An anatomical review of various superior mesenteric artery-first approaches during pancreatoduodenectomy for pancreatic cancer.

When pancreatic head cancer invades the superior mesenteric artery (SMA), attempts at curative resection are aborted. Preoperative imaging diagnostics to determine the surgical curability have yet to surpass the intraoperative information acquired via inspection, palpation, and trial dissection. Pancreatoduodenectomy (PD) is a standard measure for treating periampullary cancers. In conventional PD, SMA invasion is usually identified by dissecting the retroportal lamina, which connects the uncinate process and SMA nerve plexus after dividing the neck of the pancreas. During PD for pancreatic head cancer, this retroperitoneal margin frequently vitiates surgical curability. SMA-first approaches during PD are methods where the SMA is dissected first by severing the posterior pancreatic capsule to assess the SMA involvement of pancreatic cancer early in the operation. The first report of such an approach prompted subsequent reports of various maneuvers that are now known collectively as "artery-first" approaches. We herein review those approaches by classifying them according to (1) the side of the mesocolon from where the SMA approach occurs (supracolic or infracolic) and (2) the direction of access (right or left and anterior or posterior). The steps of the reported PD procedures are numbered according to a timeline and summarized using anatomical division of the SMA.

Intravenous leiomyomatosis is inclined to a solid entity different from uterine leiomyoma based on RNA-seq analysis with RT-qPCR validation.

INTRODUCTION: Intravenous leiomyomatosis (IVL) is currently regarded as a special variant of the common uterine leiomyoma (LM). Though IVL shows a similar histological morphology to LM, IVL is characterized by unique intravenous growth patterns and low-grade malignant potential, which are quite different from LM. There are currently few studies underlying the molecular alterations of IVL, though this information is important for understanding the pathogenesis of the disease, and for identifying potential biomarkers. METHOD: We carried out a high-throughput whole transcriptome sequencing of tumor and normal tissue samples from five IVL patients and five LM patients and compared the differentially expressed genes (DEGs) between IVL and leiomyoma. We performed multiple different enrichment and target analyses, and the expression of selected DEGs was validated using RT-qPCR in formalin-fixed samples. RESULTS: Our study identified substantial different genes and pathways between IVL and LM, and functional enrichment analyses found several important pathways, such as angiogenesis and antiapoptosis pathways, as well as important related genes, including SH2D2A, VASH2, ADAM8, GATA2, TNF, and the lncRNA GATA6-AS1, as being significantly different between IVL and LM (P = .0024, P = .0195, P = .0212, P = .0435, P = .0401, and P = .0246, respectively). CXCL8, LIF, CDKN2A, BCL2A1, COL2A1, IGF1, and HMGA2 were also differently expressed between IVL and LM groups, but showed no statistical difference (P = .2409, P = .1773, P = .0596, P = .2737, P = .1553, P = .1045, and P = .1847, respectively) due to the large differences among individuals. Furthermore, RT-qPCR results for five selected DEGs in IVL tissues and adjacent nontumor tissues were mainly consistent with our sequencing results. CONCLUSION: Our results indicated that IVL may be a solid entity that is unique and different from LM, proving consistent with previous studies. Furthermore, we identified DEGs, particularly within angiogenesis and antiapoptosis pathway-related genes that may play crucial roles in the development and pathogenesis of IVL and may be potential specific biomarkers.

Mathematical modeling reveals how the density of initial tumor and its distance to parent vessels alter the growth trend of vascular tumors.

OBJECTIVES: The aim of this study was to investigate the response of a tumor and parent vessels to stimulating factors in the tumor microenvironment in different configurations. How a tumor grows and induces angiogenesis in different distances of a parent vessel is investigated. Moreover, interstitial fluid pressure and its effects on tumor cell phenotype are considered in the model. METHODS: A multiscale continuum-discrete model of a vascular tumor is utilized to simulate the growth of a cluster of tumor cells positioned in different distances of parent vessels. An agent-based probabilistic angiogenesis model is coupled to a discrete tumor model to simulate branching, anastomosis, blood flow, wall shear stress, and interstitial tumor pressure in which tumor cells are divided to necrotic, hypoxic, and proliferative. RESULTS: Starting the simulations from 9 initial tumor cells, the model proved that tumors grow to a certain size and also reach to a certain distance before being able to induce sprouting. For tumors placed 2 and 2.5 mm away from a parent vessel, initiation of angiogenesis is delayed significantly in comparison with closer distances. For the initial cluster positioned in a distance of 2.5 mm away, first sprout is seen after 47 days. Moreover, dendritic shape of the tumor is seen prior to angiogenesis which is a sign of cells being starved and wandered in the domain to reach the oxygen source. The trend of tumor growth obeys power law function which aligns with the experimental results. DISCUSSION: The mathematical model revealed the importance of geometry and position of an initial tumor cluster in determining the behavior and final architecture of a vascular tumor. As a tumor cell appears in farther distances from a parent vessel, duration of its growth and inducing angiogenesis becomes longer and the chance of suppressing the tumor in the initial days of growth is higher. Also, the importance of angiogenesis in making tumors devastating is again corroborated by mathematical models.

An approach for vascular tumor growth based on a hybrid embedded/homogenized treatment of the vasculature within a multiphase porous medium model.

The aim of this work is to develop a novel computational approach to facilitate the modeling of angiogenesis during tumor growth. The preexisting vasculature is modeled as a 1D inclusion and embedded into the 3D tissue through a suitable coupling method, which allows for nonmatching meshes in 1D and 3D domain. The neovasculature, which is formed during angiogenesis, is represented in a homogenized way as a phase in our multiphase porous medium system. This splitting of models is motivated by the highly complex morphology, physiology, and flow patterns in the neovasculature, which are challenging and computationally expensive to resolve with a discrete, 1D angiogenesis and blood flow model. Moreover, it is questionable if a discrete representation generates any useful additional insight. By contrast, our model may be classified as a hybrid vascular multiphase tumor growth model in the sense that a discrete, 1D representation of the preexisting vasculature is coupled with a continuum model describing angiogenesis. It is based on an originally avascular model which has been derived via the thermodynamically constrained averaging theory. The new model enables us to study mass transport from the preexisting vasculature into the neovasculature and tumor tissue. We show by means of several illustrative examples that it is indeed capable of reproducing important aspects of vascular tumor growth phenomenologically.

Angiotropism in recurrent cutaneous squamous cell carcinoma: Implications for regional tumor recurrence and extravascular migratory spread.

Extravascular migratory metastasis is a form of cancer metastasis in which tumor cells spread by tracking along the abluminal aspect of vessel walls without breaking the vascular endothelial lining or intraluminal invasion. This phenomenon has been extensively described in melanoma and is being increasingly recognized in other neoplasms. Various modalities of treatment, including radiation-, chemo-, targeted-, and immune- therapies may potentially induce angiotropic behavior in neoplastic cells. Although there is a risk for tumor recurrence and metastasis, angiotropism may be under-recognized and is rarely reported. Here, we report a case of recurrent poorly-differentiated acantholytic squamous cell carcinoma of the scalp with extensive perineural invasion, previously treated with multiple therapies. There was multifocal extravascular cuffing of neoplastic cells around and focally involving the walls of small to medium-caliber blood vessels within and surrounding the tumor, without obvious tumor intravasation. In addition, small subtle nests of neoplastic keratinocytes were noted along the abluminal aspect of a large-caliber deep dermal blood vessel in an en-face margin, away from the main tumor mass. Such involvement can be difficult to identify; and thus, may be missed particularly during intra-operative frozen section evaluation, leading to false-negative margins and is therefore, a diagnostic pitfall.

[Complex pelvic and sarcoma surgery with vascular replacement]. / Komplexe Becken- und Sarkomchirurgie mit Gefäßersatz.

Due to optimization of surgical techniques in surgical oncology and vascular surgery, the most modern approaches of anesthesia and intensive care medicine and effective multimodal therapeutic strategies, locally advanced malignant tumors are resected more frequently with a potentially curative intent. In the case of extensive tumors with infiltration of vital vascular structures or of structures which are crucial for extremity preservation, the necessary surgical procedure for complete tumor removal poses a major challenge for the surgeon and incorporates a high risk of perioperative morbidity for the patient. The decision to attempt tumor resection should therefore always be based on a concept considering all aspects of the malignant disease. The treating team should be highly experienced in this complex field of surgery, not only with respect to the surgical approach but also regarding the management of postoperative complications. In this article relevant aspects of decision making, surgical technique and postoperative outcome for malignant tumors involving vascular structures of the retroperitoneum and pelvis are presented.

[ANALYSIS OF COMPLICATIONS POSTOPERATIVE CAUSES AND MORTALITY AFTER RADICAL TREATMENT FOR TUMORS OF THE LEFT ANATOMICAL SEGMENT OF THE PANCREAS].

Radical surgery for tumors of the left anatomical and surgical segment of the pancreas proved for distal resection in various versions, central resection and enucleation of tumors. The causes of early postoperative complications and mortality in 129 patients aged from 14 to 81 years, operated on for neoplastic lesions of the left anatomical segment of the pancreas in the period from 2009 to 2014 were analysed. The influence of various factors of risk of complications and mortality were studied in particular, extended resection, for tumor invasion of adjacent organs, and adjacent vessels.

Vascular invasion, but not lymphatic invasion, of the primary tumor is a strong prognostic factor in patients with colorectal cancer.

BACKGROUND: We previously showed that the presence of vascular invasion, but not lymphatic invasion, was a strong prognostic factor for breast cancer. Lymphatic invasion may represent mainly the selective affinity of cancer cells for lymph nodes. The present study was undertaken to evaluate the presence of vascular invasion that may reflect systemic disease as a predictor of disease recurrence in colorectal cancer, separate from lymphatic invasion of the primary tumor. PATIENTS AND METHODS: We retrospectively evaluated the cases of 177 consecutive patients with primary colorectal cancer who underwent colorectal resection. We examined the relationship between recurrence and the prognostic significance of clinicopathological factors, particularly lymphatic and vascular invasion. RESULTS: The presence of vascular invasion (v) was significant, while that of lymphatic invasion (ly) was not significant in univariate analysis. The presence of vascular invasion was an independent prognostic factor in multivariate analysis. Among the 60 patients in the ly-/v- group, one (1.7%) had disease recurrence, and among the 33 patients in the ly+/v- group, one (3.0%) had disease recurrence. On the other hand, among the 71 patients in the ly+/v+ group, 16 patients (22.5%) suffered recurrence, and among the 13 patients in the ly-/v+ group, four (30.8%) suffered recurrence. It is interesting to note that despite the presence of lymphatic invasion, the group without vascular invasion (ly+/v-) had a few patients with distant metastases, a result which is similar to that of the ly-/v- group. CONCLUSION: The presence of vascular invasion, but not lymphatic invasion, could be an indicator of high biological aggressiveness and may be a strong prognostic factor for colorectal cancer.

Cytologic diagnosis of intravascular papillary endothelial hyperplasia: a report of two cases and review of cytologic literature.

BACKGROUND: Intravascular papillary endothelial hyperplasia (IPEH), previously known as 'Masson's hemangioma', is a reactive endothelial proliferation that occurs most commonly in the vessels of the head, neck, and extremities. The cytologic findings of the lesion are varied and depend on the age of the lesion. CASES: Case 1 is a 61-year-old man who presented with a swelling on the medial aspect of the forearm. The clinical diagnosis was lipoma. Cytologic smears showed spindle cells tagging onto a rich capillary network and smaller round cells arranged around hyaline cores. The cytologic diagnosis was benign vascular tumor. On histolopathogic examination a diagnosis of IPEH was given. Case 2 is a 45-year-old man who presented with swelling on the dorsal aspect of the wrist. The cytologic diagnosis of giant cell tumor was made based on the presence of scattered spindled cells and multinucleate giant cells. The giant cells had various shapes like round or crescent and had 10-25 nuclei. The lesion was excised and a diagnosis of IPEH was rendered. CONCLUSION: These two cases highlight the varied cytomorphology of IPEH making the pinpoint diagnosis of this lesion difficult on cytologic smears.

In vivo characterization of tumor and tumor vascular network using multi-modal imaging approach.

We present a multi-modal optical diagnostic approach utilizing a combined use of Fluorescence Intravital Microscopy (FIM), Dynamic Light Scattering (DLS) and Spectrally Enhanced Microscopy (SEM) modalities for in vivo imaging of tumor vascular network and blood microcirculation. FIM is used for imaging of tumor surroundings and microenvironment, SEM provides information regarding blood vessels topography, whereas DLS is applied for functional imaging of vascular network and blood microcirculation. This complementary combination of the imaging approaches is extremely useful for functional in vivo imaging of blood vasculature and tumor microenvironment. The technique has also a great potential in vascular biology and can significantly expand the capabilities of tumor angiogenesis studies and notably contribute to the development of cancer treatment.

A case of angioleiomyoma presenting as a pulsatile tumor in the left ring finger.

Angioleiomyomas in the finger are rare and their preoperative diagnosis is difficult. Most of them are not associated with arteries and their chief complaint does not reveal pulsation tumor. We report a case of the angioleiomyoma in the finger which was misdiagnosed as arteriovenous fistula of tumor, based on the presence of pulsating tumor and angiography finding.

Coupled mathematical model of tumorigenesis and angiogenesis in vascular tumours.

OBJECTIVES: Mathematical models are useful for studying vascular and avascular tumours, because these allow for more logical experimental design and provide valuable insights into the underlying mechanisms of their growth and development. The processes of avascular tumour growth and the development of capillary networks through tumour-induced angiogenesis have already been extensively investigated, albeit separately. Despite the clinical significance of vascular tumours, few studies have combined these approaches to develop a single comprehensive growth and development model. MATERIALS AND METHODS: We develop a continuum-based mathematical model of vascular tumour growth. In the model, angiogenesis is initiated through the release of angiogenic growth factors (AGFs) by cells in the hypoxic regions of the tumour. The nutrient concentration within the tumour reflects the influence of capillary growth and invasion induced by AGF. RESULTS AND CONCLUSIONS: Parametric and sensitivity studies were performed to evaluate the influence of different model parameters on tumour growth and to identify the parameters with the most influence, which include the rates of proliferation, apoptosis and necrosis, as well as the diffusion of sprout tips and the size of the region affected by angiogenesis. An optimization was performed for values of the model parameters that resulted in the best agreement with published experimental data. The resulting model solution matched the experimental data with a high degree of correlation (r = 0.85).

Multiscale modelling of fluid and drug transport in vascular tumours.

A model for fluid and drug transport through the leaky neovasculature and porous interstitium of a solid tumour is developed. The transport problems are posed on a micro-scale characterized by the inter-capillary distance, and the method of multiple scales is used to derive the continuum equations describing fluid and drug transport on the length scale of the tumour (under the assumption of a spatially periodic microstructure). The fluid equations comprise a double porous medium, with coupled Darcy flow through the interstitium and vasculature, whereas the drug equations comprise advection-reaction equations; in each case the dependence of the transport coefficients on the vascular geometry is determined by solving micro-scale cell problems.

Vertebral artery reconstruction using microanastomosis and intraoperative neuromonitoring: a case report from Santiago, Chile.

Jorge Mura, M.D. performed the microsurgery presented in this report on August 22, 2006 at the Institute of Neurosurgery Asenjo in Santiago, Chile. A highly vascularized tumor was present in the patient's only functional vertebral artery. Intraoperative neuromonitoring was conducted throughout the procedure. Following resection of the tumor and completion of the vertebral artery microanastomosis, somatosensory evoked potentials were improved from baseline potentials. Motor function was stable throughout the procedure. A post-operative computerized tomography (CT) angiogram showed that the reconstructed artery was normal and three times the size of the right vertebral artery. The patient had no post operative deficits. The preliminary result of the biopsy was an angiofibroma.

The role of tumor vascularisation in benign and malignant cardiovascular neoplasms: a comparison of cardiac myxoma and sarcomas of the pulmonary artery.

Neoangiogenesis is involved in the development and progression of malignant tumors. Vascular endothelial growth factor (VEGF) and its receptors have been designated a central part in this process. Since the significance of the assessment of angiogenesis in soft tissue tumors is still a matter of debate, we investigated the vascularisation of cardiac myxomas and compared it with pulmonary artery sarcomas (PAS). Angiogenesis in 18 PAS and 20 myxomas was assessed by morphometry. An immunohistochemical analysis of growth factors and their receptors, HIF-1alpha and tumor-associated macrophages (TAM) was performed. Results showed that microvessel density (MVD) in PAS was significantly higher at the border of necrosis versus the areas without necrosis but no difference was observed between PAS and myxomas. Vascular surface area (VSA) and intervascular distances showed a higher vascularisation at the border of necrosis compared to myxomas, which was not significant. VEGF expression was higher in PAS compared to myxomas and was prominent at the sites of necrosis. HIF-1alpha expression was marked at the border of necrosis in PAS but was absent in myxomas. Infiltration of the macrophages was significantly higher in myxomas compared to the sarcomas. VEGFR-2 expression was detected in a subset of tumor cells and in blood vessels mainly at the tumor periphery, whereas VEGFR-1 was weakly expressed in the tumors but prominent in the macrophages in cardiac myxomas. PDGF receptors and their ligands are strongly present in myxomas and to a lesser extent in the sarcomas. In conclusion, benign and malignant cardiovascular tumors with a different pathophysiology develop a comparable vascularisation. Hypoxia appears to be the strongest inducer of neoangiogenesis in the sarcomas. The expression of receptor tyrosine kinases of the VEGF family provides a basis for an adjuvant therapy.

Microvessel density and VEGF/VEGF receptor status and their role in sarcomas of the pulmonary artery.

Neoangiogenesis, driven by a variety of angiogenic factors, plays an essential role during development and progression of malignant tumors. Vascular endothelial growth factor (VEGF) and its receptors have been designated a central part in the angiogenic process during malignancy. We studied the vascular parameters by means of morphology and morphometry in 7 sarcomas of the pulmonary artery (SPA) and 10 poorly differentiated leiomyosarcomas of soft tissue. Immunohistochemical analysis of VEGF and VEGFR was related to survival and prognosis. The microvessel density (MVD) and intervascular distances (IVD) differed significantly only at sites of necrosis compared to non-necrotic areas in SPA but not for soft tissue leiomyosarcomas. MVD, IVD and vascular surface area (VSA) revealed no difference between SPA and leiomyosarcomas of different origin. We found a more pronounced expression of VEGF in most tumors at sites of necrosis. The receptors were present in a subset of tumor vessels mostly at the tumor border. VEGFR-2 expression was also seen in a subset of tumor cells whereas VEGFR-1 showed only weak expression in some tumors. Local hypoxia seems to induce a higher MVD and a lower IVD at sites of necrosis compared to those areas without necrosis. The presence of necrosis in both sarcoma groups was correlated with the presence of VEGF due to local tumor hypoxia and subsequent up-regulation of VEGFR-2 and VEGFR-1 in tumor vessels as well as tumor cells. Overall and relapse-free survival showed no difference concerning all examined parameters. Thus, microvessel density does not seem to be a prognostic factor in SPA and other sarcomas.

Antiangiogenesis therapy using a novel angiogenesis inhibitor, anginex, following radiation causes tumor growth delay.

BACKGROUND: The present study investigated whether treatment with anginex, a novel antiangiogenic peptide, could block re-vascularization after radiation treatment. METHODS: A squamous cell (SCCVII) xenograft tumor mouse model was employed to assess the effects of anginex given post-radiation on tumor growth, microvessel density (MVD), and oxygen levels. The oxygen status was determined by the partial pressure of O2. RESULTS: Tumors in untreated mice increased threefold in 7.0 days, anginex-treated tumors (10 mg/kg intraperitoneal, twice) required 7.3 +/- 0.9 days, and tumors exposed to 8-Gy radiation increased threefold over 11 days. Combination treatment of anginex and radiation caused the tumors to grow threefold in 16.1 +/- 1.6 days, a delay which was significant and deemed supra-additive. Oxygen levels in tumors treated by stand-alone or combination therapies were significantly reduced; for example from 19.5 +/- 4.9 mmHg in controls to 9.7 +/- 1.9 mmHg in combination-treated, size-matched tumors. In addition, immunohistochemistry showed a decrease in MVD in the tumors treated with anginex, radiation, or the combination. These results suggest that a combination of anginex and radiation can greatly affect the amount of functional vasculature in tumors and prolong radiation-induced tumor regression. CONCLUSION: Antiangiogenesis therapy with anginex, in addition to radiotherapy, will be useful by blocking angiogenesis-dependent regrowth of vessels.

Growth hormone in vascular pathology: neovascularization and expression of receptors is associated with cellular proliferation.

Vascular tumours are common lesions of the skin and subcutaneous tissue, but also occur in many other tissues and internal organs. The well-differentiated tumours consist of irregular anastomosing, blood-filled vascular channels that are lined by variably atypical endothelial cells. The less differentiated tumours may show solid strands and sheets, resembling carcinoma or lymphoma. Several growth factors, including basic fibroblast growth factor, transforming growth factors and vascular endothelial growth factor, play a role in tumour angiogenesis. Growth hormone (GH) is mitogenic for a variety of vascular tissue cells, including smooth muscle cells, fibroblasts and endothelial cells and exerts its regulatory functions in controlling metabolism, balanced growth and differentiated cell expression by acting on specific membrane-bound receptors, which trigger a phosphorylation cascade resulting in the modulation of numerous signalling pathways and of gene expression. Essential to the initiation of a cellular response to GH, the presence of receptors for this hormone may predict the adaptation of tumour cells resulting from GH exposure. To address the site/mode of action through which GH exerts its effects, a well characterized monoclonal antibody, obtained by hybridoma technology from Balb/c mice immunized with purified rabbit and rat liver GH-receptor (GHR) and directed against the hormone binding site of the receptor, was applied, using the ABC technique to determine GHR expression in a panel of vascular tumours. The GHR was cloned from a rabbit liver cDNA library with the aid of an oligonucleotide probe based on a 19 residue tryptic peptide sequence derived from 5900 fold purified rabbit liver receptor. A total of 64 benign and malignant vascular tumours were obtained from different human organ sites, including the chest wall, skin, axillary contents, duodenum, female breast, abdomen, stomach, colon, lymph node, bladder, body flank and neck regions. The tumours were of the following pathological entities: Haemangioma (n = 12); haemangioendothelioma (n = 10); Castleman's disease (n = 3), haemangiopericytoma (n = 4); angiosarcoma, (n = 11), Kaposi's sarcoma with focal infiltration by lymphoma, HIV +ve (n = 7), Kaposi's sarcoma (n = 17). The endothelial cell marker CD-31 was used to establish endothelial cell characteristics and microvascular density. To delineate tumour cell growth, immunohistochemical analysis of cycling nuclear protein and of proliferating cell nuclear antigen, using Ki-67 and PCNA polyclonal antibodies respectively, was used to demonstrate proliferative indexes. Results show that, compared to their normal tissue counterparts, nuclear and cytoplasmic expression of GHR consistently result in strong receptor immunoreactivity in the highly malignant angiosarcomas and Kaposi's sarcomas and was localized in the cell membranes and cytoplasm, but strong nuclear immunoreactivity was also identified. The presence of intracellular GHR is the result of endoplasmic reticulum and Golgi localization. Nuclear localization is due to identical nuclear GHR-binding protein. Furthermore, there was a positive correlation of GHR immunoreactivity with neoplastic cellular proliferation and cycling, as measured by Ki-67 and PCNA. In conclusion, this study shows that GHR expression in vascular tumours is a function of malignancy and cancer progression. Malignant cells, which are highly expressive of the receptor, have a greater proliferation rate and thereby also higher survival rate compared to tumours expressing lower or minimal receptor level. The presence of GHR in endothelial cells of vascular neoplasm indicates that they are target cells and GH is of importance in the proliferation of vascular tumour angiogenesis. GH is necessary not only for differentiation of progenitor cells, but also for their subsequent clonal expansion and maintenance. The results support the hypothesis that GH is involved in the paracrine-autocrine mechanism, acting locally in regulating vascular tumour growth and will be useful for site-specific studies of the evolution of vascular cancers. The use of anti-GHR antibodies to block tumour progression is an intriguing possibility.