Proliferative Vascular Lesions Research Articles

Adjuvant Antiangiogenic Treatment for Aggressive Giant Cell Lesions of the Jaw - a 20-Year Experience at the Massachusetts General Hospital

Giant cell lesions (GCLs) are rare non-odontogenic osteolytic lesions that affect both maxillofacial and axial/appendicular skeletal structures. Aggressive lesions have a tendency to recur after surgical enucleation. To avoid en-bloc resection, adjuvant pharmacologic therapy has been used with local operative treatment. Based on the hypothesis that maxillofacial GCLs are proliferative vascular lesions and angiogenesis dependent, a protocol of at least 6 months subcutaneous interferon alpha-2a after enucleation sparing vital structures (ie. teeth and nerves) has been used since 1999 in collaboration with a hematologist/oncologist.1 The purpose of this study was to evaluate the long-term results of this standardized treatment regimen in a homogenous cohort of patients with aggressive GCLs of the maxillofacial skeleton.

Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies.

Vascular anomalies represent a spectrum of disorders from a simple "birthmark" to life- threatening entities. Incorrect nomenclature and misdiagnoses are commonly experienced by patients with these anomalies. Accurate diagnosis is crucial for appropriate evaluation and management, often requiring multidisciplinary specialists. Classification schemes provide a consistent terminology and serve as a guide for pathologists, clinicians, and researchers. One of the goals of the International Society for the Study of Vascular Anomalies (ISSVA) is to achieve a uniform classification. The last classification (1997) stratified vascular lesions into vascular malformations and proliferative vascular lesions (tumors). However, additional disease entities have since been identified that are complex and less easily classified by generic headings, such as capillary malformation, venous malformation, lymphatic malformation, etc. We hereby present the updated official ISSVA classification of vascular anomalies. The general biological scheme of the classification is retained. The section on tumors has been expanded and lists the main recognized vascular tumors, classified as benign, locally aggressive or borderline, and malignant. A list of well-defined diseases is included under each generic heading in the "Simple Vascular Malformations" section. A short definition is added for eponyms. Two new sections were created: one dealing with the malformations of individually named vessels (previously referred to as "truncular" malformations); the second groups lesions of uncertain or debated nature (tumor versus malformation). The known genetic defects underlying vascular anomalies are included in an appendix. This classification is meant to be a framework, acknowledging that it will require modification as new scientific information becomes available.

Occlusion of retinal capillaries caused by glial cell proliferation in chronic ocular inflammation.

The inner blood-retinal barrier is a gliovascular unit in which glial cells surround capillary endothelial cells and regulate retinal capillaries by paracrine interactions. During chronic ocular inflammation, microvascular complications can give rise to vascular proliferative lesions, which compromise visual acuity. This pathologic remodelling caused by proliferating Müller cells determines occlusion of retinal capillaries. The aim of the present study was to identify qualitative and quantitative alterations in the retinal capillaries in patients with post-traumatic chronic ocular inflammation or post-thrombotic vascular glaucoma. Moreover, we investigated the potential role of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines in retinal inflammation. Our electron microscopy findings demonstrated that during chronic ocular inflammation, thickening of the basement membrane, loss of pericytes and endothelial cells and proliferation of Müller cells occur with irreversible occlusion of retinal capillaries. Angiogenesis takes place as part of a regenerative reaction that results in fibrosis. We believe that VEGF and pro-inflammatory cytokines may be potential therapeutic targets in the treatment of this disease although further studies are required to confirm these findings.

Circulating biomarkers in pulmonary arterial hypertension: Update and future direction

Pulmonary arterial hypertension (PAH) is a complex disease with a poor prognosis. In recent years, great advances have occurred in our understanding of the pathophysiologic mechanisms underlying the characteristic vascular proliferative lesions, thus allowing the development of several specific drugs. Nevertheless, PAH still presents a high mortality; therefore, early diagnosis and prognostic stratification seem to be of paramount importance in order to choose the best therapeutic strategies. Circulating biomarkers have been proposed as potentially noninvasive and objective parameters for diagnosis, prognosis, and response to therapy. The molecules evaluated to date, including markers of dysfunction and neurohormonal activation, myocardial injury, inflammation and oxidative stress, vascular damage and remodelling, end-organ failure, and gene expression, reflect the complex pathophysiology of PAH. However, not one of these shows all the characteristics of the ideal biomarker; thus, a multiparameter approach is probably desirable. Moreover, future direction could be research of structural proteins specifically expressed in the pathologic tissue that act as disease-specific markers. This report presents an extensive review of circulating biomarkers in PAH and some consideration about potential future direction in this area.

PCB153-induced overexpression of ID3 contributes to the development of microvascular lesions.

Microvascular lesions resulting from endothelial cell dysfunction are produced in the brain, lung, kidney, and retina of patients of complex chronic diseases. The environmental and molecular risk factors which may contribute in the development of microvascular damage are unclear. The mechanism(s) responsible for initiating microvascular damage remain poorly defined, although several inciting factors have been proposed, including environmental toxicants-induced oxidative stress. Enhanced neovascularization has been implicated in either the development or progression of proliferative vascular lesions. Here, we present evidence for how PCB-induced ROS may contribute to the development of a neovascular phenotype with the aim of elucidating the role of environmental toxicants in endothelial dysfunction with a specific focus on the inhibitor of differentiation protein ID3. We used a combination of phenotype and immunohistochemical analysis followed by validating with protein expression and post-translational modifications with Western Blot and MALDI-TOF/TOF analysis. We also looked for a correlation between ID3 expression in vascular tissue. Our results showed that PCB-induced ROS mediated a highly tube branched neovascular phenotype that also depended on ID3 and Pyk2; and PCB153 treatment increased the size of endothelial spheroids under conditions typically used for clonal selection of stem cell spheroids. High ID3 protein expression correlated with a greater degree of malignancy and oxidative DNA damage marker 8-OHdG in blood vessels from human subjects. PCB153 treatment increased both serine and tyrosine phosphorylation of endothelial ID3. Stable ID3 overexpression increased cell survival of human microvascular endothelial cell line hCMEC/D3. In summary, our data provide evidence that ID3 may play a critical role in regulating vascular endothelial cell survival and development of microvascular lesions induced by persistent environmental pollutants such as PCB153. Findings of this study are important because they provide a new paradigm by which PCBs may contribute to the growth of microvascular lesions.

TRAIL Deficient Mice Are Protected from Sugen/Hypoxia Induced Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive lung disease diagnosed by an increase in pulmonary arterial blood pressure that is driven by a progressive vascular remodelling of small pulmonary arterioles. We have previously reported that tumor necrosis factor apoptosis-inducing ligand (TRAIL) protein expression is increased in pulmonary vascular lesions and pulmonary artery smooth muscle cells (PASMC) of patients with idiopathic PAH. The addition of recombinant TRAIL induces the proliferation and migration of PASMCs in vitro. TRAIL is required for hypoxia-induced pulmonary hypertension in mice, and blockade of TRAIL prevents and reduces disease development in other rodent models of PAH. Due to the availability of knockout and transgenic mice, murine models of disease are key to further advances in understanding the complex and heterogeneous pathogenesis of PAH. However, murine models vary in their disease severity, and are often criticized for lacking the proliferative pulmonary vascular lesions characteristic of PAH. The murine Sugen-hypoxic (SuHx) mouse model has recently been reported to have a more severe PAH phenotype consisting advanced pulmonary vascular remodelling. We therefore aimed to determine whether TRAIL was also required for the development of PAH in this model. C57BL/6 and TRAIL−/− mice were exposed to normoxia, Sugen5416 alone, hypoxia or both Sugen5416 and hypoxia (SuHx). We report here that SuHx treated C57BL/6 mice developed more severe PAH than hypoxia alone, and that TRAIL−/− mice were protected from disease development. These data further emphasise the importance of this pathway and support the use of the SuHx mouse model for investigating the importance of potential mediators in PAH pathogenesis.

Scleroderma and sudden sensorineural hearing loss

Sudden sensorineural hearing loss (SNHL) is an emergency in otolaryngological practice. The exact cause, in most of the cases cannot be found. A triad of vascular, viral, and membrane rupture are the known theories for the causation of sudden SNHL. Now various autoimmune disorders have also been suggested to play a role in the pathogenesis. Autoimmune inner ear disease in human being is an uncommon, but a distinct clinical entity. The diagnosis of the inner ear autoimmune disorder depends mainly on relatively distinct clinical course, immune laboratory tests and treatment response. The clinical picture usually consists of bilateral SNHL, bilateral reduced vestibular loss and symptoms of pressure with tinnitus and rarely tissue destruction of middle and external ear. Systemic scleroderma is an aggressive multi-system and multistage connective tissue disorder with high mortality. It is characterized by proliferative vascular lesion and marked deposition of collagen in various tissues and organs. Responses to immunosuppressive drugs are cited as evidence of an autoimmune process.

Aggressive giant cell granuloma of the jaws treated with interferon alpha: a report of two cases

Giant cell granulomas (GCGs) are benign tumours of the jaws of unknown aetiology. Aggressive lesions are difficult to manage and demonstrate a tendency to recur after surgical curettage. In the early 1980s, interferon alpha-2a was found to inhibit angiogenesis through a series of laboratory experiments and was subsequently used to treat a child with pulmonary haemangiomatosis. It has been hypothesised that GCGs are proliferative vascular lesions and would, therefor, be expected to respond to antiangiogenic therapy. The purpose of this study is to report a treatment protocol consisting of enucleation, followed by subcutaneous interferon alpha. Patients with a biopsy-confirmed giant cell lesion satisfying criteria for "aggressive" giant cell tumours were included. All lesions were enucleated, and the patients commenced interferon alpha-2a (3,000,000 units/m(2)) 48-72 h post-operatively. Two patients satisfied the criteria for aggressive giant cell lesions. All tumours were enucleated. There were no post-operative complications, and all patients tolerated the interferon therapy well. To date, there has been no evidence of tumour recurrence. The follow-up periods were 144 and 81 months, respectively. Antiangiogenic therapy, in combination with curettage, has proven to be a useful strategy for the management of these tumours. The use of interferon alpha-2a, following enucleation of these lesions, resulted in complete remission of all lesions, and decreased operative morbidity compared with conventional treatment.

Human safety risk assessment of lymph node angiomas observed in 2-year carcinogenicity studies in rats

The occurrence of mesenteric lymph node angiomas (benign vascular neoplasms including lymphangioma and hemangioma) in untreated control rats in 2-year carcinogenicity studies can range from rare to common depending on the strain used. This lesion is most common in male rats. Factors and conditions that may contribute to the etiopathogenesis of lymph node angiomas in rats include: (1) genetic drift, (2) congenital/developmental malformation, (3) sinus vascular transformation/venous obstruction of outflow, (4) “inflammatory” pseudo-tumors, and/or (5) defects of endothelial lymphatic vascular secretion/permeability. Lymph node angiomas in humans are extremely rare, not reported in mesenteric lymph nodes, and more common in females than males. The evaluation of increased mesenteric lymph node angiomas in rats for overall human safety risk assessment of novel pharmaceutical therapeutics should consider: genotoxicity of the test article, occurrence of vascular neoplasms in other locations in rats and in mice, occurrence of proliferative vascular lesions in nonclinical toxicology studies in non-rodent species, dose/exposure response, and pathophysiologic/morphologic differences and similarities of lymph node angiomas between rats and humans. Angiomas are independent lesions from angiosarcomas and are not precursors for angiosarcomas in either humans or animals. Mesenteric lymph node angiomas in rats are unlikely to be relevant for human risk assessment of pharmaceutical agents.

Small, Nondescript Ulcers With an Uncommon Etiology

Question: A 53-year-old woman presented with abdominal pain, nausea, vomiting, and weight loss of several months’ duration. Two years earlier, she was diagnosed with non-Hodgkin lymphoma and malignant pleural effusions for which she underwent treatment. She was on maintenance rituximab upon admission. She had presented several times in the previous months with similar symptoms and thorough investigations could not confirm lymphomatous involvement of the gastrointestinal tract. Upon this admission, an upper gastrointestinal series with small-bowel follow-through revealed a slow intestinal transit time and nodular and thickened mucosal folds throughout the small bowel, findings suspicious for lymphoma. She then developed multiple febrile episodes. Upper endoscopy and colonoscopy were repeated and showed innumerable small, superficial ulcers throughout her upper and lower gastrointestinal tract (Figure A, arrow at colonic ulcer), as well as upper esophageal candidiasis for which she was started on fluconazole. Multiple biopsies were taken, which confirmed the presence of acute duodenal and colonic ulcers (Figure B, arrows at residual crypts; H&E stain, original magnification, ×400); there was no evidence of lymphoma. Grocott, acid fast, and cytomegalovirus stains performed on the biopsies were negative. Clostridium difficile toxin assays, stool ova, and parasite examinations and stool cultures were also negative. During her hospital stay, she had waxing and waning mental status. She developed a left-sided, exudative pleural effusion. After pleurocenteses failed to show malignant cells, pleural and mediastinal lymph node biopsies were taken. There was no evidence of lymphoma, but necrotizing granulomatous lymphadenitis was noted. Gram, Grocott, and acid fast stains were negative for infectious organisms. A Warthin–Starry stain demonstrated numerous (black) organisms (Figure C; original magnification, ×600), and these organisms were retrospectively identified on the prior duodenal and colonic ulcer biopsies. What is the diagnosis? Look on page 1046 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. The presence of Warthin–Starry—positive organisms in necrotizing granulomatous lymphadenitis is consistent with B henselae infection. An immunohistochemical stain for B henselae is confirmatory, as noted in the duodenal and colonic ulcers (Figure D; original magnification, ×400) of this case. The patient was started on rifampin and doxycycline followed by ceftriaxone and her abdominal pain, nausea, and vomiting improved. Common clinical manifestations of infection with B henselae are cat-scratch disease (fever and localized lymphadenopathy), fever of unknown origin and hepatosplenic disease with microabscesses/granulomas evident on imaging studies. B henselae is transmitted to humans by a cat scratch, bite, lick, or even possibly from fleas (of note, the patient in our report did own 4 outdoor cats, but she did not recall being scratched or bitten). With improved therapies over the last several years, vascular proliferative lesions (bacillary angiomatosis and bacillary peliosis) are no longer common in immunosuppressed patients. Although a few cases showing endoscopic and pathologic evidence of B henselae infection involving the gastrointestinal tract have been documented in the literature, the diagnoses were bacillary angiomatosis. In one report, erythematous nodules and ulcerations were described in the colon of a man with HIV and Crohn's disease who presented with bloody diarrhea and abdominal pain; he was diagnosed with bacillary angiomatosis.1Huh Y.B. Rose S. Schoen R.B. et al.Colonic bacillary angiomatosis.Ann Intern Med. 1996; 124: 735-737Crossref PubMed Scopus (14) Google Scholar Bacillary angiomatosis, with the endoscopic appearance of ulcerated nodular lesions in the esophagus, stomach, and duodenum, was also described in a 38-year-old woman with HIV who presented with hematemesis.2Chetty R. Sabaratnam R.M. Upper gastrointestinal bacillary angiomatosis causing hematemesis: a case report.Int J Surg Pathol. 2003; 11: 241-244Crossref PubMed Scopus (17) Google Scholar The patient in the current report did not have HIV, but was immunosuppressed owing to treatment of lymphoma. Importantly, her gastrointestinal tract involvement by B henselae did not present as the erythematous nodules of bacillary angiomatosis, as in previous reports. Rather, the organism caused small, nondescript ulcers (another view of the ulcers is shown in Figure E; one is at the arrow). Although uncommon, B henselae infection should be included in the differential diagnosis when a patient develops small ulcers throughout the gastrointestinal tract that are suspected of being infectious in etiology but fail to stain for the more routine organisms such as cytomegalovirus, fungus, and acid-fast bacilli.

Laparoscopic splenectomy for splenic sclerosing angiomatoid nodular transformation: A case report

Introduction: Sclerosing angiomatoid nodular transformation (SANT) is a rare benign and proliferative vascular lesion arising within the red pulp of the spleen. The lesion is often identified incidentally on imaging and the diagnosis is confirmed on pathologic assessment of the resected spleen. The lesion can be cured by splenectomy. Until now, little has been published on the laparoscopic approach for treatment of SANT. Case Report: A 5­cm splenic tumor was discovered during a routine examination of an asymptomatic 38­ year­old man. We were initially suspicious of fibrous hamartoma, but could not rule out malignancy. Consequently, laparoscopic splenectomy was performed, and histopathological findings showed that the tumor was a sclerosing angiomatoid nodular transformation. Conclusion: We report a rare case of sclerosing angiomatoid nodular transformation, completely resected by laparoscopy. In such cases, laparoscopic splenectomy seems to be a feasible, safe, and effective treatment.

EAF2 loss enhances angiogenic effects of Von Hippel-Lindau heterozygosity on the murine liver and prostate

Von Hippel-Lindau (VHL) disease results from the inactivation of the VHL gene and is characterized by highly vascular tumors. A consequence of VHL loss is the stabilization of hypoxia-inducible factor (HIF) alpha subunits and increased expression of HIF target genes, which include pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF). In mice, homozygous deletion of VHL is embryonic lethal due to vascular abnormalities in the placenta; and, VHL+/− mice develop proliferative vascular lesions in several major organs, most prominently the liver. Loss of ELL-associated factor (EAF2) in murine models has also been shown to induce increased vascular density in the liver as well as the prostate. Previously, EAF2 was determined to be a binding partner of VHL and loss of EAF2 induced a reduction in pVHL levels and an increase in hypoxia induced factor 1α (HIF1α) levels in vitro. Here we characterized the cooperative effects of VHL- and EAF2-deficiency on angiogenesis in the liver and prostate of male mice. VHL deficiency consistently increased the incidence of hepatic vascular lesions across three mouse strains. These vascular lesions where characterized by an increase in microvessel density, and staining intensity of VHL target proteins HIF1α and VEGF. EAF2−/−VHL+/− mice had increased incidence of proliferative hepatic vascular lesions (4/4) compared to VHL+/− (10/18) and EAF2−/− (0/5) mice. Prostates of EAF2−/−VHL+/− mice also displayed an increase in microvessel density, as well as stromal inflammation and prostatic intraepithelial neoplasia. These results suggest that cooperation of VHL and EAF2 may be critical for angiogenic regulation of the liver and prostate, and concurrent loss of these two tumor suppressors may result in a pro-angiogenic phenotype.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-011-9217-1) contains supplementary material, which is available to authorized users.

Differentiation of vascular tumors from vascular malformations by expression of Wilms tumor 1 gene: Evaluation of 126 cases

Vascular tumors and malformations can be challenging to diagnose. Although they may initially appear very similar, they have distinct clinical courses and management. Wilms tumor 1 (WT1) gene expression has been reported in many different tumors including hematologic malignancies and some solid tumors. We sought to evaluate the expression of WT1 in 126 vascular lesions (64 vascular tumors, one Masson tumor, and 61 vascular malformations). Based on the International Society for the Study of Vascular Anomalies classification of vascular anomalies, we studied the expression of WT1 in vascular tumors composed of infantile hemangioma, congenital hemangiomas (non-involuting, rapidly involuting, and not otherwise specified), pyogenic granuloma, tufted angioma, cherry angioma, Kaposi sarcoma, and angiosarcoma. We also studied WT1 expression in vascular malformations composed of angiokeratoma/verrucous hemangioma, combined vascular malformations, venous malformations, glomuvenous malformations, lymphatic malformations/lymphangioma, telangiectasia, and targetoid hemosiderotic hemangioma. All vascular tumors and proliferations had positive WT1 cytoplasmic endothelial immunostaining whereas only 3 vascular malformations were WT1 positive. Moreover the positivity of WT1 in these vascular malformations was focal and involved only re-endothelialized neovessels within thrombi. The low number of malignant vascular tumors is a limitation. Immunohistochemical detection of WT1 could be a useful tool to routine evaluation of vascular anomalies allowing the distinction of vascular tumors and proliferations from vascular malformations. Staining for WT1 may guide the clinician in difficult cases, as positive results would suggest a proliferative vascular lesion whereas negative results might point to a vascular malformation.

Antiproliferation of cardamonin is involved in mTOR on aortic smooth muscle cells in high fructose-induced insulin resistance rats

The objective of this study was to determine possible effects and potential mechanisms of cardamonin on improving insulin resistance and vascular proliferative lesions in the rat's model system. Fed with 60% fructose-enriched diet for 12 weeks, male Sprague–Dawley (SD) rats developed insulin resistance and hyperinsulinemia. They also showed excessive proliferation of the vascular smooth muscle cells (VSMCs) and activation of the mammalian target of rapamycin (mTOR)/translation control proteins p70 ribosomal S6 kinase (P70S6K1)/eukaryotic initiation factor 4E binding protein 1 (4E-BP1) signaling in the rat thoracic aorta. From weeks 9–12, cardamonin was injected into the peritoneal cavity once daily. Under the detection of microscopy and electron microscopy, cardamonin improved hyperinsulinemia and inhibited proliferation of VSMCs in the thoracic aorta of rats in a dose-dependent manner. By the Real-Time RT-PCR, mRNA expression of mTOR, P70S6K1 and 4E-BP1 was significantly reduced in cardamonin treated rats. Similarly, protein over-expression of mTOR and p-P70S6K1 was obviously inhibited by immunohistochemical analyses. These findings suggest that cardamonin may play a role in ameliorating insulin resistance and smooth muscle hyperplasia of major vessels in fructose-induced rats, possibly via a mechanism that involves the modulation of insulin/mTOR signaling.

Sclerosing angiomatoid nodular transformation of the spleen: CT, MR, PET, and 99mTc-sulfur colloid SPECT CT findings with gross and histopathological correlation

Sclerosing angiomatoid nodular transformation (SANT) is a benign, proliferative vascular lesion affecting the spleen. Few reports detailing the cross sectional and PET appearance of this lesion are available, and the lesion’s behavior with 99mTc-sulfur colloid scintigraphy is previously unreported. Sclerosing nodular transformation of the spleen shows increased tracer accumulation on positron emission tomography, and a central scar-like appearance with an enhancing capsule and radiating septae on CT and MR studies that reflects the gross and histopathological features of the lesion may be visible. An understanding of this pathological finding may allow prospective recognition of the sclerosing nodular transformation of the spleen on cross sectional imaging studies.

O.195 Midface distraction osteogenesis – monobloc vs Le Fort III

Vascular anomalies are divided in two groups of vascular tumors and vascular malformation. Hemangioma and lymphangioma are both examples of vascular tumors. Hemangiomas are known as proliferative vascular lesions. They present at birth and are characterized with increased cellular turn over. On the other hand lymphangiomas are hamartomatous tumors of lymphatic vessels. In contrast to these vascular tumors, vascular malformations could be considered as structural anomalies of blood vessels of different origin such as vein, capillaries, lymphatic vessels or combinations.In this article, we presented a case of 23 year-old male with a chief complaint of swelling of the buccal mucosa, which caused some asymmetry in the lower lip. Clinical and histopathological findings clear out this lesion as a combination form of vascular malformations.

Histopathology Of Hemangiosarcomas in Mice and Hamsters and Liposarcomas/Fibrosarcomas in Rats Associated with PPAR Agonists

Peroxisome proliferator-activated receptors (PPAR) are involved in the pathogenesis of insulin resistance, diabetes, and related complications. Consequently, the identification of PPAR subtypes and the potential for their activation provides promising therapeutic targets for the management of type 2 diabetes mellitus. Available data from rodent carcinogenicity studies, however, demonstrate that PPAR agonists can be tumorigenic in one or more species of rodents at multiple sites. In 2005, the Health and Environmental Sciences Institute (HESI) PPAR Agonist Project Committee was established by a group of pharmaceutical companies to advance research on and to understand the modes of action and human relevance of this emerging rodent tumor data for PPAR agonists. Since the most commonly observed tumor types reported in rodents are hemangiosarcomas, fibrosarcomas and liposarcomas, the PPAR Agonist Project Committee approved a Pathology Working Group (PWG) to develop consensus of morphologic criteria for tumor diagnoses and consistency of diagnoses across multiple studies for hemangiosarcomas in mice and hamsters and liposarcomas/fibrosarcomas in rats. Therefore, the focus of the PWG review was to establish consistent tumor diagnostic criteria, to assess evidence of potentially preneoplastic changes and to identify distinguishing morphologic differences which may exist between spontaneous changes present in control animals with similar changes from treated animals. Specific diagnostic criteria and nomenclature are recommended for the classification of proliferative vascular lesions which may be present in mice or hamsters and for proliferative mesenchymal changes in rats in studies that are conducted with PPAR agonists.

Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension

Idiopathic pulmonary arterial hypertension (IPAH) is characterized by plexiform vascular lesions, which are hypothesized to arise from deregulated growth of pulmonary artery endothelial cells (PAEC). Here, functional and molecular differences among PAEC derived from IPAH and control human lungs were evaluated. Compared with control cells, IPAH PAEC had greater cell numbers in response to growth factors in culture due to increased proliferation as determined by bromodeoxyuridine incorporation and Ki67 nuclear antigen expression and decreased apoptosis as determined by caspase-3 activation and TdT-mediated dUTP nick end labeling assay. IPAH cells had greater migration than control cells but less organized tube formation in in vitro angiogenesis assay. Persistent activation of signal transducer and activator of transcription 3 (STAT3), a regulator of cell survival and angiogenesis, and increased expression of its downstream prosurvival target, Mcl-1, were identified in IPAH PAEC. A Janus kinase (JAK) selective inhibitor reduced STAT3 activation and blocked proliferation of IPAH cells. Phosphorylated STAT3 was detected in endothelial cells of IPAH lesions in vivo, suggesting that STAT3 activation plays a role in the proliferative pulmonary vascular lesions in IPAH lungs.

Giant cell granuloma of the jawbones – a proliferative vascular lesion? Immunohistochemical study with vascular endothelial growth factor and basic fibroblast growth factor

To estimate the angiogenic activity in central giant cell granuloma (CGCG) by immunohistochemical stains for vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). VEGF and bFGF immunoreactivity of the lesional mononuclear (MC) and giant (GC) cells was also investigated. The study consisted of 41 cases of CGCG. Vascularity was quantified by microvascular volume (MVV) as determined by point counting. In five cases of CGCG, regions at the surrounding border, which demonstrated reactive vascular-rich inflammatory areas, served as control. Immunoreactivity of the MC and GC was assessed as the percentage of VEGF- and bFGF-positive cells from the total number of the respective cell type. Within CGCG lesions the extent of angiogenesis was low; MVV did not exceed 5% for either VEGF (88% of lesions) or bFGF (78% of lesions). The mean MVV of VEGF- and bFGF-positive blood vessels was 2.9% +/- 2.4% and 3.46% +/- 2.35%, respectively, significantly lower than in the control areas (27.5% +/- 7.3% and 28.08% +/- 5.5%, respectively) (P = 0.043). VEGF-positive and bFGF-positive MC and GC were found in nearly all lesions and in less than half of the lesions, respectively. The low mean MVV of VEGF- and bFGF-positive blood vessels implies low angiogenic activity, which does not support the designation of CGCG as a true proliferative vascular lesion. MC and GC immunoreactivity for the angiogenic factors is assumed to play an important role in the osteoclastogenesis process, thus contributing to additional growth of the CGCG lesions.

Cryotherapy in the treatment of pyogenic granuloma

Pyogenic granuloma is a benign, acquired, proliferative vascular lesion of the skin and mucous membranes. Many different treatments have been used for pyogenic granuloma with variable success rates. To evaluate the efficacy of cryotherapy in the treatment of pyogenic granuloma. In a prospective observational study, 135 patients with pyogenic granuloma were treated with cryotherapy using liquid nitrogen. The patients were followed up every 3 weeks until 3 months after disappearance of the lesion. Complete resolution of the pyogenic granuloma was achieved in all patients after a mean of 1.58 treatments (range, 1-4 treatments). At the end of follow-up period, there was a flat imperceptible scar, smaller than the treated lesion, in 16 patients (11.8%). A hypertrophic scar, 3 mm in diameter, was observed in one patient. Hypopigmentation was observed in seven patients (5.1%). No other complication or side-effect was recorded in the study. We believe that pyogenic granuloma can be treated simply and effectively with cryotherapy.