Risk Of Spontaneous Hemorrhage Research Articles

Thrombocytopenia following iron repletion with ferrous gluconate.

Immune thrombocytopenia (ITP) is an autoimmune disorder marked by low platelet counts that puts patients at risk for spontaneous bleeding. A rare trigger for ITP is iron repletion, which has only been reported in a few cases. In this article, we present a unique case of a 54-year-old male with a history of recurrent ITP who experienced rapid thrombocytopenia following iron repletion with ferrous gluconate. Discontinuation of ferrous medications resulted in platelet counts returning to the normal baseline. Following more than 30 years of the patient's clinical timeline, this case demonstrates the chronic nature of ITP and the complexity of its causes. Further studies are needed to determine the prevalence of iron repletion-induced thrombocytopenia and its underlying mechanisms.

Management of patients with immune thrombocytopenia in the Moscow region

Background. Idiopathic thrombocytopenic purpura (ITp) is an autoimmune disease characterized by antibody-mediated platelets destruction and impairment of their production, which manifests itself as: isolated thrombocytopenia, risk of spontaneous hemorrhage and bleeding of varying severity. ITp is a hematological, orphan disease with an incidence of 1–4 cases per 100,000 population. In modern literature, primary and secondary immune thrombocytopenias are distinguished. primary immune thrombocytopenia is a diagnosis of exclusion. To verify it, a certain diagnostic search is required.Aim. To evaluate clinical characteristics and treatment efficacy in patients with a confirmed primary immune thrombocytopenia in the Moscow region.Materials and methods. This article presents the results of an analysis of more than 2,400 outpatient records of patients diagnosed with thrombocytopenia (for the period from 2010 to 2022). Of these, about 400 confirmed clinical cases of various ITp forms were included in the ITp registry of the Moscow Region. All patients live in the Moscow region, receive treatment and are observed at the Center for Orphan diseases of the M.f. vladimirskiy Moscow Regional Research Clinical Institute.Results. There are 415 patients with a verified diagnosis of ITp in the register of the Moscow Region Center for Orphan diseases of the M.f. vladimirskiy Moscow Regional Research Clinical Institute (71 % (n = 294) are female). In 69.8 % (n = 290) of patients at the time of disease manifestation, hemorrhagic syndrome was recorded. As a first-line therapy, 92.8 % (n = 385) of patients received corticosteroids (prednisolone, methylprednisolone, dexamethasone), in the second-line therapy, 82 % (n = 340) of patients were recommended therapy with thrombopoietin receptor agonists (romiplostim, eltrombopag). The options for third-line therapy in patients with ITp are rituximab monotherapy, splenectomy, and intravenous immunoglobulin. Splenectomy was performed in 3.37 % (n = 14) of patients.Conclusion. when evaluating this register, the highest efficiency of thrombopoietin receptor agonists (romiplostim, eltrombopag) is observed – 84.1 % of the objective response.

LGG-31. Pediatric low-grade gliomas with FGFR1 mutations and spontaneous hemorrhage: case series

Pediatric low-grade gliomas (pLGG) are the most common pediatric CNS neoplasms. Thanks to the advent of molecular tumor diagnostics, we have begun exploring the clinical relevance of FGFR1 (c.1632C>A; p.N546K) mutations in the pLGG population. However, the risk of spontaneous hemorrhage in pLGG patients harboring FGFR1 mutations is even less understood. We present four pLGG cases with FGFR1 mutation and hemorrhagic episodes. Patient 1 presented with an intraventricular hemorrhage and leptomeningeal disease. Pathology was consistent with suprasellar pilocytic astrocytoma, FGFR1, and PTPN11 mutations. Initial therapy consisted of Carboplatin/Vinblastine per ADVL0515. The patient has had several recurrences, and treatment regimens have included ACNS0223, Everolimus, and A9952 regimen A. Patient 2 was diagnosed with an optic pathway glioma, and pathology confirmed FGFR1, MEK2, PTPN11, and NF1 splice site mutations. The patient also has a history of Noonan’s Syndrome and has undergone several chemotherapy regimens, including A9952 Regimen A, COG MATCH with Erdafitinib, and Avastin. The best tumor response was seen while on Avastin. The patient has presented with two episodes of intratumoral hemorrhage, both after treatment with Avastin. Patient 3 presented with a sudden brain stem hemorrhage and underwent a biopsy and debulking. The pathology was consistent with a pilocytic astrocytoma with an FGFR1 mutation confirmed by Next-generation sequencing (NGS). Treatment regimens for this patient include A9952 Regimen A and Vinblastine. Patient 4 presented with acute headache and vomiting and was found to have a hemorrhagic suprasellar mass. The patient underwent tumor debulking, and pathology was consistent with low-grade glioma. NGS revealed FGFR1 and KRAS mutations. The patient received therapy as per A9952 Regimen A. Greater surveillance of this molecular and clinical finding is warranted to uncover the association between FGFR1 mutations and hemorrhage in patients with low-grade gliomas.

Spontaneous Spinal Subdural Hematoma Secondary to Hemophilia A and Zanubrutinib

Spontaneous spinal subdural hematomas (SSH) are rare occurrences that can occur most commonly secondary to vascular malformations or coagulopathies. Only a small fraction of spontaneous SSHs are caused by acquired coagulation disorders such as leukemia, hemophilia, and thrombocytopenia. This case report describes a patient with a history of Guillain–Barré syndrome (GBS), hemophilia A, and mantle cell lymphoma, on zanubrutinib therapy, a Bruton tyrosine kinase inhibitor associated with a risk of spontaneous hemorrhage. This patient developed a spontaneous spinal subdural hematoma, most likely due to the zanubrutinib therapy and exacerbated due to hemophilia. Treatment was delayed due to the patient's history of GBS that confounded the clinical diagnosis. This case is the first report of a spontaneous SSH in a patient on zanubrutinib, highlighting the need for a high index of suspicion for CNS hemorrhage in patients on Bruton's tyrosine kinase (BTK) inhibitor therapy.

Abstract 1122‐000027: Bilateral Vertebral Artery Occlusion and Involvement of the Posterior Circulation

Introduction : Rationale: Bilateral vertebral artery occlusion with collateral reconstitution is a rare finding. Compared to patients with acute occlusion, symptom progression may be much slower [1]. Atherosclerotic risk factors lead to occlusion, including hypertension and hyperlipidemia, but it is unclear what leads to collateral reconstitution [2]. These patients may have collateral circulation from anterior and posterior circulation sources that are well developed [1] [2]. Sufficient collateral flow correlates with lower rates of hemorrhagic transformation following recanalization [3] [4]. However, given the risk of spontaneous hemorrhage from microvascular collaterals, the hemorrhagic risk associated with thrombolytic therapy in patients with moyamoya collaterals, due to the fragility of these vessels [5], must be balanced with the benefit of therapy in the presence of severe neurologic deficits along with the mortality and morbidity that may stem from the occlusion. Patient concerns: 67 year old Caucasian male with past medical history of coronary artery disease, abdominal aortic aneurysm, hypertension, history of tobacco use and type 2 diabetes mellitus presents with acute right‐sided weakness. Methods : Diagnoses: On admission, CTA Head and Neck suggested chronic total occlusion of bilateral V4 segments from their origin to the midportion with tandem bilateral high‐grade stenoses throughout the imaged distal V2 and V3 segments bilaterally. MRI could not be obtained because of old lumbar fusion spinal hardware. Cerebral angiography showed microvascular reconstitution, analogous to moyamoya, with slow mid basilar flow, which could be either due to occlusion or competitive flow from top of the basilar collaterals. Interventions: Patient received intra‐arterial integrilin and tPA thrombolysis with TICI 1 reperfusion. Results : Outcomes: Patient presented with NIHSS 18 notable for right sided weakness (2/5 strength in his right upper extremity and 1/5 strength in RLE), bilateral hemianopia, severe dysarthria and right gaze preference. Patient had significant improvement in his exam the next day following thrombolysis. Notably, patient had 5/5 strength in his right upper and right lower extremities compared to his strength on presentation. Repeat head CT on the following day after thrombolysis showed left pontine infarct. Repeat NIHSS was 3 at 24 hours for partial hemianopia, minor nasolabial flattening and mild dysarthria. Conclusions : Conclusion: Bilateral intracranial vertebral artery stenosis and occlusion commonly occurs distal to PICA and near the vertebrobasilar junction [2]. Proximal (specifically areas supplied by PICA) and distal territories within the posterior circulation are often infarcted [2], which can yield a unique exam upon presentation that can help accurately guide diagnosis and treatment when appropriately recognized. The involvement of collateral circulation can play a crucial role in patients undergoing endovascular revascularization therapy [6]. In the setting of bilateral vertebral occlusion with microvascular reconstitution, patients can still undergo catheter based thrombolysis, but not thrombectomy.

Endoscopic Procedures In Patients Taking Novel Oral Anticoagulants

The use of direct oral anticoagulants (DOAC) for the treatment of atrial fibrillation and prevention of strokes is encouraged by their superior properties compared to vitamin K antagonists: predictable anticoagulant effect, greater patient compliance, few drug interactions, low risk of intracranial hemorrhages. Although practicing gastroenterologists may never prescribe a DOAC, they are likely to encounter DOAC-related GI adverse events (gastrointestinal bleeding), and they will need to manage DOACs around the time of endoscopy. The present paper aims to present the management possibilities of the patient treated with DOAC undergoing endoscopy, most studies performed so far focusing on the risk of spontaneous bleeding in this category of subjects. The current guidelines provided by the British Society of Gastroenterology and the European Society of Gastrointestinal Endoscopy orientate us, but endoscopic maneuvers should be preceded by a detailed analysis of the risks of secondary bleeding and thrombosis associated with DOAC users.

Surgical resection of a congenital hemangiopericytoma involving the thoracic spine

Abstract A congenital hemagiopericytoma (HPC) is an uncommon tumor derived from vascular pericytes; HPCs involving the central nervous system are rare. No report of a congenital HPC involving the spinal cord has yet appeared. Most adult HPCs become malignant, but infantile HPCs are benign. However, resection is necessary because the tumors grow rapidly and the risk of spontaneous bleeding is high. We here report a congenital HPC involving the back, thoracic cavity, and spinal cord. This is the first report of a congenital HPC that invaded the spine.

A Single Intravenous Infusion of FLT180a Results in Factor IX Activity Levels of More Than 40% and Has the Potential to Provide a Functional Cure for Patients with Haemophilia B

Introduction: Haemophilia B is an X-linked disease caused by mutations of the F9 gene coding for Factor IX (FIX). It is classified as mild, moderate, or severe based on FIX level, which correlates to clinical outcomes including frequency and severity of bleeding. Current standard of care is regular prophylaxis with FIX concentrate which aims to maintain FIX level above 1% to decrease the annualised bleed rate (ABR). However, compliance is variable and treatment is expensive so not available to all patients. Somatic gene therapy for haemophilia B offers the potential for durable endogenous production of FIX after a single infusion. A number of gene therapies for haemophilia B are in development and have shown the ability to raise FIX activity and reduce ABR and factor consumption. The most significant adverse effect observed to date, is a self-limiting increase in liver enzymes occurring between Week 4 and 12, which is associated with a loss of FIX expression. This can be treated with steroids but these must be started without delay to be fully effective and prevent loss of FIX expression. FLT180a is a next generation gene therapy for the treatment of haemophilia B consisting of single stranded adeno-associated virus (AAV) in which a codon optimised variant FIX transgene is under the control of a new small synthetic liver specific promoter and is encapsidated in a novel synthetic capsid that has been shown to significantly improve the transduction of human hepatocytes. Based on in-vitro and in-vivo data, FLT180a has the potential to produce continuous high levels of endogenous FIX activity sufficient to normalise FIX levels and eliminate the risk of spontaneous and traumatic bleeds, thus allowing patients to lead a normal life.Methods: In this first-in-human Phase 1/2, open-label, multicentre, ascending single dose, safety study sponsored by UCL (NCT03369444) FLT180a is administered to patients with severe (<1% FIX activity) or moderate (1-2% FIX activity with a severe bleeding phenotype) haemophilia B, with no current/previous evidence of inhibitors and a negative transduction inhibition assay for the vector. The primary endpoint is safety. Secondary endpoints include FIX activity levels, ABR, FIX consumption, immune response, and viral shedding. To address the risk of transaminitis and protect against loss of gene expression all patients participating in the study are to receive prophylactic steroids between Week 4 and Week 12.Results: As of 26 June 2018, two patients had been treated with FLT180a at the low dose of 4.5 x 1011 vg/kg and observed for 20 and 14 weeks, respectively. Within 4 weeks of receiving a single infusion of FLT180a, both patients achieved FIX levels of >30%, which is well within the mild haemophilia range where the risk of spontaneous bleeding is absent and bleeding occurs only after major surgery or injury. Patients 1 and 2 had peak FIX expression around Week 12 with levels of 48% and 66%, respectively. After the discontinuation of prophylactic steroids FIX levels stabilised at 46% and 48%, respectively.No serious adverse events have been reported and there has not been any significant increase in liver enzymes. Prophylaxis with exogenous coagulation factor was stopped within the first week post FLT180a administration due to sufficient rise in patients endogenous FIX. Neither patient has required exogenous coagulation factor after this first week. No spontaneous bleeds have occurred. A traumatic bleed was reported by Patient 1 (right middle finger cut) at Week 10 but did not require treatment with FIX concentrates. The patient's FIX activity at the time was 38%.Conclusions: Current treatments have reduced life-threatening bleeds, chronic joint disease and disability; however, people with haemophilia B continue to have significantly decreased quality of life. This study has shown a single infusion of low dose FLT180a leads to FIX levels of >40%, greatly reducing the risk of spontaneous or traumatic bleeds and raises the prospect of achieving a functional cure by normalising FIX levels with a higher dose. This will reduce the risk of life-threatening bleeds following trauma and surgery, transform quality of life and thus represents a major therapeutic advance for people with haemophilia B. DisclosuresChowdary:Bayer, CSL Behring, Novo Nordisk, Pfizer, and SOBI (publ): Research Funding; Baxalta (Shire), Baxter, Biogen Idec, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, Shire, and SOBI: Consultancy. Shapiro:Freeline Therapeutics Ltd: Consultancy. Alade:Freeline: Employment. Brooks:Freeline Therapeutics Ltd: Employment. Dane:Freeline: Employment. McIntosh:Freeline: Consultancy. Short:Freeline Therapeutics Ltd: Employment. Tuddenham:BioMarin: Consultancy, Patents & Royalties; Freeline: Consultancy. Nathwani:Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Individualized approach to profilactic treatment in patients with severe hemophilia A

Patients with a severe and moderate form of hemophilia A have traditionally been prescribed standard prevention with a coagulation factor VIII (FVIII), the goal of which is to achieve zero bleedings per year and a remaining activity of FVIII no fewer than 1 %. The standard approach does not allow achieving these goals in many patients due to a variety of factors: age of the patient, lifestyle, level of physical activity, condition of joints, muscle tone, patient compliance, individual pharmacokinetic (PK) response to FVIII administration. The target remaining activity of FVIII may be 2, 3 or even 5 % depending on the level of physical activity. Nowadays an individualized approach to the treatment of patients with severe hemophilia A based on the patient's PK profile is actively being explored and implemented in clinical practice. Individualization of prevention in patients with severe hemophilia is a real need for the physician and patient. There is a high variability in the values of the half-life period of FVIII in different patients. It is necessary to monitor the duration of the time period when the remaining activity of FVIII is less than 1 %, i.e., the period which is directly linked to the risk of spontaneous hemorrhage. For the patients getting treatment of Octocog alfa there has been developed the software (SW) myPKFiT* on the basis of web application which allows to simulate a dosage regimen taking into account the patient's PC profile based on the determination of FVIII activity in 2 blood sample. The SW allows changing (increase) the target level of the remaining activity of FVIII considering the lifestyle and the level of physical activity of the patient. The ability of SW allows the patient to demonstrate the activity of FVIII at various doses and intervals of drugs, as well as identify the risks that arise when a drug is missed. Therefore, myPKFiT solves an important task of the individualized approach to selection and correction of therapy, improves the collaboration and mutual understanding between the physician and the patient, up regulates of the patient adherence to the therapy and achieves optimal results.

Management of invasive procedures in patients with platelet disorders or thrombocytopenia Guidelines by French expert group on inherited platelet diseases

Inherited platelet disorders (thrombocytopenia, functional defects or both) are rare and extremely heterogeneous with variable risk of spontaneous bleeding, but they are frequently diagnosed after haemorrhages following a surgical procedure or a trauma. Clinical studies focusing on these disorders are scarce due to their paucity, and thus they did not allow defining strong recommendations on the haemostasis treatment of these patients. On the basis of literature review and the experience of his members, the Reference Centre on inherited platelet disorders in France provides practical recommendations on the perioperative management, according to the type of underlying disease, to the bleeding risk associated to the invasive procedure, and to the clinical history of the patient. The indication and use of platelet concentrates and of various drugs i.e. tranexamic acid, desmopressin, recombinant factor VIIa, von Willebrand factor concentrates, and thrombopoietin receptor agonists are discussed in this text.

Bevacizumab for the treatment of radiation necrosis in melanoma patients.

e13548 Background: Radiation necrosis (RN) can be a late complication of radiotherapy for CNS malignancy, often associated with neurological morbidity. High dose corticosteroids or surgical resection have been the standard of care treatment (tx), but protracted steroid course can lead to significant side effects and surgery is not always feasable. While there is evidence that the anti-VEGF antibody bevacizumab (Bev) can be effective for RN in other cancer types, evidence supporting its use for RN in melanoma patients (pts) is lacking, due to known risk of spontaneous bleeding in melanoma brain metastasis (MBM) and increased bleeding risk with Bev. Methods: We retrospectively identified 6 melanoma pts who received Bev for RN, and demographics, systemic and radiation tx history were obtained. Diagnosis of RN was established by MRI in all pts, and pathology confirmed RN in one pt. Results: Description of the 6 pts identified are shown in Table 1. Conclusions: We present 6 melanoma pts who developed RN after CNS radiation and who were treated with 2-6 doses of Bev. None of these pts developed bleeding, and all pts experienced improvement in symptoms and quality of life, with concurrent improvement of imaging in 5 pts. Our series suggests that in selected melanoma pts Bev may be a safe and effective treatment for RN for MBM and should be evaluated in a prospective setting. [Table: see text]

Adrenal tumors with unexpected outcome: a review of the literature.

The finding of an adrenal mass should induce a diagnostic work-up aimed at assessing autonomous hormone production and differentiating between benign and (potentially) malignant lesions. The common differential diagnosis in adrenal incidentaloma consists of (non-)functioning adenoma, pheochromocytoma, myelolipoma, metastasis, and primary carcinoma. There remains a category of lesions that are hormonally inactive and display nonspecific imaging characteristics. We provide a succinct literature review regarding pathologies from this category. Imaging and histological characteristics are discussed, as well as clinical management. In conclusion, an adrenal mass may present a diagnostic challenge. After exclusion of most common diagnoses, it can be difficult to differentiate between possible pathologies based on preoperative diagnostic tests. Surgical resection of possibly harmful tumors is indicated, for example, lesions with malignant potential or risk of spontaneous hemorrhage. Resection of an obviously benign lesion is not necessary, unless problems due to tumor size are expected.

Spontaneous isolated pericardial tamponade associated with warfarin.

To the Editor, An 83-year-old female patient was admitted to the emergency department with progressive dyspnea and orthopnea for 3 days. She was discharged with warfarin therapy (5 mg per day) due to pulmonary embolism 5 months previously. On admission she was orthopneic and tachypneic. Her arterial blood pressure was 90/60 mmHg and heart rate was 115/min with sinus rhythm. On cardiac auscultation, S1 and S2 intensity were decreased, and pathologic murmur and pericardial friction were not observed. Other physical examination findings were unremarkable. An increased cardio-thoracic ratio was revealed on chest X-ray (Figure 1a). Decreased QRS voltage and sinus tachycardia was evaluated on electrocardiogram. The internalised normalised ratio (INR) level was 8.6 and the prothrombin time was 70 seconds. Haemoglobin was determined to be 11.1 g/dL. The other laboratory findings were normal. An emergency thoracic computed tomography (CT) scan was performed to exclude recurrent pulmonary embolism, and surprisingly showed a massive pericardial effusion (Figure 1b). However, echocardiography revealed severe pericardial effusion that was compressing the right ventricle. Therefore, vitamin K and fresh frozen plasma infusion were administered promptly. As a result, the INR was decreased to 1.4 and 800 mL haemorrhagic fluid was drained percutaneously (P/S) with the apical approach. The patient’s blood pressure, orthopnoea and dyspnoea improved dramatically. There was no other source of bleeding except haemopericardium. Consequently, the cardiac tamponade in our patient, secondary to haemopericardium, was considered to be the result of the incorrect dosage of Warfarin. On control echocardiography, there was no recurrence of pericardial fluid and the patient was discharged on the 5th day. FIG. 1. a, b. Increased cardio-thoracic ratio due to pericardial effusion on chest X-ray (a). CT scan of chest showing large pericardial effusion (see arrow) (b) Cardiac tamponade is a life-threatening emergency condition. It is an acute type of pericardial effusion in which fluid accumulates in the intrapericardial space. This creates a mechanical pressure in the cardiac chambers which disrupts cardiac filling. (1). The common causes of pericardial effusion resulting in tamponade are pericarditis, malignancy, acute myocardial infarction, congestive heart failure, collagen vascular diseases, end stage renal disease, viral and bacterial infections (1). Cardiac tamponade secondary to haemopericardium is rarely seen and occurs with traumatic and non-traumatic causes. Non-traumatic causes are less common and associated with a number of conditions such as malignancy, infection, uraemia or coagulopathy (2). Today, warfarin sodium is still the most commonly used agent for anticoagulant therapy. The risk of spontaneous bleeding in patients using warfarin is less than 10%, whereas the risk of bleeding into the pericardial space is less than 1% (3). Echocardiography, which is the diagnostic test of choice, evaluates the haemodynamic consequences and guides transcutaneous drainage; CT is useful for further workup. These methods are superior to echocardiography for anatomical information, characterisation of the effusion, and providing information about the adjacent structures (2). The primary treatment of pericardial tamponade is pericardiocentesis.. Echocardiography-guided pericardiocentesis has been shown to be a safe and effective method which can be performed at the patient’s bedside (4). Isolated haemopericardium and cardiac tamponade secondary to warfarin are seen very rare. Haemorrhagic cardiac tamponade should be excluded in patients on warfarin with unexplained hypotension and excessive anticoagulation. Close monitoring of INR level is very important in the management of patients, especially in the elderly receiving warfarin treatment (5).

O1.05 * AXITINIB, A SELECTIVE VEGFR-1,-2,-3 TYROSINE KINASE INHIBITOR, INHIBITS TUMOR GROWTH AND INCREASES INFILTRATION OF IMMUNE CELLS IN AN INTRACRANIAL MELANOMA MOUSE MODEL

VEGF is a key mediator of pathological cancer associated neoangiogenesis and immunosuppression. VEGFR targeted therapy holds promise to counteract cancer associated neoangiogenesis but also to alleviate cancer associated immune suppression. Melanoma patients are at high risk for developing brain metastases. These lesions are strongly vascularized and have a high risk for spontaneous bleeding. Melanoma is susceptible to immunotherapy and patients affected by brain metastases might benefit from combining immunotherapy with anti-VEGFR therapy. The aim of this study was to investigate the effect of axitinib, a small molecule tyrosine kinase inhibitor of VEGFRs, on MO4 melanoma cell growth in vitro and on the composition of tumor-infiltrating immune cells in a subcutaneous and intracranial melanoma syngeneic mouse model. We first treated MO4 melanoma cells in vitro with increasing concentrations of axitinib and found no induction of apoptosis. Furthermore, increasing amounts of axitinib had no effect on T-cell proliferation or DC maturation, thus excluding a potential suppressive effect of axitinib on antigen presenting and T-cell function. When subcutaneous tumor-bearing mice were treated with axitinib (oral gavage, 25 mg/kg, bid), tumor growth was strongly inhibited and survival was significantly improved as compared to the control group. Next, subcutaneous and intracranial tumor bearing mice were treated with axitinib. After 7 days of treatment a significant increase in the number of total immune cells (CD45 + cells) within the spleen, subcutaneous and intracranial tumor was observed. Whereas the increase in immune cells within the spleen was most marked for CD3 + CD8 + T cells, a significant increase in the number of CD11b + cells was noted within the tumors. Upon further characterizing of this CD11b+ population, we found that there was a significant increase in cells with a monocytic myeloid derived suppressor cell phenotype (moMDSCs,CD11b + Ly6ChighLy6G-). However, in vitro proliferation assays using highly purified splenic MDSCs showed that moMDSCs isolated from axitinib-treated mice to have a reduced suppressive capacity on CD4+ and CD8+ T cells than those isolated from vehicle-treated mice on a per cell basis. When highly purified tumor MDSCs were used in in vitro proliferation assays we found that moMDSCs isolated from axitinib-treated mice almost lost their suppressive capacity on CD4+ and CD8+ T cells. Based on these observations we conclude that axitinib delays tumor growth, increases survival and is associated with an increased infiltration of the tumor micro-environment with immune cells both in subcutaneous as well as intracranial localizations. Axitinib seems to specifically increase moMDSCs within the CD11b+ cell population but to reduce their suppressive capacity. Further investigation of combination therapies with axitinib and immunotherapy seems warranted.

The Role of Partial Nephrectomy without Arterial Embolization in Giant Renal Angiomyolipoma

Angiomyolipoma is a benign neoplasm composed of varying admixtures of blood vessels, smooth muscle cells, and adipose tissue. Because of an increased risk of spontaneous haemorrhage, surgical approach is needed greater than 4–8 cm size. We here report our partial nephrectomy experience in the 24 cm size giant angiomyolipoma. 26-year-old woman referred to our clinic with a 24 cm size angiomyolipoma in her lower pole of right kidney. The inferior vena cava was deviated to the left by the mass. All the blood tests were normal and we offered her the choices of partial nephrectomy or nephrectomy. Right subcostal approach was used. The patient underwent resection of the mass with a safety region of 1 cm. Frozen section evaluation was consistent with angiomyolipoma and free for surgical margin. Warm ischemia time was 35 min. and intraoperative bleeding volume was 200 cc. Postoperative 2nd day the drain was taken and hospital stay was 4 days. In literature we observed very rare angiomyolipoma cases with such a large dimension treated by partial nephrectomy without arterial embolization. If technically suitable partial nephrectomy is the main chioce in this kind of benign lesions in young patients.

The risk of spontaneous rupture of liver hemangiomas: a critical review of the literature

The risk of spontaneous bleeding or rupture of liver hemangiomas still remains unknown. The aim of this review was to analyze the problem of spontaneous bleeding or rupture in liver hemangiomas and to identify factors leading to bleeding in these cases. A MEDLINE search was undertaken to identify articles in English, French, German, Italian, and Spanish from 1898 to 2010. Basic data such as age and sex of patients were collected. Additional data such as risk factors or causes of rupture were also analyzed. Cases were divided into spontaneous and non-spontaneous ruptures. A total of 97 cases are described. In 51 of the 97 patients (52.6%) a non-spontaneous rupture was identified. Only in 46 out of the 97 cases (47.4%) was a spontaneous rupture found. Non-spontaneous rupture was significantly more frequent in patients aged <40 years than in older ones (p = 0.0099). Mean size of the ruptured lesions was 11.2 cm (range 1-37 cm). Massive bleeding occurred in 88 patients (90.7%). Reported mortality over the past 20 years has been significantly lower than before (p < 0.001). The overall mortality for the period under study was ~35%. The spontaneous rupture of a hepatic hemangioma is to be considered an exceptional event. Preventive surgery should be considered only for lesions of at least 11-cm size in special cohorts of patients.

Systematic review of hepatocellular adenoma in China and other regions

Hepatocellular adenoma (HCA) is a benign liver neoplasm with a risk of spontaneous bleeding and malignant transformation. The aim of this review article is to review all the case reports and case series of patients with HCA from 1998 to 2008 in China and other parts of the world in order to compare clinical presentation, surgical management and outcomes. A search for all reports of HCA in the world literature from 1998 to 2008 was performed. A total of 356 patients were identified, including 191 patients from China, 104 from Europe, 46 from North America, and 15 from South-East Asia. A female predominance was not observed in Chinese patients in contrast to the other regions. Acute/chronic abdominal pain was the main clinical presentation in all regions. Twenty patients were diagnosed with coexistent hepatocellular carcinoma (HCC), and hepatitis B virus infection (HBV) was found among six of them. The management of HCA consisted of resection in most cases. The clinical presentation of HCA in China differed from other parts of the world regarding male predominance and a higher incidence of coexistent HCC in China. This might be the result of the birth control policy in China, limited oral contraceptive use, and the higher incidence of HBV.

The incidence of thrombocytopenia in children with Cornelia de Lange syndrome

Thrombocytopenia was first reported in Cornelia de Lange syndrome (CdLS) by Froster in 1993. Despite early reports, thrombocytopenia has been rarely reported in this disorder. We performed a retrospective analysis of a large cohort of patients with CdLS. We calculated prevalence of thrombocytopenia in three subsets of this cohort: the entire cohort (n = 1,740), a subset of subjects with substantial clinical records (n = 695) and a subset of subjects with clinical information regarding platelet counts (n = 85). This analysis revealed that 15 have had thrombocytopenia (18% of those with available blood counts); seven had immune thrombocytopenia (ITP). The reported prevalence of pediatric ITP is between 5 and 13 per 100,000 persons. The prevalence of ITP in this cohort is between 7/1,740 and 7/85, giving a relative risk of ITP of between 30 (CI 12-77) and 633 (CI 259-1,549). Contrary to the reported cases in the literature, none of our patients have had progression of the thrombocytopenia nor have they developed other cytopenias. All 15 patients with thromobocytopenia had CdLS based on clinical criteria. Of the 10 patients tested for mutations in NIBPL, 8 had mutations identified. These data support an increased incidence of thrombocytopenia and ITP in CdLS. Subsequently, patients are at risk for spontaneous hemorrhage, and likely increased risk secondary to the high frequency of self-injurious behavior. Although further studies are needed to better define the scope of the problem and to define the mechanisms of thrombocytopenia in CdLS, we would recommend screening for thrombocytopenia upon diagnosis and at 5-year intervals thereafter.

Splenic peliosis – a potentially fatal condition which can mimick malignancy

Isolated splenic peliosis is an extremely rare occurrence, and this disease often manifests itself with spontaneous haemoperitoneum.We report a case where an otherwise healthy patient was found to have splenomegaly on clinical examination. On computerised tomography, a diagnosis of splenic malignancy was made, and the patient underwent a splenectomy. Histological examination gave the diagnosis of splenic peliosis, which had not been considered prior to the operation. In retrospect, splenectomy was the most prudent course of action, as the risk of spontaneous haemorrhage and fatality was eliminated. This case emphasises the need to retain an index of suspicion for this condition, even in otherwise healthy patients, and is a reminder of the usefulness of total splenectomy in the current era of minimally invasive diagnostic techniques.

Predictors of hemorrhage in patients with untreated brain arteriovenous malformation

Background: Intracranial hemorrhage is a serious possible complication in patients with brain arteriovenous malformation (AVM). Several morphologic factors associated with hemorrhagic AVM presentation have been established, but their relevance for the risk of subsequent AVM hemorrhage remains unclear. Methods: The authors analyzed follow-up data on 622 consecutive patients from the prospective Columbia AVM database, limited to the period between initial AVM diagnosis and the start of treatment (i.e., any endovascular, surgical, or radiation therapy). Univariate and multivariate logistic regression and Cox proportional hazard models were applied to analyze the effect of patient age, gender, AVM size, anatomic location, venous drainage pattern, and associated arterial aneurysms on the risk of intracranial hemorrhage at initial presentation and during follow-up. Results: The mean pretreatment follow-up was 829 days (median: 102 days), during which 39 (6%) patients experienced AVM hemorrhage. Increasing age (hazard ratio [HR] 1.05, 95% CI 1.03 to 1.08), initial hemorrhagic AVM presentation (HR 5.38, 95% CI 2.64 to 10.96), deep brain location (HR 3.25, 95% CI 1.30 to 8.16), and exclusive deep venous drainage (HR 3.25, 95% CI 1.01 to 5.67) were independent predictors of subsequent hemorrhage. Annual hemorrhage rates on follow-up ranged from 0.9% for patients without hemorrhagic AVM presentation, deep AVM location, or deep venous drainage to as high as 34.4% for those harboring all three risk factors. Conclusions: Hemorrhagic arteriovenous malformation (AVM) presentation, increasing age, deep brain location, and exclusive deep venous drainage appear to be independent predictors for AVM hemorrhage during natural history follow-up. The risk of spontaneous hemorrhage may be low in AVMs without these risk factors.