Abstract Intermittent treatment schedules have been proposed to improve the tolerance of drugs for cancer chemoprevention. However, determining a maximum tolerated dose, and the extent of the improvement, has been challenging experimentally and clinically. In order to determine the quantitative advantage of intermittent pulse treatment schedules for the chemoprevention of colon cancer we have used a computer model of human colon crypts calibrated with measurements of human biopsy specimens. In simulations, crypts were treated with an agent that increases the probability that cells, both normal and mutant, would be removed at the top of the crypt. Sulindac, which increases apoptosis at the lumen surface, is such an agent. The effect of intermittent pulse drug treatment schedules were compared with constant drug treatment schedules. Crypts treated with intermittent pulse schedules have three times the maximum tolerated dose than crypts treated with constant schedules, and have a 10 year delay in the appearance of adenomas. Intermittent treatment schedules have previously been proposed for chemoprevention. Here computer simulations have quantified the effect on human colon crypts of intermittent treatment schedules and constant treatment schedules of a chemotherapeutic drug. Intermittent pulses have an advantage, they allow an increased maximum tolerated dose, and result in an increased chemoprevention by delay.

In the tumour microenvironment, cancer cells directly interact with both the immune system and the stroma. It is firmly established that the immune system, historically believed to be a major part of the body's defence against tumour progression, can be reprogrammed by tumour cells to be ineffective, inactivated, or even acquire tumour promoting phenotypes. Likewise, stromal cells and extracellular matrix can also have pro-and anti-tumour properties. However, there is strong evidence that the stroma and immune system also directly interact, therefore creating a tripartite interaction that exists between cancer cells, immune cells and tumour stroma. This interaction contributes to the maintenance of a chronically inflamed tumour microenvironment with pro-tumorigenic immune phenotypes and facilitated metastatic dissemination. A comprehensive understanding of cancer in the context of dynamical interactions of the immune system and the tumour stroma is therefore required to truly understand the progression toward and past malignancy.

Abstract Surgery, radiation therapy and chemotherapy are the primary modes of therapeutic intervention in current clinical practice. The price often paid for effective treatment is the development of a secondary malignancy several decades after successful treatment of the primary tumor, as a result of the mutagenic effects of the initial cancer treatments on normal cells. In this work, we employ a biologically motivated mathematical model to estimate the radiation and chemotherapy-induced relative risks of thyroid malignancies in four childhood cancer study survivors (CCSS) data sets. A sensitivity analysis is performed on various chemotherapy treatment variables to evaluate their impact on second cancer risks. Furthermore, the predictions of radiation and chemotherapy-induced relative risks of secondary thyroid malignancies using the mathematical model are compared against four clinical datasets from the CCSS cohort. Moreover, the extracted average value of growth rate of premalignant cells is 0.8175 (d −1 ) and the extracted chemotherapy-induced mutation rate is of the order of 10 −10 (per unit of chemotherapeutic dose). In addition, our model predictions of sequential therapy induced carcinogenic risks are in line with the clinical data in secondary thyroid cancers. Our in silico risk predictions can provide insight into the impact of therapy sequencing on secondary cancer risks, while at the same time eliminating the primary tumor. These findings might potentially guide clinicians in developing optimal treatment regimens that minimize secondary cancer risks.

Lung cancer is often classified by the presence of oncogenic drivers, such as epidermal growth factor receptor (EGFR), rather than patterns of anatomical distribution. While metastatic spread may seem a random and unpredictable process, we explored the possibility of using its quantifiable nature as a measure of describing and comparing different subsets of disease. We constructed a database of 664 non-small cell lung cancer (NSCLC) patients treated at the University of Southern California Norris Comprehensive Cancer Center and the Los Angeles County Medical Center. Markov mathematical modeling was employed to assess metastatic sites in a spatiotemporal manner through every time point in progression of disease. Our findings identified a preferential pattern of primary lung disease progressing through lung metastases to the brain amongst EGFR mutated (EGFR m) NSCLC patients, with exon 19 deletions or exon 21 L858R mutations, as compared to EGFR wild type (EGFR wt). The brain was classified as an anatomic "sponge", with a higher ratio of incoming to outgoing spread, for EGFR m NSCLC. Bone metastases were more commonly identified in EGFR wt patients. Our study supports a link between the anatomical and molecular characterization of lung metastatic cancer. Improved understanding of the differential biology that drives discordant patterns of anatomic spread, based on genotype specific profiling, has the potential to improve personalized oncologic care.

Applied radiofrequency (RF) energy induces hyperthermia in tissues, facilitating vascular perfusion This study explores the impact of RF radiation on the integrity of the luminal endothelium, and then predominately explores the impact of altering the conductivity of biologically-relevant solutions on RF-induced heating rates and cell death. The ability of cells to survive high sucrose (i.e. hyperosmotic conditions) to achieve lower conductivity as a mechanism for directing hyperthermia is evaluated. RF radiation was generated using a capacitively-coupled radiofrequency system operating at 13.56 MHz. Temperatures were recorded using a FLIR SC 6000 infrared camera. RF radiation reduced cell-to-cell connections among endothelial cells and altered cell morphology towards a more rounded appearance at temperatures reported to cause in vivo vessel deformation. Isotonic solutions containing high sucrose and low levels of NaCl displayed low conductivity and faster heating rates compared to high salt solutions. Heating rates were positively correlated with cell death. Addition of sucrose to serum similarly reduced conductivity and increased heating rates in a dose-dependent manner. Cellular proliferation was normal for cells grown in media supplemented with 125 mM sucrose for 24 hours or for cells grown in 750 mM sucrose for 10 minutes followed by a 24 h recovery period. Sucrose is known to form weak hydrogen bonds in fluids as opposed to ions, freeing water molecules to rotate in an oscillating field of electromagnetic radiation and contributing to heat induction. The ability of cells to survive temporal exposures to hyperosmotic (i.e. elevated sucrose) conditions creates an opportunity to use sucrose or other saccharides to selectively elevate heating in specific tissues upon exposure to a radiofrequency field.

The potential for local radiation therapy to elicit systemic (abscopal) anti-tumor immune responses has been receiving a significant amount of attention over the last decade. We recently developed a mathematical framework designed to simulate the systemic dissemination of activated T cells among multiple metastatic sites. This framework allowed the identification of non-intuitive patterns of T cell redistribution after localized therapy, and offered suggestions as to the optimal site to irradiate in order to increase the magnitude of an immune-mediated abscopal response. Here, we evaluate the potential for such a framework to provide clinical decision making support to radiation oncologists. Several challenges such as efficient segmentation and delineation of multiple tumor sites on PET/CT scans, validation of model prediction performance, and effective clinical trial design remain to be addressed prior to the incorporation of such a tool in the clinical setting.

Abstract Rheology of living cells has developed an increasing need for high throughput measurements. Diseases such as cancer heavily remodel the cytoskeleton and impinge on cellular functions. Cells affected by such diseases show altered rheologic responses on many different levels rendering cells’ mechanical fingerprints—a potential target for diagnostics. To counteract naturally occurring distributions of properties in samples of living cells and foster the validity of experiments, high numbers of single cell measurements are necessary. Here, we present the ‘in flow optical stretcher’ (IFOS), a concept of non-invasive optical cytometry capable of high throughput rates, while working in a regime of long measurement times and low frequencies. The setup deforms whole cells in a continuous flow by optical forces, bypassing steps of cell positioning that are unavoidable in state-of-the-art optical stretcher devices. A prototype was built using polydimethylsiloxane soft lithography. In a proof of premise experiment, we show that in the IFOS it is possible to deform cells of mammalian origin which have been treated with cytochalasin. All recorded successful experiments took place in less than 2 s each, as opposed to 10–20 s in state-of-the-art optical stretcher devices. Although other microfluidic rheology devices achieve significantly higher throughput rates, they operate in different frequency regimes and probe different mechanical responses. The IFOS still captures viscoelastic properties and active responses of cells while aiming to maximize the throughput at creep times on the order of seconds. It can be assumed that an automatic IFOS reaches a throughput an order of magnitude higher than current devices that are based on optical stretching for cell rheology.

Platelets are anucleate cells in the blood at concentrations of 150,000 to 400,000 cells/µL and play a key role in hemostasis. Several studies have suggested that platelets contribute to cancer progression and cancer-associated thrombosis. In this review, we provide an overview of the biochemical and biophysical mechanisms by which platelets interact with cancer cells and review the evidence supporting a role for platelet-enhanced metastasis of cancer, and venous thromboembolism (VTE) in patients with cancer. We discuss the potential for and limitations of platelet counts to discriminate cancer disease burden and prognosis. Lastly, we consider more advanced diagnostic approaches to improve studies on the interaction between the hemostatic system and cancer cells.

Abstract The immune system features the interaction of many cell types via multiple chemical pathways. Not surprisingly, such a complex system might exhibit multistability, which means that multiple operating states might be allowed under the same external conditions, the actual state being determined by system history. In the context of cancer immunotherapy, understanding how signals from the cancer cells might bias the immune system to emphasize certain of these states might help inform therapeutic strategies. Here, we propose a series of coarse-grained models of the immune system in order to explore the mechanisms that lead to bistability between immune-promoting and immune-suppressing states. We discuss in detail using this modeling framework to help interpret existing experimental data and to predict outcomes for various perturbations to some of the interacting components.

Using patient-derived colorectal cancer xenografts, we demonstrate a practicable workflow for single cell proteomics in clinically relevant samples and thus a potential translational route for single cell proteomics into medical diagnostics. Using a microfluidic antibody capture (MAC) chip we measured the expression of the tumour suppressor protein p53 and of its post-translationally modified form phosphorylated at serine-15. Aberrant expression of these has commonly been found in colorectal cancers and has been widely investigated for prognostic significance. Our results show that the MAC technology is viable for quantitatively assessing protein expression and phosphorylation at the single cell level in microscopic amounts of clinically relevant tumour material. Thus, this could become a useful tool in therapeutic-associated single cell protein analysis. We also found dramatic variability of p53 and phosphorylated p53 quantities between individual cancer cells from the same sample, demonstrating the power of this single cell technology to study functional intratumour heterogeneity.