Tumor-host Interface Research Articles

The Peritumoral CD8+/FOXP3+ Cell Ratio Has Prognostic Value in Triple-negative Breast Cancer.

Compelling data has demonstrated the prognostic significance of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), a subtype generally associated with a poor clinical outcome but highly heterogeneous in nature. There have been limited studies investigating the importance of subsets of T cells in TILs. Further, the significance of intratumoral versus peritumoral TILs remains controversial. We examined the prognostic value of tumor-associated CD8+ cytotoxic T cells and FOXP3+ regulatory T cells in 35 chemotherapy-naive TNBC cases with a tumor-host interface in the tissue sections. The CD8+ and FOXP3+ cell count was expressed by immunoreactive cells per high-power field in an average of 10 high-power fields. There was a wide range of CD8+ and FOXP3+ T cells within the peritumoral and intratumoral stroma. Both CD8+ and FOXP3+ TILs were significantly higher at the former location as compared with the latter (P<0.0001 and 0.003, respectively). The numbers of CD8+ and FOXP3+ T cells, either within peritumoral or intratumoral stroma, were not significantly associated with distant relapse-free or disease-specific survival. However, the peritumoral CD8+/FOXP3+ ratio of TILs was significantly associated with prolonged relapse-free survival (P=0.04) and disease-specific survival (P=0.02). This association was not observed with the CD8+/FOXP3+ ratio of intratumoral TILs. These observations suggest that the immunologic balance in the tumor microenvironment might determine antitumor immunity. Further, the peritumoral TILs appear to play a more important role in the progression of TNBC when compared with the intratumoral TILs, thus reaffirming the necessity of revisiting the method for the assessment of TILs.

Nasopharyngeal carcinoma ecology theory: cancer as multidimensional spatiotemporal "unity of ecology and evolution" pathological ecosystem.

Nasopharyngeal carcinoma (NPC) is a particular entity of head neck cancer that is generally regarded as a genetic disease with diverse intertumor and intratumor heterogeneity. This perspective review mainly outlines the up-to-date knowledge of cancer ecology and NPC progression, and presents a number of conceptual stepping-stones. At the beginning, I explicitly advocate that the nature of NPC (cancer) is not a genetic disease but an ecological disease: a multidimensional spatiotemporal "unity of ecology and evolution" pathological ecosystem. The hallmarks of cancer is proposed to act as ecological factors of population fitness. Subsequently, NPC cells are described as invasive species and its metastasis as a multidirectional ecological dispersal. The foundational ecological principles include intraspecific relationship (e.g. communication) and interspecific relationship (e.g. competition, predation, parasitism and mutualism) are interpreted to understand NPC progression. "Mulberry-fish-ponds" model can well illustrate the dynamic reciprocity of cancer ecosystem. Tumor-host interface is the ecological transition zone of cancer, and tumor buddings should be recognized as ecological islands separated from the mainland. It should be noted that tumor-host interface has a significantly molecular and functional edge effect because of its curvature and irregularity. Selection driving factors and ecological therapy including hyperthermia for NPC patients, and future perspectives in such field as "ecological pathology", "multidimensional tumoriecology" are also discussed. I advance that "nothing in cancer evolution or ecology makes sense except in the light of the other". The cancer ecology tree is constructed to comprehensively point out the future research direction. Taken together, the establishment of NPC ecology theory and cancer ecology tree might provide a novel conceptual framework and paradigm for our understanding of cancer complex causal process and potential preventive and therapeutic applications for patients.

Integrating Spatial Transcriptomics and Single-nucleus RNA Sequencing Reveals the Potential Therapeutic Strategies for Uterine Leiomyoma.

Uterine leiomyoma is the most common gynecological tumor in reproductive women. Tumor-host interface is a complex ecosystem with intimate cell-cell communications and a critical scenario for tumor pathogenesis and progression. The pseudocapsule is the main tumor-host interface of uterine leiomyoma, but its cellular spatial disposition and gene expression are poorly explored. This study mapped the cellular architecture and corresponding gene profiles of the leiomyoma and its surrounding pseudocapsule by integrating spatial transcriptomics and single-nucleus RNA-sequencing at the first time. Here, we reported that estrogen receptor alpha and progesterone receptor mediated the occurrence and development of uterine leiomyoma and that estrogen receptor beta involved in the angiogenesis, which explained the effectiveness of hormonotherapy. Therapeutic targets including ERK1/ERK2 pathway and IGF1-IGF1R were found and might be applied for non-hormonal therapy of uterine leiomyoma. Furthermore, the injection of prostaglandin E2 was initially presented for bleeding control during myomectomy, injection site should be located at the junction between pseudocapsule and leiomyoma, and surrounding pseudocapsule should not be eliminated. Collectively, a single-cell and spatially resolved atlas of human uterine leiomyoma and its surrounding pseudocapsule was established. The results revealed potentially feasible strategies for hormonotherapy, non-hormonal targeted therapy and bleeding control during myomectomy.

Infiltration pattern predicts metastasis and progression better than the T-stage and grade in pancreatic neuroendocrine tumors: a proposal for a novel infiltration-based morphologic grading

AbstractThe advancing edge profile is a powerful determinant of tumor behavior in many organs. In this study, a grading system assessing the tumor-host interface was developed and tested in 181 pancreatic neuroendocrine tumors (PanNETs), 63 of which were <=2 cm. Three tumor slides representative of the spectrum (least, medium, and most) of invasiveness at the advancing edge of the tumor were selected, and then each slide was scored as follows. Well-demarcated/encapsulated, 1 point; Mildly irregular borders and/or minimal infiltration into adjacent tissue, 2 points; Infiltrative edges with several clusters beyond the main tumor but still relatively close, and/or satellite demarcated nodules, 3 points; No demarcation, several cellular clusters away from the tumor, 4 points; Exuberantly infiltrative pattern, scirrhous growth, dissecting the normal parenchymal elements, 5 points. The sum of the rankings on the three slides was obtained. Cases with scores of 3–6 were defined as “non/minimally infiltrative” (NI; n = 77), 7–9 as “moderately infiltrative” (MI; n = 68), and 10–15 as “highly infiltrative” (HI; n = 36). In addition to showing a statistically significant correlation with all the established signs of aggressiveness (grade, size, T-stage), this grading system was found to be the most significant predictor of adverse outcomes (metastasis, progression, and death) on multivariate analysis, more strongly than T-stage, while Ki-67 index did not stand the multivariate test. As importantly, cases <=2 cm were also stratified by this grading system rendering it applicable also to this group that is currently placed in “watchful waiting” protocols. In conclusion, the proposed grading system has a strong, independent prognostic value and therefore should be considered for integration into routine pathology practice after being evaluated in validation studies with larger series.

Prognostic Impact of Tumor Budding in Intrahepatic Cholangiocellular Carcinoma.

Background: Intrahepatic cholangiocarcinoma (ICC) represents an aggressive carcinoma with a dismal prognosis. For resection specimens, histopathological prognosticators are limited to standard AJCC parameters. Tumor budding (TB), a quantitative leviable parameter for tumor cell separation and infiltration is a promising prognostic factor for several cancers. This retrospective study investigated the prognostic impact of tumor budding in ICC, using a semi-automated approach.Method: From the Memorial Sloan-Kettering Cancer Center pathology archives, tissue specimens from ICC patients were HE stained and digitized. Tumor budding was analyzed according to the International Tumor Budding Consensus Conference 2016 via QuPath in ten 0.785 mm² vision fields within the tumor center and the tumor-host interface. Within each field, automated QuPath cell detection was conducted and manually reviewed. Tumor budding was correlated with clinico-pathological parameters including AJCC 8th edition classification, hepatitis status, age, ethnicity, treatment, sex, patient overall (OS) and recurrence free survival (RFS) via uni- and multivariate analyses.Results: From 89 patients, 1780 Vision fields comprising 6006 tumor buds were analyzed and correlated with patients' OS and RFS. The median value for tumor budding in tumor budding hot spots was five within the tumor-host interface and six within the tumor center. Tumor budding correlated significantly with patient OS and RFS in uni- and multivariate analyses (p<0.001).Conclusion: Our data supports tumor budding, assessed using a digitally enhanced technique, as an independent prognosticator in ICCs for patient's OS and RFS.

Characterizing the Invasive Tumor Front of Aggressive Uterine Adenocarcinoma and Leiomyosarcoma.

The invasive tumor front (the tumor–host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.

Image‐Based Modeling of the Invasive Vascular Front in Breast Cancer

The vascular microenvironment at the tumor-host interface is known to play a crucial role in cancer progression and metastasis. This angiogenic interface involves the development of an invasive vascular front that undergoes dynamic remodeling as the tumor progresses. While immunohistochemistry for vascular markers and corrosion casting studies have improved our understanding of the properties of these interfacial blood vessels, they do not recapitulate the functional changes in this vascular bed. As a result, our understanding of this angiogenic microenvironment remains incomplete. Therefore, in this study we employed our existing library of eight whole-tumor microvascular networks from a preclinical breast cancer model to develop a computational image-based workflow to simulate the hemodynamics in the invasive vascular front. This was accomplished by computing tumor-wide 3D distributions of angiogenic characteristics such as vascular length density (mm/mm2) and surface area density (mm2/mm3), as well as simulating the perfusion density (ml/min/mm3) distributions using high-fidelity, 3D micro-CT images of the vasculature. Tumor boundary-to-center profiles were then employed to characterize how these parameters varied between the invasive vascular front and tumor center. We found that vascular and perfusion densities were highest within 0.5-1 mm from the boundary in all tumor samples. Interestingly, the vascular front in all tumor samples also exhibited patches of poorly vascularized regions. This structural and functional heterogeneity along the invasive vascular front was suggestive of a preferential direction of angiogenic growth in these tumors. In summary, this 3D image-based modeling workflow could be readily applied to any preclinical cancer model to characterize other features of the angiogenic microenvironment. Moreover, boundary-to-center profiles generated from this workflow could be incorporated in computational oncology drug delivery models or in silico investigations of the angiogenic microenvironment in cancer and other diseases.

Tumor-host interface in oral squamous cell carcinoma: Impact on nodal metastasis and prognosis.

To evaluate tumor-host interface in oral squamous cell carcinoma (OSCC) by the Brandwein-Gensler histological risk score (BG risk score); to assess its association with clinicopathological features and impact on survival outcomes in a contemporary cohort staged as per AJCC 8th edition pTNM classification. This retrospective cohort study at a tertiary care centre included 178 cases of OSCC treated by primary surgical resection from 2013 to 2016. Pathological lymph node status, disease-free survival (DFS), overall survival (OS) were assessed. BG risk score assessment categorized 25 (14%) cases as low-risk, 93 (52%) as intermediate-risk, and 60 (34%) as high-risk. BG risk score category progression from low to intermediate to high risk was associated with an incremental risk of worsening pN status, DFS, and OS. BG risk score categories significantly demarcated 2-year DFS (96% in low-risk, 51.6% in intermediate-risk, 15% in high-risk; p < 0.001) and OS (96% in low-risk, 66.7% in intermediate-risk, 31.3% in high-risk; p < 0.001). On stratified analysis, BG risk score could further demarcate prognosis in early (I/II) and late (III/IV) stage subgroups (p < 0.001). Multivariate analysis indicated the prognostic impact of BG risk score categories to be additional to, and of equal magnitude to, impact of pTNM stage. BG risk score is a powerful prognostic tool in OSCC additional to pTNM staging. It can enable risk stratification and inform decisions regarding post-surgical adjuvant treatment. It is undertaken with routine histopathological evaluation, with no increased expense or turnaround time. A case is made for its inclusion in OSCC reporting guidelines.

Abstract PS19-08: Intratumoral heterogeneity of second-harmonic generation scattering from tumor collagen and its effects on metastatic risk prediction

Abstract Second harmonic generation (SHG) is an intrinsic optical signal that can be generated from fibrillar collagen. The directionality of SHG emission is influenced by the diameter and spacing of collagen fibrils, and the disorder in their packing within collagen fibers. One measure of SHG directionality is the ratio of forward- to backward-scattered SHG, or “F/B”. F/B has been used to assess healthy vs diseased tissue in breast, ovarian, and lung cancer, and is an independent prognostic indicator of metastasis free survival time in ER+, lymph node-negative (N0), invasive ductal carcinoma (IDC). Here we assess the heterogeneity in F/B within tumor sections from ER+ N0 IDC, and its effect on the use of F/B for metastatic risk prediction. We find that F/B of tumor collagen varies between the tumor/host interface and the more cellular tumor bulk (p&amp;lt;0.0001, Student’s t-test), and that F/B from the tumor/host interface, but not tumor bulk, is prognostic of metastasis free survival in 95 IDC ER+ N0 patients (p=0.0020 and 0.10, respectively, log rank test for trend). This result was repeated with two additional image analysis procedures to generate F/B with reduced user input and hence reduced possibility of bias. Using Random Survival Forests to generate a data-driven predictive model, we find that F/B from the tumor/host interface, but not bulk, as well as a 21-gene prognostic score inferred from Affymetrix data, both contribute to predicting metastasis-free survival in this cohort. Any tool to help predict metastasis and assist with treatment decisions is likely to be applied in combination with the now well-established genomic scores. To understand how F/B can support genomic methods for guiding treatment decisions we divided our patient samples into two cohorts based upon the value of their 21-gene score relative to the TAILORx cutoff of 26 (separating low-intermediate and high-risk groups). The F/B value from tumor-host interface identifies a subgroup of patients in the low-intermediate risk group with poor clinical outcome (p=0.045, log rank test for trend). Overall, this data reveals that intratumor heterogeneity can impact the ability of F/B to predict patient outcome, and that F/B specifically from the tumor-host interface may provide a tool to better identify patients in need of adjuvant treatment or enrollment in clinical trials. Citation Format: Edward Brown, Danielle Desa, Wencheng Wu, Robert Hill, John Martens, Robert Strawderman, Bradley Turner. Intratumoral heterogeneity of second-harmonic generation scattering from tumor collagen and its effects on metastatic risk prediction [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-08.

405 TUMOR BUDDING AS A PROGNOSTIC MARKER FOR ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Carcinomas of the esophagus are the sixth most common malignancy worldwide in males. Esophageal cancer occurs in two histological types: SCC and adenocarcinoma, 90% is SCC in developing countries. The presence of tumor budding (TB) at the tumor–host interface of gastrointestinal cancers has been recognized as a hallmark of unfavorable disease biology. TB is defined as the presence of isolated malignant cells or small clusters of up to five cells at the tumor invasive front. Methods The study done by taking formalin fixed paraffin blocks of 13 esophagectomy specimens from the year 2014-2019. TB score was calculated at the invasive front of the tumor in 200x magnification. 10 fileds were screened and a hotspot was found. &amp;lt;5 buds were taken as a low grade budding. ≥5 buds were taken as a high grade budding. Results The study showed that 53.85% were found to be males &amp; 46.15% were females. In pT staging, T3 was the most common. 61.5% of the cases showed high grade budding while low grade budding was seen in only 38.5%. This tells us 69.2% fell under T3 stage of which 88.89% had high grade TB while only 11.11% had low grade budding. Of the 4 present cases of LVI, 75% had high grade TB &amp; 25% had low grade budding. Of the 3 margin involved cases, 67% had high grade TB while 33% had low grade budding. Conclusion To conclude, TB is a valuable prognostic factor and indicator of aggressive diseases. Presence of TB correlates to unfavorable clinico-pathological features. It also provides an important value of risk stratification. 1. Risk stratification 2. High grade TB benefit from esophagectomy.

Peri-tumoural stroma collagen organization of invasive ductal carcinoma assessed by polarized light microscopy differs between OncotypeDX risk group.

A commercially available genomic test, OncotypeDX has emerged as a useful postsurgical treatment guide for early stage breast cancer. Despite widespread clinical adoption, there remain logistical issues with its implementation. Collagenous stromal architecture has been shown to hold prognostic value that may complement OncotypeDX. Polarimetric analysis of breast cancer surgical samples allows for the quantification of collagenous stroma abundance and organization. We examine intratumoural collagen abundance and alignment along the tumor-host interface for 45 human samples of invasive ductal carcinoma categorized as low or higher risk by OncotypeDX. Furthermore, we probe the separatory power of collagen alignment patterns to classify unlabeled samples as low or higher OncotypeDX risk group using a linear discriminant (LD) model. No significant difference in mean collagen abundance was found between the two risk groups. However, collagen alignment along the tumor boundary was found to be significantly lower in higher risk samples. The LD model achieved a 71% total accuracy and 81% sensitivity to higher risk samples. Prognostic information extracted from the stromal morphology has potential to complement OncotypeDX as an easy-to-implement prescreening methodology.

The impact of competition between cancer cells and healthy cells on optimal drug delivery

Cell competition is recognized to be instrumental to the dynamics and structure of the tumor-host interface in invasive cancers. In mild competition scenarios, the healthy tissue and cancer cells can coexist. When the competition is aggressive, competitive cells, the so called super-competitors, expand by killing other cells. Novel chemotherapy drugs and molecularly targeted drugs are commonly administered as part of cancer therapy. Both types of drugs are susceptible to various mechanisms of drug resistance, obstructing or preventing a successful outcome. In this paper, we develop a cancer growth model that accounts for the competition between cancer cells and healthy cells. The model incorporates resistance to both chemotherapy and targeted drugs. In both cases, the level of drug resistance is assumed to be a continuous variable ranging from fully-sensitive to fully-resistant. Using our model we demonstrate that when the competition is moderate, therapies using both drugs are more effective compared with single drug therapies. However, when cancer cells are highly competitive, targeted drugs become more effective. The results of the study stress the importance of adjusting the therapy to the pre-treatment resistance levels. We conclude with a study of the spatiotemporal propagation of drug resistance in a competitive setting, verifying that the same conclusions hold in the spatially heterogeneous case.

Neoadjuvant Therapy Remodels the Pancreatic Cancer Microenvironment via Depletion of Protumorigenic Immune Cells.

Neoadjuvant therapy (neoTx) has dramatically improved the prognosis of patients with locally advanced and borderline resectable pancreatic ductal adenocarcinoma, yet its mechanisms of action on tumor cells and the tumor microenvironment are still unknown. Here, we aimed to characterize the multiple facets of neoTx-induced alterations in the pancreatic cancer microenvironment. We performed the currently most comprehensive histopathologic analysis of desmoplasia, angiogenesis, neural invasion, and immune cell infiltration at the tumor-host interface of pancreatic cancer after neoTx (n = 37) versus after primary resection (n = 37) through quantitative IHC and double immunofluorescence using automated and software-based quantification algorithms. We demonstrate that, independently of the applied pretreatment, neoadjuvant regimes are able to reverse the immunosuppressive behavior of malignant cells on pancreatic cancer microenvironment. Here, neoTx-driven selective depletion of regulatory T cells and myeloid-derived suppressor cells was associated with enrichment of antitumor immune cells in the peritumoral niche, decreased stromal activation, and less neural invasion. Importantly, the degree of this antitumor immune remodeling correlates to the degree of histopathologic response to neoTx. Survival analysis revealed that the tumor proliferation rate together with the activation of the stroma and the intratumoral infiltration with CD4+ T cells and natural killer cells constitute as independent prognostic factors for neoadjuvantly treated pancreatic cancer. NeoTx is not only cytotoxic but has pleiotropic, beneficial effects on all cellular and noncellular components of pancreatic cancer. Combinational approaches including immunotherapy may unleash long-term and more effective antitumor responses and improve prognosis of pancreatic cancer.

Extravasating Neutrophils Open Vascular Barrier and Improve Liposomes Delivery to Tumors.

Liposomes are the most extensively used nanocarriers in cancer therapy. Despite the advantages these vehicles provide over free drugs, there are still limitations with regards to the efficiency of liposomes delivery to tumors and off-target accumulation. A better understanding of nanodrugs extravasation mechanisms in different tumor types and normal vessels is needed to improve their antitumor activity. We used intravital microscopy to track for fluorescent liposomes behavior in xenograft tumor models (murine breast cancer 4T1 and melanoma B16, human prostate cancer 22Rv1) and normal skin and identified two distinct extravasation patterns. Microleakage, a local perivascular nanoparticle deposition, was found both in malignant and healthy tissues. This type of liposomes leakage does not provide access to tumor cells and is presumably responsible for drug deposition in normal tissues. In contrast, macroleakage penetrated deep into tissues and localized predominantly on the tumor-host interface. Although neutrophils did not uptake liposomes, their extravasation appeared to initiate both micro- and macroleakages. Based on neutrophils and liposomes extravasation dynamics, we hypothesized that microleakage and macroleakage are subsequent steps of the extravasation process corresponding to liposomes transport through endothelial and subendothelial barriers. Of note, extravasation spots were detected more often in the proximity of neutrophils, and across studied tumor types, neutrophils counts correlated with leakage frequencies. Reduced liposomes accumulation in 4T1 tumors upon Ly6G depletion further corroborated neutrophils role in nanoparticles delivery. Elucidating liposomes extravasation routes has a potential to help improve existing strategies and develop effective nanodrugs for cancer therapy.

Second-harmonic generation directionality is associated with neoadjuvant chemotherapy response in breast cancer core needle biopsies.

.Neoadjuvant chemotherapy (NACT) is routinely administered to subsets of breast cancer patients, including triple negative (TN) or human epidermal growth factor receptor 2-positive (HER2+) cancers. After NACT and subsequent surgical resection, 5% to 30% of patients have no residual invasive carcinoma, termed pathological complete response. Unfortunately, many patients experience little-to-no response after NACT and unnecessarily suffer its side effects. Methods are needed to predict an individual patient’s response to NACT. Core needle biopsies, taken before NACT, consist of tumor cells and the surrounding extracellular matrix. We performed second-harmonic generation (SHG) imaging of fibrillar collagen in core needle biopsy sections as a possible predictor of response to NACT. The ratio of forward-to-backward scattering (F/B) SHG was assessed in the “tumor bulk” and “tumor–host interface” in HER2+ and TN core needle biopsy sections. Patient response was classified post-treatment using the Residual Cancer Burden (RCB) score. In HER2+ biopsies, RCB class was associated with F/B derived from the tumor–stromal interface, but not tumor bulk. F/B was not associated with RCB class in TN biopsies. These findings suggest that F/B from needle biopsy sections may be a useful predictor of which patients will respond favorably to NACT, with the potential to help reduce overtreatment.

Hallmarks of cancer: Tumor budding as a sign of invasion and metastasis in head and neck cancer.

Invasion and metastasis are hallmarks of cancer. The concept of tumor budding at tumor-host interface has been documented in many carcinomas. A growing body of evidence indicates that tumor budding is a sign of invasion and early step for metastasis of many epithelial cancers including head and neck squamous cell carcinoma (HNSCC). In addition, recent research has underlined the importance of tumor budding as a promising prognosticator in HNSCC. This review summarizes the findings regarding tumor budding in HNSCC and focuses on the role of tumor budding in invasion and metastasis. Also, we highlight the prognostic significance of tumor budding in HNSCC and its potential for improving clinical decision making in terms of recommending optimal individualized treatment for this patient population.

Nonlinear simulation of an elastic tumor-host interface

Abstract We develop a computational method for simulating the nonlinear dynamics of an elastic tumor-host interface. This work is motivated by the recent linear stability analysis of a two-phase tumor model with an elastic membrane interface in 2D [47]. Unlike the classic tumor model with surface tension, the elastic interface condition is numerically challenging due to the 4th order derivative from the Helfrich bending energy. Here we are interested in exploring the nonlinear interface dynamics in a sharp interface framework. We consider a curvature dependent bending rigidity (curvature weakening [22]) to investigate metastasis patterns such as chains or fingers that invade the host environment. We solve the nutrient field and the Stokes flow field using a spectrally accurate boundary integral method, and update the interface using a nonstiff semi-implicit approach. Numerical results suggest curvature weakening promotes the development of branching patterns instead of encapsulated morphologies in a long period of time. For non-weakened bending rigidity, we are able to find self-similar shrinking morphologies based on marginally stable value of the apoptosis rate.

Expression of urokinase-type plasminogen activator and its receptor in squamous cell carcinoma of the oral tongue.

Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) act in the proteolysis of basement membrane and extracellular matrix structures, facilitating tumor invasion. The purpose of this study was to evaluate the relationship between these proteins and clinicopathological parameters in squamous cell carcinoma of the oral tongue (SCCOT). Sixty cases of SCCOT were submitted to immunohistochemistry and analyzed semiquantitatively at the invasion front and in the tumor core. The results were associated with lymph node metastasis, clinical stage, locoregional recurrence, clinical outcome and histological grade of malignancy. A higher expression of uPA was observed in cases of tumors of high-grade versus low-grade malignancy (p = 0.010). Moreover, the cases with the worst pattern of invasion presented an overexpression of uPA (p = 0.011). The presence of locoregional recurrence was associated with uPAR (p = 0.039), and the expression of both biomarkers was much higher at the invasion front than in the tumor core (p < 0.001). The results suggest uPA and uPAR are involved in the progression and aggressiveness of SCCOT, mainly at the tumor-host interface.

Morphological stability of an elastic tumor–host interface

Abstract The ability of tumors to metastasize is preceded by morphological instabilities such as chains or fingers that invade the host environment. Therefore, parameters that control the morphology of the tumor may also contribute to its invasive ability. Previous analyses on morphological changes were performed using surface energy of the tumor–host interface. In an effort to understand the role the interface stiffness plays on tumor evolution, here we model the tumor–host interface as an elastic membrane governed by the Helfrich bending energy. Using an energy variation approach, we derive a modified Laplace–Young condition for the stress jump across the interface in the Stokes equation. We then perform a linear stability analysis and investigate how physical parameters such as viscosity, bending rigidity, and apoptosis affect the morphological instability. Results show that increased bending rigidity versus mitosis rate contributes to a more stable morphological tumor behavior. On the other hand, increasing tumor viscosity or apoptosis may lead to invasive fingering morphologies. Comparison with experimental data on glioblastoma spheroids shows good agreement especially for tumors with high adhesion and low proliferation.

Tumor fragmentation estimated by volume surface ratio of tumors measured on 18F-FDG PET/CT is an independent prognostic factor of diffuse large B-cell lymphoma.

Our aim was to study the prognostic value of two new 18F-FDG PET biomarkers in diffuse large B-cell lymphoma (DLBCL). We examined the total tumor surface (TTS), describing the tumor-host interface, and the tumor volume surface ratio (TVSR), corresponding to the ratio between the total metabolic tumor volume (TMTV) and TTS, describing the tumor fragmentation. We retrospectively included 215 patients with DLBCL. Patients underwent initial 18F-FDG PET/CT before R-CHOP (73%) or intensified R-CHOP (R-ACVBP) regimens (27%). The TMTV was measured using a fixed threshold value of 41% of SUVmax. To calculate TTS and TVSR, the surface was measured using an in-house software based on the marching cube algorithm. Spearman's rank correlation coefficient (ρ) was computed between TMTV, TTS, and TVSR, and ROC analysis was performed. Survival functions at 5years were studied using a Kaplan-Meier method and uni/multivariate Cox analysis. TVSR was poorly correlated with TMTV (ρ = 0.5) and TTS (ρ = 0.26), while TTS was highly correlated with TMTV (ρ = 0.94) and was, therefore, excluded from the analysis. TMTV had the highest area under the ROC curve (0.711) and the best sensitivity (0.797), while TVSR had the best specificity (0.745). The optimal cut-off values to predict 5-year OS were 222cm3 for TMTV and 6.0mm for TVSR. Patients with high TMTV and TVSR had significantly worse prognosis in Kaplan-Meier and Cox univariate analysis. In a multivariate Cox analysis combining the International Prognostic Index (IPI), the type of chemotherapy, TMTV, and TVSR, all parameters were independent and significant prognostic factors (HR [95%CI]: IPI 1.4 [1.1-1.8], type of chemotherapy 4.5 [2.0-10.5], TMTV 2.8 [1.4-5.5], TVSR 2.1 [1.3-3.4]). A synergistic effect between TMTV and TVSR was observed in a Kaplan-Meier analysis combining the two parameters. TVSR measured on the initial 18F-FDG PET is an independent prognostic factor in DLBCL and has an additional prognostic value when combined with TMTV, IPI score and chemotherapy.