Mathematical modeling of the dynamics of the bladder cancer and the immune response applied to a patient: Evolution and short-term prediction

[EN] Bladder cancer is one of the most common malignant diseases in the urinary system and a highly aggressive neoplasm. The prognosis is not favorable usually, and its evolution for particular patients is very difficult to find out. In this paper, we propose a dynamic mathematical model that describes the bladder tumor growth and the immune response evolution. This model is customized for a single patient, determining appropriate model parameter values via model calibration. Due to the uncertainty of the tumor evolution, using the calibrated model parameters, we predict the tumor size and the immune response evolution over the next few months assuming three different scenarios: favorable, neutral, and unfavorable. In the former, it is not expected any trace of the cancer in the middle of September 2018 (after 16 mo). In the neutral scenario, at the same date, a 7- to 8-mm tumor is expected. In the worst case, a 40-mm tumor is expected. The patient was cited on 10 September 2018 to check the tumor size, and according to the doctors, there was no sign of recurrence. It seems that we are in the favorable scenario. The patient will be called again for follow-up in mid-2019.This work has been supported by the Ministerio de Economía, Industria y Competitividad grant MTM2017-89664-P.Burgos-Simon, C.; García-Medina, N.; Martínez-Rodríguez, D.; Villanueva Micó, RJ. (2019). Mathematical modeling of the dynamics of the bladder cancer and the immune response applied to a patient: Evolution and short-term prediction. Mathematical Methods in the Applied Sciences. 42(17):5746-5757. https://doi.org/10.1002/mma.5536S574657574217Official Site for Spanish Medic Oncology Society.https://www.seom.org. Accessed: 25/09/2018.Greenlee, R. T., Hill-Harmon, M. B., Murray, T., & Thun, M. (2001). Cancer Statistics, 2001. CA: A Cancer Journal for Clinicians, 51(1), 15-36. doi:10.3322/canjclin.51.1.15Holmang, S., Hedelin, H., Anderstrom, C., & Johansson, S. L. (1995). The Relationship Among Multiple Recurrences, Progression and Prognosis of Patients with Stages TA and T1 Transitional Cell Cancer of the Bladder Followed for at least 20 years. Journal of Urology, 153(6), 1823-1827. doi:10.1016/s0022-5347(01)67321-xRedelman-Sidi, G., Glickman, M. S., & Bochner, B. H. (2014). The mechanism of action of BCG therapy for bladder cancer—a current perspective. Nature Reviews Urology, 11(3), 153-162. doi:10.1038/nrurol.2014.15Bladder Cancer Treatment (PDQ)‐Health Professional Version.https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq. Accessed: 25/09/2018.Bladder Cancer Treatment (PDQ)‐Patient Version.https://www.cancer.gov/types/bladder/patient/bladder-treatment-pdq. Accessed: 25/09/2018.Official Site for Hospital Universitari i Politècnic La Fe Valencia Spain.http://www.hospital-lafe.com. Accessed: 25/09/2018.Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of Cancer: The Next Generation. Cell, 144(5), 646-674. doi:10.1016/j.cell.2011.02.013Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., … Chen, L. (2002). Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nature Medicine, 8(8), 793-800. doi:10.1038/nm730Fernandez, N. C., Lozier, A., Flament, C., Ricciardi-Castagnoli, P., Bellet, D., Suter, M., … Zitvogel, L. (1999). Dendritic cells directly trigger NK cell functions: Cross-talk relevant in innate anti-tumor immune responses in vivo. Nature Medicine, 5(4), 405-411. doi:10.1038/7403Factsheet of OncoTICE 2 − 8 × 108UFC powder for suspension intravesical (in Spanish).https://www.aemps.gob.es/cima/pdfs/es/ft/61377/61377_ft.pdf. Accessed: 25/09/2018

Histotripsy Homogenization of the Prostate: Thresholds for Cavitation Damage of Periprostatic Structures

Background and Purpose: Histotripsy is a noninvasive, pulsed ultrasound technology that produces mechanically homogenized tissue within targeted volumes. Previous work has demonstrated prostatic tissue debulking in a canine model. The aim was to establish safety thresholds by evaluating histologic changes of urinary sphincter, neurovascular bundle (NVB), and rectum after targeted histotripsy treatment of these critical structures. Materials and Methods: Rectum, urinary sphincter, and NVB in five anesthetized canines were targeted for histotripsy treatment (50 total points). Locations received 1k, 10k, or 100k acoustic pulses (4 microsecond, 1-MHz) at a repetition frequency of 500-Hz. Canine subjects were euthanized immediately (2), survived 3 days (1), or 2 weeks (3) after treatment. Prostates, periprostatic tissue, and rectum were harvested and processed for histology. Results: The sphincter was structurally intact with minimal muscle fiber disruption even after 100k pulses (n=10). Undamaged nerves, arteries, and veins of the NVB were seen despite mechanical homogenization of surrounding loose connective tissue (n=19). The rectum, however, exhibited dose-dependent damage (n=20). 1k pulses yielded mild submucosal hemorrhage. 10k pulses resulted in moderate collagen disruption and focal mucosal homogenization. 100k pulses produced damage to the mucosa and muscularis propria with extensive hemorrhage and collagen disruption. One canine treated with 100k pulses needed early euthanasia (day 3) because of complications from a urine leak. Conclusions: Histotripsy histologic tissue effect varied based on targeted structure with substantial structural preservation of NVB and sphincter. Rectal subclinical damage was apparent after 1k pulses and increased in extent and severity with escalating doses. Future work will include assessment of functional outcomes and refinement of these initial safety thresholds.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90446/1/end-2E2010-2E0648.pd

Interference of flavonoids with enzymatic assays for the determination of free fatty acid and triglyceride levels

Flavonoids are bioactive food compounds with potential lipid-lowering effects. Commercially available enzymatic assays are widely used to determine free fatty acid (FFA) and triglyceride (TG) levels both in vivo in plasma or serum and in vitro in cell culture medium or cell lysate. However, we have observed that various flavonoids interfere with peroxidases used in these enzymatic assays, resulting in incorrect lower FFA and TG levels than actually present. Furthermore, addition of isorhamnetin or the major metabolite of the flavonoid quercetin in human and rat plasma, quercetin-3-O-glucuronide, to murine serum also resulted in a significant reduction of the detected TG levels, while a trend was seen for FFA levels. It is concluded that when applying these assays, vigilance is needed and alternative analytical methods, directly assessing FFA or TG levels, should be used for studying the biological effects of flavonoids on FFA and TG levels

A Cost-Utility Analysis of Prostate Cancer Screening in Australia

Background and Objectives: The Göteborg randomised population-based prostate cancer screening trial demonstrated that Prostate Specific Antigen (PSA) based screening reduces prostate cancer deaths compared with an age matched control group. Utilising the prostate cancer detection rates from this study we have investigated the clinical and cost-effectiveness of a similar PSA-based screening strategy for an Australian population of men aged 50-69 years. Methods: A decision model that incorporated Markov processes was developed from a health system perspective.The base case scenario compared a population-based screening programme with current opportunistic screening practices. Costs, utility values, treatment patterns and background mortality rates were derived from Australian data. All costs were adjusted to reflect July 2015 Australian dollars. An alternative scenario compared systematic with opportunistic screening but with optimisation of active surveillance (AS) uptake in both groups. A discount rate of 5% for costs and benefits was utilised. Univariate and probabilistic sensitivity analyses were performed to assess the effect of variable uncertainty on model outcomes. Results: Our model very closely replicated the number of deaths from both prostate cancer and background mortality in the Göteborg study. The incremental cost per quality-adjusted life-year (QALY) for PSA screening was $AU147,528. However, for years of life gained (LYGs) PSA based screening ($AU45,890/LYG) appeared more favourable. Our alternative scenario with optimised AS improved cost-utility to $AU45,881/QALY, with screening becoming cost-effective at a 92$AU50,000/QALY. It appears more cost-effective if LYGs are used as the relevant outcome, and is more cost effective than the established Australian breast cancer screening programme on this basis. Optimised utilisation of AS increases the cost-effectiveness of prostate cancer screening dramatically

Organ preservation surgery for laryngeal cancer

The principles of management of the laryngeal cancer have evolved over the recent past with emphasis on organ preservation. These developments have paralleled technological advancements as well as refinement in the surgical technique. The surgeons are able to maintain physiological functions of larynx namely speech, respiration and swallowing without compromising the loco-regional control of cancer in comparison to the more radical treatment modalities. A large number of organ preservation surgeries are available to the surgeon; however, careful assessment of the stage of the cancer and selection of the patient is paramount to a successful outcome. A comprehensive review of various organ preservation techniques in vogue for the management of laryngeal cancer is presented