted in the exponential increase in characterized cancer genomes. While a subset of genomic ...alterations is clinically actionable, the majority of somatic events remain classified as variants of unknown significance and will require functional characterization. A careful cataloging of the genomic alterations and their response to therapeutic intervention should allow the compilation of an "actionability atlas" and the creation of a genomic taxonomy stratified by tumor type and oncogenic pathway activation. The next phase of genomic medicine will therefore require talented bioinformaticians, genomic navigators, and multidisciplinary approaches to decode complex cancer genomes and guide potential therapy. Equally important will be the ethical and interpretable return of results to practicing oncologists. Finally, the integration of genomics into clinical trials is likely to speed the development of predictive biomarkers of response to targeted therapy as well as define pathways to acquired resistance.
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