Tumor Cords Research Articles

Establishment and refinement of a DEN-induced hepatocellular carcinoma model in rats

Abstract Objectives Hepatocellular carcinoma is one of the most common malignant tumors in the world with complex etiology, high tumor heterogeneity, and low efficacy of treatment. The establishment of an animal model that is close to the clinical situation of hepatocellular carcinoma and can be successfully modeled many times is of great significance to the study of the pathogenesis, diagnosis and treatment of hepatocellular carcinoma. Methods We used Diethylnitrosamine (DEN) to induce hepatocellular carcinoma in rodents and compared four models of DEN-induced hepatocellular carcinoma. Group C (Control): rats were fed a standard laboratory rat diet and freely drank normal water. Group P (Peritoneal injection): rats were administered an IP injection (50 mg/kg/week) between 5 and 23 weeks after birth. Ten microliter of DEN solution would be injected per g of rat. Group O (DEN-Fed group): rats were allowed unrestricted access to water contaminated with 0.01 % DEN between the ages of 7 and 15 weeks. 0.2 mL of DEN drinking water was consumed per gram of rat. Group P+O (Combined peritoneal injection and Oral feeding): rats were administered an IP injection (50 mg/kg) at weeks 3 and 5 post-birth, and they freely drank water contaminated with 0.012 % DEN between weeks 7 and 14 post-birth. We used an ultrasound scan, biochemical testing, haematoxylin, and eosin staining, Masson staining, Wolf scarlet staining, Ki67, CD34, a-SMA, CD8, and CD68 staining to compare between groups. Results Liver dissection and ultrasound scan showed that compared to other groups, the liver of Group P+O was darker in color, with more grey-white cancer nodules and larger localized tumors, and the structure of the tumors was slightly disorganized, with the elastography hardness of the middle lobe and the right lobe was slightly increased. The alanine aminotransferase and total bilirubin of Group P+O were higher than those of Group O but lower than those of Group P. Haematoxylin and eosin staining showed that the tumors of Group P+O were large, with large tumor cords and pseudo-glandular, the degree of differentiation was medium and surrounded by more fatty lesions. Conclusions We conclude that combined DEN treatment is more effective, stable, and has the advantage of multiple modalities, leading to faster tumor formation.

Machine Learning Quantification of Intraepithelial Tumor-Infiltrating Lymphocytes as a Significant Prognostic Factor in High-Grade Serous Ovarian Carcinomas.

The prognostic and predictive role of tumor-infiltrating lymphocytes (TILs) has been demonstrated in various neoplasms. The few publications that have addressed this topic in high-grade serous ovarian carcinoma (HGSOC) have approached TIL quantification from a semiquantitative standpoint. Clinical correlation studies, therefore, need to be conducted based on more accurate TIL quantification. We created a machine learning system based on H&E-stained sections using 76 molecularly and clinically well-characterized advanced HGSOC. This system enabled immune cell classification. These immune parameters were subsequently correlated with overall survival (OS) and progression-free survival (PFI). An intense colonization of the tumor cords by TILs was associated with a better prognosis. Moreover, the multivariate analysis showed that the intraephitelial (ie) TILs concentration was an independent and favorable prognostic factor both for OS (p = 0.02) and PFI (p = 0.001). A synergistic effect between complete surgical cytoreduction and high levels of ieTILs was evidenced, both in terms of OS (p = 0.0005) and PFI (p = 0.0008). We consider that digital analysis with machine learning provided a more accurate TIL quantification in HGSOC. It has been demonstrated that ieTILs quantification in H&E-stained slides is an independent prognostic parameter. It is possible that intraepithelial TIL quantification could help identify candidate patients for immunotherapy.

CANALICULAR ADENOMA IN UPPER LIP: A CASE REPORT IN YOUNG PATIENT

Canalicular adenoma (CA) is an uncommon benign neoplasm of salivary glands, which mainly affects the minor glands. This neoplasm is more prevalent in females, over 50 years old. The objective is to report the case of a CA in the oral cavity. A Caucasian 18-year-old female patient attended the stomatology service with complaint of swelling in the mouth. The intraoral examination revealed an asymptomatic nodular lesion, sessile and normochromic, with fibrous consistency, slow-growing, and localized to the upper labial mucosa. The clinical diagnosis was traumatic fibroma and an excisional biopsy was performed. Microscopic examination revealed neoplastic cells in a monomorphic pattern in single layered cords in parallel rows, resulting in a bilayered appearance of the tumor cords as well as canals. The anatomopathological examination established the diagnosis of CA. The patient is under a 2-year follow-up with no signs of recurrence.

Computational Modelling of Cancer Development and Growth: Modelling at Multiple Scales and Multiscale Modelling.

In this paper, we present two mathematical models related to different aspects and scales of cancer growth. The first model is a stochastic spatiotemporal model of both a synthetic gene regulatory network (the example of a three-gene repressilator is given) and an actual gene regulatory network, the NF-[Formula: see text]B pathway. The second model is a force-based individual-based model of the development of a solid avascular tumour with specific application to tumour cords, i.e. a mass of cancer cells growing around a central blood vessel. In each case, we compare our computational simulation results with experimental data. In the final discussion section, we outline how to take the work forward through the development of a multiscale model focussed at the cell level. This would incorporate key intracellular signalling pathways associated with cancer within each cell (e.g. p53-Mdm2, NF-[Formula: see text]B) and through the use of high-performance computing be capable of simulating up to [Formula: see text] cells, i.e. the tissue scale. In this way, mathematical models at multiple scales would be combined to formulate a multiscale computational model.

GLYCOGEN-RICH CLEAR CELL SQUAMOUS CELL CARCINOMA ORIGINATING IN THE ORAL CAVITY

Clear cell squamous cell carcinoma (CCSCC) is a rare histological subtype of squamous cell carcinoma (SCC) that was originally described in the skin. Here, we report a case of a 66-year-old female patient who presented with a fungating ulcerative mass of the left lateral tongue extending anteriorly to the floor of the mouth, and posteriorly to the left retromolar fossa and the oropharynx. The patient had a history of SCC of the left posterior tongue that was treated with partial glossectomy and adjuvant radiotherapy. Representative biopsies were obtained from the floor of the mouth, tongue and retromolar fossa. The examined biopsies showed various degrees of dysplastic surface epithelium with transition into infiltrating epithelial tumor nests and cords with clear cytoplasm and malignant cellular features. Pancytokeratin, CK5/6, and p63 were all diffusely positive. S-100, Calponin, and smooth muscle actin (SMA) were negative. PAS stain was diffusely positive and diastase labile in the tumor clear cells. Sparse areas of mucicarmine positivity were noted. Based on these findings a final diagnosis of a glycogen-rich CCSCC was given. This case represents a very rare histological variant of oral SCC, which is significant for the histological differential diagnosis of clear cell tumors of the oral cavity.

Canalicular Adenoma: A Clinicopathologic and Immunohistochemical Analysis of 67 Cases with a Review of the Literature

There is a lack of a comprehensive immunohistochemical (IHC) analysis of canalicular adenoma (CanAd), especially when combined with a description of the unique histologic features. Given the usual small biopsies, IHC may be useful in distinguishing CanAd from other tumors in the differential diagnosis. Retrospective. The patients included 54 females and 13 males (4.2:1), aged 43-90years, with a mean age at presentation of 69.9years. Clinical presentation was generally a mass (n=61) slowly increasing in size (mean 38.5months), affecting the upper lip (n=46), buccal mucosa (n=17) or palate (n=4), involving the right (n=29), left (n=24) or midline (n=9), without any major salivary gland tumors. The tumors ranged in size from 0.2 to 3cm (mean 1.2cm). Most tumors were multilobular or bosselated (76%), often surrounded by a capsule. Histologically, the tumors were characterized by cystic spaces, tumor cords with beading, tubule formation, and by the presence of luminal squamous balls (n=41). The cells were cuboidal to columnar with stippled chromatin. Mitoses were inconspicuous. A myxoid stroma (n=64), sclerosis (n=42), luminal hemorrhage (n=51), and luminal microliths (calcifications) (n=33) were characteristic. Nine (13.4%) were multifocal. CanAd showed the following characteristic immunohistochemistry findings: CK-pan and S100 protein (strong, diffuse reaction); peripheral or luminal GFAP reaction; CK5/6 and p16 luminal squamous ball reaction; SOX10 nuclear reaction; cytoplasmic p63 reaction. CanAd are unique minor salivary gland tumors showing a distinct architecture and phenotype. They predilect to older women, with the majority multilobulated and affecting the upper lip, multifocal in 13%; no major salivary gland tumors were identified. S100 protein, CK-pan, GFAP and SOX10 are positive, with luminal squamous balls highlighted by CK5/6 or p16.

A multiphase model for three-dimensional tumor growth

Several mathematical formulations have analyzed the time-dependent behavior of a tumor mass. However, most of these propose simplifications that compromise the physical soundness of the model. Here, multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the thermodynamically constrained averaging theory. A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TCs), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HCs); and an interstitial fluid for the transport of nutrients. The equations are solved by a finite element method to predict the growth rate of the tumor mass as a function of the initial tumor-to-healthy cell density ratio, nutrient concentration, mechanical strain, cell adhesion and geometry. Results are shown for three cases of practical biological interest such as multicellular tumor spheroids (MTSs) and tumor cords. First, the model is validated by experimental data for time-dependent growth of an MTS in a culture medium. The tumor growth pattern follows a biphasic behavior: initially, the rapidly growing TCs tend to saturate the volume available without any significant increase in overall tumor size; then, a classical Gompertzian pattern is observed for the MTS radius variation with time. A core with necrotic cells appears for tumor sizes larger than 150 μm, surrounded by a shell of viable TCs whose thickness stays almost constant with time. A formula to estimate the size of the necrotic core is proposed. In the second case, the MTS is confined within a healthy tissue. The growth rate is reduced, as compared to the first case—mostly due to the relative adhesion of the TCs and HCs to the ECM, and the less favorable transport of nutrients. In particular, for HCs adhering less avidly to the ECM, the healthy tissue is progressively displaced as the malignant mass grows, whereas TC infiltration is predicted for the opposite condition. Interestingly, the infiltration potential of the tumor mass is mostly driven by the relative cell adhesion to the ECM. In the third case, a tumor cord model is analyzed where the malignant cells grow around microvessels in a three-dimensional geometry. It is shown that TCs tend to migrate among adjacent vessels seeking new oxygen and nutrients. This model can predict and optimize the efficacy of anticancer therapeutic strategies. It can be further developed to answer questions on tumor biophysics, related to the effects of ECM stiffness and cell adhesion on TC proliferation.

Microenvironments and Cellular Characteristics in the Micro Tumor Cords of Malignant Solid Tumors

Because of the accelerated proliferation of cancer cells and the limited distance that molecular oxygen can diffuse from functional tumor blood vessels, there appears to be a unique histology in malignant solid tumors, conglomerates of micro tumor cords. A functional blood vessel exists at the center of each tumor cord and is sequentially surrounded by well-oxygenated, oxygen-insufficient, and oxygen-depleted cancer cells in the shape of baumkuchen (layered). Cancer cells, by inducing the expression of various genes, adapt to the highly heterogeneous microenvironments in each layer. Accumulated evidence has suggested that not only tumor microenvironments but also cellular adaptive responses to them, influence the radioresistance of cancer cells. However, precisely how these factors affect one another and eventually influence the therapeutic effect of radiation therapy remains to be elucidated. Here, based on recent basic and clinical cancer research, we deduced extrinsic (oxygen concentration, glucose concentration, pH etc.) and intrinsic (transcriptional activity of hypoxia-inducible factor 1, metabolic pathways, cell cycle status, proliferative activity etc.) parameters in each layer of a tumor cord. In addition, we reviewed the latest information about the molecular mechanism linking these factors with both tumor radioresistance and tumor recurrence after radiation therapy.

Tumor hypoxia and genetic alterations in sporadic cancers

The cancer genome contains many gene alterations. How cancer cells acquire these alterations is a matter for discussion. One hypothesis is that cancer cells obtain mutations in genome stability genes at an early stage of tumor development, which results in genetic instability and generates a gene pool that enhances cellular proliferation and survival. Another hypothesis puts its emphasis on the natural selection of gene mutations for fitness. Recent data for systematic cancer genome sequencing shows that mutations in stability genes are rare in human sporadic cancers. Instead, many “passenger” mutations that do not drive the carcinogenesis process have been found in the cancer genome. Both the hypotheses mentioned above fall short in explaining recent data. Recently, many studies demonstrate the role of the tumor microenvironment, especially hypoxia and reoxygenation, in genetic instability. In this review, literature will be presented which supports a third hypothesis, i.e. that hypoxia/re-oxygenation induces genetic instability.

Mathematical modelling of the Warburg effect in tumour cords

The model proposed here links together two approaches to describe tumours: a continuous medium to describe the movement and the mechanical properties of the tissue, and a population dynamics approach to represent internal genetic inhomogeneity and instability of the tumour. In this way one can build models which cover several stages of tumour progression. In this paper we focus on describing transition from aerobic to purely glycolytic metabolism (the Warburg effect) in tumour cords. From the mathematical point of view this model leads to a free boundary problem where domains in contact are characterized by different sets of equations. Accurate stitching of the solution was possible with a modified ghost fluid method. Growth and death of the cells and uptake of the nutrients are related through ATP production and energy costs of the cellular processes. In the framework of the bi-population model this allowed to keep the number of model parameters relatively small.

Bifurcations for a multidimensional free boundary problem modeling the growth of tumor cord

This paper is devoted to studying bifurcations of a multidimensional free boundary problem modeling the growth of tumor cords. The model comprises two coupled elliptic equations defined in a bounded domain in R 2 whose boundary is made up of two disjoint closed curves, one given and the other a priori unknown. By reducing this problem into an abstract operator equation in a certain Banach space and employing the well-known bifurcation theorem of Crandall and Rabinowitz, we prove that for the well-studied radially symmetric solution of this problem, there exists a series of numbers γ k such that at each γ k there exists a branch of radially non-symmetric solutions bifurcating from the radially symmetric solution.

Multiphase modelling of tumour growth and extracellular matrix interaction: mathematical tools and applications

Resorting to a multiphase modelling framework, tumours are described here as a mixture of tumour and host cells within a porous structure constituted by a remodelling extracellular matrix (ECM), which is wet by a physiological extracellular fluid. The model presented in this article focuses mainly on the description of mechanical interactions of the growing tumour with the host tissue, their influence on tumour growth, and the attachment/detachment mechanisms between cells and ECM. Starting from some recent experimental evidences, we propose to describe the interaction forces involving the extracellular matrix via some concepts coming from viscoplasticity. We then apply the model to the description of the growth of tumour cords and the formation of fibrosis.

Eosinophil-rich squamous carcinoma of the oral cavity: a study of 13 cases and delineation of a possible new microscopic entity

We report 13 cases of squamous cell carcinoma (SCC) of the oral cavity characterized by a prominent eosinophilic infiltration of the stroma. All patients were adults, 10 men and 3 women (aged 54 to 92 years; median, 71 years). They presented with tumors of the gingiva (5 cases), tongue (3 cases), palatine tonsil (2 cases), palate (2 cases), and mucosal aspect of lip (1 case). Metastatic involvement of regional lymph nodes was seen in 5 cases. The metastatic foci were associated with heavy eosinophilia as well. No patient had an abnormal eosinophil count in blood. Microscopically, the clusters of eosinophils were characteristically noticed in intimate admixture with the advancing edge of squamous carcinoma, either as nests or small tumor cords. The pattern of eosinophilic infiltration was comparable, regardless of tumor site or grade. Data from our series indicate that SCC with a reactive inflammatory infiltrate rich in eosinophils is consistently associated with stromal invasion. This observation may be useful in dealing with small tissue fragments where subepithelial stromal invasion cannot be easily assessed by conventional criteria. In addition, our data seem to confirm that eosinophil-rich SCC, although associated with metastatic involvement of cervical lymph node, seems to pursue a less aggressive course if compared with ordinary SCC.

Reoxygenation and Split-Dose Response to Radiation in a Tumour Model with Krogh-Type Vascular Geometry

After a single dose of radiation, transient changes caused by cell death are likely to occur in the oxygenation of surviving cells. Since cell radiosensitivity increases with oxygen concentration, reoxygenation is expected to increase the sensitivity of the cell population to a successive irradiation. In previous papers we proposed a model of the response to treatment of tumour cords (cylindrical arrangements of tumour cells growing around a blood vessel of the tumour). The model included the motion of cells and oxygen diffusion and consumption. By assuming parallel and regularly spaced tumour vessels, as in the Krogh model of microcirculation, we extend our previous model to account for the action of irradiation and the damage repair process, and we study the time course of the oxygenation and the cellular response. By means of simulations of the response to a dose split in two equal fractions, we investigate the dependence of tumour response on the time interval between the fractions and on the main parameters of the system. The influence of reoxygenation on a therapeutic index that compares the effect of a split dose on the tumour and on the normal tissue is also investigated.

Multiphase modeling and qualitative analysis of the growth of tumor cords

In this paper a macroscopic model of tumor cord growth is developed, relying on the mathematical theory of deformable porous media. Tumor is modeled as a saturated mixture of proliferating cells, extracellular fluid and extracellular matrix, that occupies a spatial region close to a blood vessel whence cells get the nutrient needed for their vital functions. Growth of tumor cells takes place within a healthy host tissue, which is in turn modeled as a saturated mixture of non-proliferating cells. Interactions between these two regions are accounted for as an essential mechanism for the growth of the tumor mass. By weakening the role of the extracellular matrix, which is regarded as a rigid non-remodeling scaffold, a system of two partial differential equations is derived, describing the evolution of the cell volume ratio coupled to the dynamics of the nutrient, whose higher and lower concentration levels determine proliferation or death of tumor cells, respectively. Numerical simulations of a reference two-dimensional problem are shown and commented, and a qualitative mathematical analysis of some of its key issues is proposed.

Microcystic Adnexal Carcinoma

Microcystic adnexal carcinoma (MAC) is an uncommon, locally aggressive neoplasm of the skin appendages that exhibits eccrine and follicular differentiation. The tumor is typically described as slow growing but destructive. Histologic sections demonstrate keratinized cysts, eccrine ducts, and bland tumor cords within a desmoplastic stroma. MAC is characteristically devoid of striking atypia, mitotic figures, and necrosis. The deeply invasive process starts in the superficial dermis but may extend into the subcutaneous tissue and skeletal muscle. Bland clinical and histologic features combined with characteristically superficial or small incomplete biopsies often result in a misdiagnosis and delay curative treatment. In this article, we report a case of MAC followed by a comparative discussion of the most common histologic differential diagnoses.

Intensified Doxorubicin-Based Regimen Efficacy in Residual Non-Hodgkin's Lymphoma Disease: Towards a Computationally Supported Treatment Improvement

Despite recent advances, treatment of patients with aggressive Non-Hodgkin's lymphoma (NHL 2 ) has yet to be optimally designed. Notwithstanding the contribution of molecular treatments, intensiflcation of chemotherapeutic regimens may still be beneflcial. Hoping to aid in the design of intensifled chemotherapy, we put forward a mathematical and computational model that analyses the efiect of Doxorubicin on NHL over a wide range of patho-physiological conditions. The model represents tumour growth both in difiusion-limited settings, that is, in small avascular tumours and tumour cords, and in perfusion-limited settings, e.g. in well-vascularized tumours. Model simulations indicated the presence of a critical regimen intensity below which treatment will fall short of tumour elimination. Taking this critical intensity into account, we compared two regimen intensiflcation strategies: Dose escalation and regimen densiflcation, i.e. reducing the inter-dosing interval. In the difiusion-limited setting, dose escalation was somewhat more e-cient than regimen densiflcation. In the perfusion-limited setting, both intensiflcation strategies yielded similar results. The present study coupled with a realistic myelotoxicity model may add insight on the optimisation of NHL intensifled chemotherapy design.

Cell resensitization after delivery of a cycle-specific anticancer drug and effect of dose splitting: Learning from tumour cords

After a single dose of an anticancer agent, changes due to cell death are expected to occur in the distribution of cells between proliferating and quiescent compartment as well as in the oxygenation and nutritional state of surviving cells. These changes are transient because tumour regrowth tends to restore the pretreatment status. The reoxygenation due to the decrease of oxygen consumption is expected to induce cell recruitment from quiescence into proliferation, and consequently to increase the sensitivity of the cell population to a successive treatment by a cycle-specific drug. In previous papers we proposed a model of the response of tumour cords (cylindrical arrangements of tumour cells growing around a blood vessel of the tumour) to single-dose treatments. The model included the motion of cells and oxygen diffusion and consumption. On the basis of that model suitably extended to better account for the action of anticancer drugs, we study the time course of the oxygenation and of the redistribution of cells between the proliferating and quiescent compartments. By means of simulations of the response to a dose delivered as two spaced equal fractions, we investigate the dependence of tumour response on the spacing between the fractions and on the main parameters of the system. A time window may be found in which the delivery of two fractions is more effective than the delivery of the undivided dose.

Dynamics of tumour cords following changes in oxygen availability: A model including a delayed exit from quiescence

In this paper, we investigate the formation of tumour cords (cylindrical arrangements of tumour cells around blood vessels) within a tumour tissue. The shrinkage and the expansion of the cord following a stepwise decrease or, respectively, increase of oxygen tension in the blood vessel are also described. The model represents the tumour cell population as a continuum and includes two novel aspects with respect to our previous works: cell death does not occur instantaneously, but is preceded by a reversible prenecrotic state; the recruitment of cells from quiescence into proliferation may require a recovery period. Model predictions are compared with experimental data reported by Hirst et al..

Interstitial Pressure And Fluid Motion In Tumor Cords

This work illustrates the behavior of the interstitial pressure and of the interstitial fluid motion in tumor cords (cylindrical arrangements of tumor cells growing around blood vessels of the tumor) by means of numerical simulations on the basis of a mathematical model previously developed. The model describes the steady state of a tumor cord surrounded by necrosis and its time evolution following cell killing. The most relevant aspects of the dynamics of extracellular fluid are by computing the longitudinal average of the radial fluid velocity and of the pressure field. In the present paper, the necrotic region is treated as a mixture of degrading dead cells and fluid.