Coupling biomechanics to a cellular level model: An approach to patient-specific image driven multi-scale and multi-physics tumor simulation

Modeling of tumor growth has been performed according to various approaches addressing different biocomplexity levels and spatiotemporal scales. Mathematical treatments range from partial differential equation based diffusion models to rule-based cellular level simulators, aiming at both improving our quantitative understanding of the underlying biological processes and, in the mid- and long term, constructing reliable multi-scale predictive platforms to support patient-individualized treatment planning and optimization. The aim of this paper is to establish a multi-scale and multi-physics approach to tumor modeling taking into account both the cellular and the macroscopic mechanical level. Therefore, an already developed biomodel of clinical tumor growth and response to treatment is self-consistently coupled with a biomechanical model. Results are presented for the free growth case of the imageable component of an initially point-like glioblastoma multiforme tumor. The composite model leads to significant tumor shape corrections that are achieved through the utilization of environmental pressure information and the application of biomechanical principles. Using the ratio of smallest to largest moment of inertia of the tumor material to quantify the effect of our coupled approach, we have found a tumor shape correction of 20\% by coupling biomechanics to the cellular simulator as compared to a cellular simulation without preferred growth directions. We conclude that the integration of the two models provides additional morphological insight into realistic tumor growth behavior. Therefore, it might be used for the development of an advanced oncosimulator focusing on tumor types for which morphology plays an important role in surgical and/or radio-therapeutic treatment planning.

CD8+ T cells and NK cells from blister fluid of an EEM/SJS overlap highly express Fas ligand and Granulysin

INTRODUCTION Erythema exsudativum multiforme majus (EEMM) and Stevens-Johnson Syndrome (SJS) are severe cutaneous reaction patterns caused by infections or drug hypersensitivity. The mechanism by which widespread keratinocyte death is mediated by the immune system in EEMM/SJS are still to be elucidated. Here, we characterized the blister cells isolated from a patient with EEMM/SJS overlap and investigated its cause. METHODS Clinical classification of the cutaneous eruption was done according to the consensus definition of severe blistering skin reactions and histological analysis. Common infectious causes of EEMM were investigated using standard clinical techniques. T cell reactivity for potentially causative drugs was assessed by lymphocyte transformation tests (LTT). Lymphocytes isolated from blister fluid were analyzed for their expression of activation markers and cytotoxic molecules using flow cytometry. RESULTS The healthy 58 year-old woman suffered from mild respiratory tract infection and therefore started treatment with the secretolytic drug Ambroxol. One week later, she presented with large palmar and plantar blisters, painful mucosal erosions, and flat atypical target lesions and maculae on the trunc, thus showing the clinical picture of an EEMM/SJS overlap (Fig. 1). This diagnosis was supported by histology, where also eosinophils were found to infiltrate the upper dermis, thus pointing towards a cutaneous adverse drug reaction (cADR). Analysis of blister cells showed that they mainly consisted of CD8+ and CD4+ T cells and a smaller population of NK cells. Both the CD8+ T cells and the NK cells were highly activated and expressed Fas ligand and the cytotoxic molecule granulysin (Fig. 2). In addition, in comparison to NK cells from PBMC, NK cells in blister fluids strongly upregulated the expression of the skin-homing chemokine receptor CCR4 (Fig 4). Surprisingly, the LTT performed on PBMCs in the acute phase was positive for Ambroxol (SI=2.9) whereas a LTT from a healthy but exposed individual did not show unspecific proliferation. Laboratory tests for common infectious causes of EEMM were negative (HSV-1/-2, M. pneumoniae, Parvovirus B19). However, 6 weeks later, specific proliferation to Ambroxol could no longer be observed in the LTT (Fig 4.).

[Drug-induced Stevens-Johnson syndrome in a patient with AIDS]

The Stevens-Johnson syndrome is a severe potentially life-threatening form of the erythema multiforme, affecting both skin and mucous membranes. We present a case of a 49-year-old male patient with AIDS who developed a Stevens-Johnson syndrome while being treated with pyrimethamine, sulfadiazine and phenytoin for cerebral toxoplasmosis. Further diagnostic evaluation of this dangerous cutaneous affection may prove difficult for several reasons. In particular, in patients with AIDS who are more susceptible for adverse drug reactions and who are simultaneously receiving a variety of drugs with a considerable potential of cutaneous side effects, therapy cannot be withhold for lack of therapeutic alternatives. Moreover, the low lymphocyte count in this case may have made reliable testing with lymphocyte transformation studies impossible. The evaluation and the differential diagnosis of the drug-induced Stevens-Johnson syndrome are discussed. Especially long- and moderately long-acting sulfonamides belong to the most important agents that can cause a drug-induced Stevens-Johnson syndrome. The pathogenesis and the risk factors for cutaneous hypersensitivity reactions in HIV-infected patients are only poorly understood. These kind of reactions, however, seem to occur more often in patients with a more advanced immunodeficiency.

Unusual Eruptions Associated with Mycoplasma pneumoniae Respiratory Infections: Review of the Literature.

BACKGROUND Maculopapular or urticarial eruptions and erythema multiforme sometimes occur in patients affected with Mycoplasma pneumoniae respiratory infections. Further eruptions have also been reported. OBJECTIVE To review the literature addressing M. pneumoniae respiratory infection and rather unusual eruptions. METHODS Computer-based search in the U.S. National Library of Medicine database as well as in the search engine Google. RESULTS We found a possible relationship between M. pneumoniae infection and Fuchs' syndrome (n = 37), varicella-like eruptions (n = 8), Henoch-Schönlein syndrome and further leukocytoclastic vasculitides (n = 21) and erythema nodosum (n = 11). A temporal relationship was also observed with 2 cases of Gianotti-Crosti syndrome. Finally, there exists reasonable evidence that pityriasis rosea Gibert and pityriasis lichenoides et varioliformis acuta Mucha-Habermann are not associated with Mycoplasma infections. CONCLUSION This review implies that M. pneumoniae may cause, in addition to erythematous maculopapular (or urticarial) eruptions and erythema multiforme, Fuchs' syndrome and varicella-like eruptions. Furthermore, there is an intriguing link with leukocytoclastic vasculitides or erythema nodosum that deserves further investigation.