Perfusion and permeability as diagnostic biomarkers of cavernous angioma with symptomatic hemorrhage.

Cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of rebleeding, and hence an accurate diagnosis is needed. With blood flow and vascular leak as established mechanisms, we analyzed perfusion and permeability derivations of dynamic contrast-enhanced quantitative perfusion (DCEQP) MRI in 745 lesions of 205 consecutive patients. Thirteen respective derivations of lesional perfusion and permeability were compared between lesions that bled within a year prior to imaging (N = 86), versus non-CASH (N = 659) using machine learning and univariate analyses. Based on logistic regression and minimizing the Bayesian information criterion (BIC), the best diagnostic biomarker of CASH within the prior year included brainstem lesion location, sporadic genotype, perfusion skewness, and high-perfusion cluster area (BIC = 414.9, sensitivity = 74%, specificity = 87%). Adding a diagnostic plasma protein biomarker enhanced sensitivity to 100% and specificity to 85%. A slightly modified derivation achieved similar accuracy (BIC = 321.6, sensitivity = 80%, specificity = 82%) in the cohort where CASH occurred 3-12 months prior to imaging after signs of hemorrhage would have disappeared on conventional MRI sequences. Adding the same plasma biomarker enhanced sensitivity to 100% and specificity to 87%. Lesional blood flow on DCEQP may distinguish CASH after hemorrhagic signs on conventional MRI have disappeared and are enhanced in combination with a plasma biomarker.

A Roadmap for Developing Plasma Diagnostic and Prognostic Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH).

BACKGROUND: Cerebral cavernous angioma (CA) is a capillary microangiopathy predisposing more than a million Americans to premature risk of brain hemorrhage. CA with recent symptomatic hemorrhage (SH), most likely to re-bleed with serious clinical sequelae, is the primary focus of therapeutic development. Signaling aberrations in CA include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammatory/immune processes, and anticoagulant vascular domain. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and iron deposition on magnetic resonance imaging are biomarkers that have been correlated with CA hemorrhage. OBJECTIVE: To optimize these biomarkers to accurately diagnose cavernous angioma with symptomatic hemorrhage (CASH), prognosticate the risk of future SH, and monitor cases after a bleed and in response to therapy. METHODS: Additional candidate biomarkers, emerging from ongoing mechanistic and differential transcriptome studies, would further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Integrative combinations of levels of plasma proteins and characteristic micro-ribonucleic acids may further strengthen biomarker associations. We will deploy advanced statistical and machine learning approaches for the integration of novel candidate biomarkers, rejecting noncorrelated candidates, and determining the best clustering and weighing of combined biomarker contributions. EXPECTED OUTCOMES: With the expertise of leading CA researchers, this project anticipates the development of future blood tests for the diagnosis and prediction of CASH to clinically advance towards precision medicine. DISCUSSION: The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use, with an approach applicable to other neurological diseases with similar pathobiologic features.

Biomarkers of cavernous angioma with symptomatic hemorrhage.

BACKGROUNDCerebral cavernous angiomas (CAs) with a symptomatic hemorrhage (CASH) have a high risk of recurrent hemorrhage and serious morbidity.METHODSEighteen plasma molecules with mechanistic roles in CA pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as that minimizing the Akaike information criterion and validated using machine learning, and was compared with the prognostic CASH biomarker predicting bleeding in the subsequent year. Biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the lesional neurovascular unit (NVU) transcriptome and in plasma miRNAs from CASH and non-CASH patients.RESULTSThe diagnostic CASH biomarker included a weighted combination of soluble CD14 (sCD14), VEGF, C-reactive protein (CRP), and IL-10 distinguishing CASH patients with 76% sensitivity and 80% specificity (P = 0.0003). The prognostic CASH biomarker (sCD14, VEGF, IL-1ß, and sROBO-4) was confirmed to predict a bleed in the subsequent year with 83% sensitivity and 93% specificity (P = 0.001). Genes associated with diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen plasma miRNAs were differentially expressed between CASH and non-CASH patients.CONCLUSIONShared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA are mechanistically linked to lesional transcriptome and miRNA. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice.FUNDINGNIH, William and Judith Davis Fund in Neurovascular Surgery Research, Be Brave for Life Foundation, Safadi Translational Fellowship, Pritzker School of Medicine, and Sigrid Jusélius Foundation.

Reevaluation of T2-weighted fast field echo (T2FFE): application to rapid volumetric black-blood imaging.

T2-fast field echo (T2FFE) sequence is a rapid T2-weighted steady state free precession sequence, but has not become a widely utilized MR-imaging strategy because of its low signal-to-noise ratio and high sensitivity to motion. These effects have seriously limited the clinical use of T2FFE and therefore T2FFE has not been used for routine clinical studies. Nevertheless, in this study, we have investigated the possibility of clinical application by re-optimization of the T2FFE on the current MRI systems. Our purpose in this study was to explore the sensitivity of T2FFE to flow spins using a flow phantom and a contrast optimization/comparison with 2D turbo spin-echo (TSE) T2-weighted images, and to evaluate its feasibility in volunteers and patients. This study demonstrated that the T2FFE sequence achieves rapid 3D T2-weighted black-blood imaging while minimizing the impact of motion using a low flip angle under the shortest repetition time and the shortest echo time conditions. Furthermore, 3D T2FFE with use of an optimal flip angle (30°-40°) can provide contrast equivalent to that of 2D TSE T2-weighted images. This proposed T2FFE sequence might be promising for numerous clinical applications.

[Application of Qu single abdominal aorta clamping for bloodless hepatectomy and Pringle hepatectomy in 118 cases of liver tumors].

OBJECTIVE: To compare the results of application of Qu single abdominal aorta clamping for bloodless hepatectomy and Pringle hepatectomy in 118 cases of liver tumors. METHODS: The clinical data of 118 patients, including 59 patients undergoing Qu single abdominal aorta clamping for bloodless hepatectomy (Group QG) and 59 patients undergone Pringle first hepatic portal clamping hepatectomy (Group PG) since March 2009 in the Ningbo Tumor Hospital and Jiangxi Provincial Hospital were retrospectively reviewed. The changes of blood pressure, oxygen saturation, urine volume, intravenous fluid volume, amount of bleeding, time of abdominal aorta (or first hepatic portal) clamping, duration of operation and anesthesia, and other intraoperative indexes of the two groups were compared, and the changes of peritoneal drainage, blood tests, liver functions, etc. before operation and 1, 3, 7, 14 days after the hepatectomy in the two groups were also analyzed. RESULTS: After taking appropriate measures for intraoperative blood pressure control, only small fluctuations of blood pressure, which could be safely adjusted and controlled with stable vital signs, was observed in the group QG. The amount of intraoperative bleeding in the group QG was (96.25 ± 18.45) ml, significantly less than (536.25 ± 35.65) ml in the group PG (P < 0.05). In the group QG, both the duration of operation time [(227.58 ± 28.20) min] and duration of anesthesia [(249.48 ± 31.35) min] were significantly shorter than that [(261.46 ± 32.12) min and (286.58 ± 35.62) min, respectively] in the group PG (both P < 0.05). The postoperative liver dysfunction in the group QG was also milder than that in the group PG (P < 0.05). CONCLUSIONS: For liver tumor patients, Qu single abdominal aorta clamping for bloodless hepatectomy can basically achieve the goal of bloodless hepatectomy. This surgical operation is simple and safe, worthy of recommendation to skillful liver surgeons in hospitals there are some difficulties of blood supply.

Polycythemia and elevated serum erythropoietin associated with a liver haemangioma.

BACKGROUND: Secondary polycythemia is a rare condition, which is usually associated to neoplasia or chronic pulmonary disorders. CASE REPORT: A 41-year-old man man with no history of liver disease was admitted for erythrocytosis. The paraclinical investigations revealed an increased erythropoietin level in the serum and a voluminous hepatic tumor but its identification was unclear. A liver resection was performed and the histopathological examination concluded that the tumor was a giant cavernous haemangioma with extensive myxoid changes. After surgical resection of the haemangioma, normal haemoglobin and serum erythropoietin were obtained without any further treatment. CONCLUSION: Liver haemangioma must be included in rare cause of secondary polycythemia, and surgical resection of the haemangioma should be considered as the standard to induce complete remission.

Hemorrhage from a cavernous hemangioma with fatal blood aspiration: A rare cause of sudden unexpected death.

Blood aspiration may be fatal, even when caused by a minor hemorrhage, and then it is important to localize and identify the source of bleeding in order to determine its origin as traumatic, spontaneous or iatrogenic. The present case deals with the clinically unexpected sudden death of a 73-year-old woman who underwent pulmonary artery catheterization (PAC) 11 days before because of known pulmonary hypertension. The forensic autopsy revealed a previously undiagnosed cavernous hemangioma of the right lung which had led to a local intrapulmonary hemorrhage with secondary bleeding into the bronchial tree. The fatal blood aspiration was preceded by recurrent episodes of hemoptysis, and its occurrence was probably promoted by the pre-existing pulmonary hypertension. The present case and other reports in the medical literature suggest that vessel malformations of the lung have to be considered as a potential cause of unexpected sudden death. Careful investigation is needed for post-mortem identification of the bleeding site.

Serum levels of basic fibroblastic growth factor (bFGF) in children with vascular anomalies: Another insight into endothelial growth.

OBJECTIVES: Dysregulation of angiogenesis has been proposed to play a central role in hemangioma pathogenesis. The aim of the study was to determine the peripheral and local serum levels of bFGF in patients with hemangiomas and vascular malformations (VM). DESIGN AND METHODS: The study group consisted of 52 children with infantile hemangioma, 14 with VM and 36 healthy patients. bFGF serum levels were analyzed by an ELISA assay. Urinary bFGF was determined in 11 individuals with hemangioma. RESULTS: The serum peripheral bFGF concentrations in children with proliferating hemangiomas were lower than in healthy controls (p=0,03). There was no correlation between the measured cytokine level and hemangioma size, as well as patients' age. The serum local bFGF levels in 29 children with hemangiomas were higher than in the peripheral blood (p=0.022). Urinary bFGF in hemangioma patients did not differ statistically from healthy controls. CONCLUSIONS: (1) Determination of bFGF serum levels is not helpful in differentiating the phases of hemangioma growth and distinguishing hemangiomas from VM; (2) serum levels of bFGF cannot distinguish between extrinsic and intrinsic theories of endothelial cell proliferation in hemangiomas.

[Portal vein thrombosis after splenectomy in childhood: report of 4 cases]. / Thrombose portale après splénectomie chez l'enfant: à propos de 4 observations.

Portal vein thrombosis is a major complication of splenectomy. Its frequency is underestimated because of asymptomatic cases. Mesenteric occlusion with intestinal infarcts is the first cause of mortality. Secondarily, in the absence of repermeabilisation, a portal hypertension can occur. We present in this study 4 cases of portal vein thrombosis in childhood. Portal vein thrombosis is frequent (8% of splenectomies) and may be asymptomatic. Doppler postoperative surveillance is justified. Thrombocytosis seems to be a determinant factor. Early diagnosis and treatment may reduce lethal outcome.

A case of adrenal cavernous hemangioma presenting with progressive enlargement and apparent hormonal hypersecretion.

OBJECTIVE: To report the case of a man with an adrenal cavernous hemangioma presenting as a progressively enlarging adrenal mass with apparent hormonal hypersecretion. METHODS: We report the clinical, laboratory, imaging findings, and clinical course of this patient, and we highlight the important atypical features of this case. The literature is reviewed for the typical presentations of adrenal cavernous hemangiomas. RESULTS: A 59-year-old man presented with an adrenal incidentaloma that had an imaging phenotype suggestive of a pheochromocytoma or an adrenal carcinoma. The hormonal profile also suggested a state of aldosterone and catecholamine hypersecretion. Surgery, however, proved the diagnosis to be an adrenal cavernous hemangioma. CONCLUSION: Although adrenal cavernous hemangioma is a rare entity, it should be considered in the differential diagnosis of an adrenal incidentaloma. Its radiologic features are not specific, and the presence of hormonal hypersecretion does not exclude the diagnosis.

Ovarian hemangioma presenting with hyperandrogenism and endometrial cancer: a case report.

BACKGROUND: Hemangiomas are very rare tumors of the ovary. Here, we report a case of a mixed capillary and cavernous ovarian hemangioma and endometrial carcinoma presenting with postmenopausal bleeding, male pattern receding frontal hairline, and high serum androgen and estradiol levels. CASE: A 70-year-old White female underwent laparotomy for endometrial carcinoma. Intraoperative frozen-section examination of the uterus revealed a 3.5 x 3 cm, grade 1 endometrioid adenocarcinoma of the endometrium with more than 50% myometrial invasion. The left ovary contained a 1.5 x 1 x 1 cm, well-circumscribed hemorrhagic nodule on the cut surface. Final histopathological examination of the small nodule demonstrated multiple, enlarged, blood-filled vascular channels lined by a single layer of flattened regular endothelial cells with no atypical features. Vascular spaces within the tumor were of different sizes, ranging from small to large, and were separated by connective tissue. The surrounding ovarian stroma was hyperplastic and contained clusters of luteinized stromal cells. Microscopy of the right ovary showed minimal stromal proliferation and no luteinization of the ovarian stroma. CONCLUSION: This is the first case of an ovarian hemangioma synchronous with a well-differentiated endometrial carcinoma. Absence of estrogen and progesterone receptors in the endothelial cells of the hemangioma suggests that ovarian hemangiomas may occur independent of stimulation by estrogen and progesterone.

Risk factors associated with intra-operative blood loss in hepatectomized patients with giant cavernous hemangioma of the liver.

BACKGROUND/AIMS: The aim of this study was to clarify risk factors associated with intra-operative blood loss in hepatectomized patients with giant cavernous hemangioma (GCH) of the liver. METHODOLOGY: Twenty patients with GCH of the liver were treated by hepatectomy. Eleven patients with intra-operative blood loss > 2000 ml (mean: 7145 +/- 7080 m; Group 1) were reviewed retrospectively and compared to 9 patients with intra-operative hemorrhage < 2000 ml (mean: 918 +/- 429 ml; Group 2). RESULTS: Although there were no significant differences in pre-operative AST, ALT, and ICG-15 or fibrinogen and platelets between the two groups, pre-operative total bilirubin and fibrin degradation product (FDP) in Group 1 was significantly higher than in Group 2. Mean operation time and intra-operative blood transfusion in Group 1 versus Group 2 were 433 min vs. 213 min (p < 0.0001) and 3036 ml vs. 422 ml (p = 0.0072), respectively. The weight of resected liver (r = 0.821, p < 0.0001), maximum diameter of tumor (r = 0.782, p < 0.0001) and operation time (r = 0.748, p < 0.0001) were the most highly correlated with intra-operative blood loss, followed by pre-operative total bilirubin (r = 0.605, p = 0.0038), FDP level (r = 0.576, p = 0.0068) and intra-operative blood transfusion (r = 0.561, p = 0.0089). CONCLUSIONS: These findings suggest that pre-operative management to reduce the tumor size, total bilirubin and FDP levels may be essential to minimize intra-operative hemorrhage and blood transfusion.

Giant cavernous hemangioma of the liver: is tumor size a risk factor for hepatectomy?

The aim of this study was to evaluate whether hepatic giant cavernous hemangioma (GCH) tumor size is a risk factor for hepatectomy. Twenty patients with GCH of the liver were treated by hepatic resection. Eleven patients with maximum resected specimen tumor size of >10 cm (mean tumor size, 18.5 cm; group 1) were compared with the 9 patients with tumor size. <10 cm (mean tumor size, 8.6 cm; group 2). The incidence of major hepatectomy in group 1 was significantly higher than that in group 2 (P = 0.0241). Although there were no significant differences in preoperative liver function, or in fibrinogen or platelet counts between the two groups, the level of preoperative fibrin degradation product (FDP) in group 1 was significantly higher than that in group 2 (P = 0.0116). Mean intraoperative hemorrhage volume, blood transfusion volume, and operation time in group 1 vs group 2 were 7003 ml vs 1092 ml (P = 0. 0251), 2927 ml vs 556 ml (P = 0.0169), and 431 min vs 216 min (P < 0. 0001), respectively. The incidence of postoperative complications in group 1 (45.5%) was higher than that in group 2 (22.2%), although not significantly so. There was no operative mortality in either group. Tumor size significantly correlated with intraoperative blood loss, operation time, weight of resected liver, intraoperative blood transfusion volume, and preoperative FDP levels. GCH tumor size is a significant risk factor for hepatectomy mainly because of the massive intraoperative blood loss and blood transfusion associated with major hepatic resection. More careful preoperative management to decrease tumor size may increase the safety of surgery for GCH of the liver.

Successful excision of hemorrhagic cavernous angioma in a patient with severe factor VII deficiency: perioperative treatment with factor VII concentrate.

A case of an uncomplicated neurosurgical procedure in a patient affected by a rare bleeding disorder is described. The interest is twofold: first because of the possible influence of underlying coagulopathy in disclosing the vascular anomaly. And second although surgery in factor VII deficiency has been reported before, with and without replacement therapy, to our knowledge, this is the first neurosurgical case in which factor VII concentrate was used. This treatment allowed safe surgery and protected the patient from complications associated with plasma and protrombin complex use.

Primary pulmonary germ cell tumor with blastomatous differentiation.

We describe the clinical and pathologic findings of a patient with mixed blastoma-germ cell malignancy primary in the lung. Serum alpha-fetoprotein levels were elevated at presentation, and normalized with anti-germ cell chemotherapy. The resection specimen contained massively necrotic germ cell tumor with viable mature neural tissue, plus viable biphasic blastoma with stromal bone and skeletal muscle differentiation. It is not clear whether the germ cell component represents unusual differentiation of a somatic cell line or whether the blastoma component represents an unusual pattern of teratomatous differentiation.

[Kasabach-Merritt syndrome. A differential diagnosis in thrombocytopenia]. / Kasabach-Merritts syndrom. En differensialdiagnose ved trombocytopeni.

The Kasabach-Merritt syndrome consists of hemangioma in association with thrombocytopenia and localized consumption coagulopathy. It is primarily a disease of childhood, but may be seen in adult patients too. When untreated, it involves considerable risk of mortality. Two adult patients are described. The disease can be cured by surgery. We discuss different options for treatment when surgery is not feasible.

[Cavernous hemangioma of the spleen with a localized intravascular coagulation syndrome (Kasabach-Merritt syndrome). Ultrastructural study]. / Hemangioma cavernoso del bazo con síndrome de coagulación intravascular localizada (síndrome de Kasabach-Merritt). Estudio ultraestructural.

Haemangioma is the commonest non-malignant tumour of the spleen. Cytopenia and coagulopathy, secondary to cell trapping and coagulation factors consumption inside the haemangioma, respectively. May occasionally occur as accompanying phenomena. A woman is presented who had splenic haemangioma associated with leucopenia and thrombocytopenia along with decrease fibrinogen and prolonged prothrombin time as well as low complement rates. She had massive splenomegaly with portal hypertension, and the partial oxygen pressure values in mesenteric and portal blood were concurrent with the presence of arteriovenous shunts. The leucocyte and platelet count, the serum complement, the fibrinogen rate and the prothrombin time recovered after splenectomy. The cavernous characteristics of the spleen, containing multiple thrombi, were confirmed upon scanning electron microscope examination. The pathophysiology of the cytopenias and clotting factors consumption is discussed, stress being laid on the ultrastructural findings. A review is presented of the clinical aspects, differential diagnosis and treatment.

Reversal of coagulopathy in Kasabach-Merritt syndrome with tranexamic acid.

An infant with a giant cavernous haemangioma developed a severe consumption coagulopathy and systemic bleeding. Replacement therapy with cryoprecipitate produced only a transient improvement in the abnormal clotting, but the addition of tranexamic acid resulted in sustained correction, permitting corrective surgery to be performed.