Pre- and Posttherapy Risk Factors for Vasculopathy in Pediatric Patients With Craniopharyngioma Treated With Surgery and Proton Radiation Therapy.

PURPOSE: Vasculopathy (VAS) is a significant complication associated with radiation therapy in patients treated for brain tumors. We studied the type, location, severity, timing, and resolution of VAS in children with craniopharyngioma treated with proton radiation therapy (PRT) and evaluated predictors of stenosis (STN) using a novel patient and imaging-based modeling approach. METHODS AND MATERIALS: Children with craniopharyngioma (n = 94) were treated with 54 Gy relative biological effectiveness PRT in a clinical trial, NCT01419067. We evaluated VAS type, location, severity, and resolution. VAS events were segmented and related to their location, operative corridor, PRT dose, and vascular territory to facilitate mixed effect logistic regression modeling of spatial predictors of STN events. RESULTS: Forty-five (47.9%) patients had 111 instances of confirmed VAS (pre-PRT n = 37, 33.3%). The median time to post-PRT VAS was 3.41 years (95% confidence interval, 1.86-6.11). STN events were observed post-PRT in 23.4% (n = 22) of patients. Post-PRT VAS was detected by cerebral angiogram in 9.6% (n = 9), severe in 4.3% (n = 4), and compensated on perfusion in 2.1% (n = 2). Revascularization was required for 5 (5.3%) patients. Postsurgical, pre-PRT VAS, and PRT dose to unperturbed vessels were predictive of STN. The effect of PRT on STN was negligible within the surgical corridor. CONCLUSIONS: VAS often precedes PRT and was the strongest predictor of post-PRT STN. The adverse effect of PRT on STN was only apparent in unperturbed vasculature beyond the operative corridor.

Diffusion Tensor Imaging-Based Analysis of Baseline Neurocognitive Function and Posttreatment White Matter Changes in Pediatric Patients With Craniopharyngioma Treated With Surgery and Proton Therapy.

PURPOSE: To determine the preirradiation baseline association of white matter integrity with neurocognitive function and to assess posttreatment changes in pediatric patients with craniopharyngioma treated with proton therapy. METHODS AND MATERIALS: Ninety children and adolescents (2-20 years old) with craniopharyngioma were treated with proton therapy (54 Gy[RBE]) in a prospective therapeutic trial. Neurocognitive performance at the postoperative baseline before proton therapy and diffusion tensor imaging (DTI) data acquired at baseline and at annual follow-up were analyzed. Tract-based spatial statistics and structural connectomics were used to derive global and local white matter features from DTI. Baseline DTI features were compared for patients with average and below-average neurocognitive performance. Longitudinal DTI data were analyzed to determine the proton dose effect on white matter structures in relation to the irradiated brain volume and baseline age. RESULTS: Before proton therapy, patients with below-average working memory, processing speed, verbal fluency, verbal learning, or fine motor dexterity exhibited more globally degraded white matter structures compared with their counterparts with average performance, as indicated by lower mean fractional anisotropy, decreased global efficiency, or higher modularity. Surgery, obstructive hydrocephalus, and preoperative hypothalamic involvement appeared to be related to this degradation. In local analyses, tract-based spatial statistics revealed left-lateralized associations with verbal and motor functions, which supported surgical approaches to midline tumors via the right hemisphere. The mean fractional anisotropy of the brain and the global efficiency derived from DTI increased over the 5 years after proton therapy. The rate of increase was lower with larger irradiated brain volumes and in older children. CONCLUSIONS: Below-average baseline neurocognitive performance in patients with craniopharyngioma before proton therapy appeared to be related to structural degradation of white matter tracts. Posttherapy longitudinal DTI showed improving trends in global integrity and efficiency measures, particularly in children in whom a smaller brain volume was irradiated.

Propofol Total Intravenous Anesthesia as an Intervention for Severe Radiation-Induced Phantosmia in an Adolescent with Ependymoma.

Radiation-induced phantosmia has been reported both in children and adults. A fraction of these patients have nausea and vomiting triggered by phantosmia. Radiation-induced phantosmia, although transient, can be distressing enough to prevent a patient from staying still during radiation therapy. To date, specific interventions for radiation-induced phantosmia, including anesthesia, have not been reported. We report for the first time anesthesia as an intervention for transient severe radiation-induced phantosmia, in a 16-year-old girl with ependymoma undergoing proton therapy, and we discuss the pros and cons of techniques for anesthesia and airway management.

Thromboembolic events in cancer patients on active treatment with cisplatin-based chemotherapy: another look!

BACKGROUND: The risk of thromboembolic events is higher among cancer patients, especially in patients undergoing chemotherapy. Cisplatin-based regimens claim to be associated with a very high thromboembolic rate. In this study, we report on our own experience with thrombosis among patients on active cisplatin-based chemotherapy. METHODS: Medical records and hospital databases were searched for all the patients treated with any cisplatin-based regimen for any kind of cancer. Thrombosis was considered cisplatin-related if diagnosed any time after the first dose and up to 4 weeks after the last. The Khorana risk assessment model was performed in all cases. RESULTS: A total of 1677 patients (65.5% males, median age: 50 years) treated with cisplatin-based regimens were identified. Head and neck (22.9%), lung (22.2%), lymphoma and gastric (11.4% each) were the most common primary tumors. Thromboembolic events were reported in 110 (6.6%); the highest was in patients with gastric cancer (20.9%) and the lowest in patients with head and neck cancers (2.3%) and lymphoma (1.6%). Thrombosis included deep vein thrombosis (DVT) in 69 (62.7%), pulmonary embolism (PE) in 18 (16.9%) and arterial thrombosis in 17 (15.6%). A majority (51.1%) of the patients had stage IV disease and only 16% had stage I or II.In a multivariate analysis, significantly higher rates of thrombosis were associated with gastric as the primary tumor, advanced-stage disease, female sex but not age, and the Khorana risk score or type of cisplatin regimen. While the presence of CVC was significantly associated with the risk of thrombosis (p < 0.0001) in the univariate analysis, and such significance was lost in the multivariate analysis (odds ratio, 1.098; 95%CI, 0.603-1.999, p = 0.7599). CONCLUSIONS: Thromboembolic events in cancer patients on active cisplatin-based chemotherapy were commonly encountered. Gastric cancer, regardless of other clinical variables, was associated with the highest risk.

The Application of Current Proposed Venous Thromboembolism Risk Assessment Model for Ambulatory Patients With Cancer.

Venous thromboembolism (VTE) is a commonly encountered problem in patients with cancer. In recent years, cancer treatment paradigm has shifted with most therapy offered in ambulatory outpatient settings. Excess of half VTEs in patients with cancer occur in outpatient settings without prior hospitalization, where current practice guidelines do not recommend routine prophylaxis. Risk assessment models (RAMs) for VTE in such patients were recently introduced. This study aims to assess the practical application of one of these models in clinical practice. Medical records and hospital electronic database were searched for patients with cancer having VTE. Known risk factors were collected, and risk assessment was done using the Khorana RAM. Over a 10-year period, 346 patients developed VTE in ambulatory settings. Median age was 57 and 59.0% were females. Lower extremities were involved in 196 (56.6%), while 96 (27.7%) had pulmonary embolism. Most (76.6%) patients had stage IV disease, only 9.0% had stage I or II disease. Only 156 (45.1%) patients were on active chemotherapy, for whom Khorana risk assessment score was calculated. In these patients, high risk was identified in 31 (19.9%) patients, while 81 (51.9%) had intermediate risk and 44 (28.2%) had low risk. No patients were on prophylaxis prior to VTE. Most ambulatory patients with cancer who developed VTE were not on chemotherapy, and many of those who were on active treatment had low Khorana risk scores. This illustrates the need to modify the model or develop a new one that takes into consideration this group of patients.

Inferior vena cava filters in patients with advanced-stage cancer.

BACKGROUND: Cancer and its treatment are recognized risk factors for venous thromboembolism (VTE). Inferior vena cava (IVC) filters are utilized to provide mechanical thromboprophylaxis to prevent pulmonary embolism (PE) or to avoid bleeding from systemic anticoagulation. PATIENTS AND METHODS: A retrospective analysis of 107 cancer patients who had IVC filters inserted and followed up at our institution was performed. All patients had active cancer; a majority (> 90%) had advanced-stage disease, whereas only five patients (5.8%) had stages I or II disease. RESULTS: Eighty six patients (80.3%) had their IVC filter placed through a jugular approach. Filter insertion was not without complications; recurrent deep vein thrombosis (DVT) was reported in 10 (9.3%), PE in three (2.8%) and filter thrombosis in one patient. The value of IVC filter in patients with advanced stage disease was very limited: among 59 patients with stage IV disease for whom survival data was available, the median survival was only 1.31 months (0.92-2.20) with 23 patients (39.0%) surviving less than a month, and 40 (67.8%) surviving less than three months. CONCLUSIONS: Systemic anticoagulation can be safely offered for the majority of cancer patients. When the risk of bleeding or PE is high, IVC filters can be utilized. However, the placement of such filters should take into consideration the stage of disease and life expectancy of such patients. Patients with advanced-stage disease may gain little benefit from IVC filter insertion.

The application of clinical variables and models to predict pulmonary embolism in cancer patients: a comprehensive single cancer center experience.

INTRODUCTION: Prompt diagnosis and treatment of pulmonary embolism (PE) can help reduce its associated morbidity and mortality. Computed tomography chest angiography (CTA) scanning is the most widely used diagnostic modality. In noncancer patients, only 10% of such studies are positive for PE. Clinical variables, individual or in combination, that can predict test positivity are highly needed. MATERIALS AND METHODS: All CTAs requested to confirm or exclude a diagnosis of PE in a single comprehensive cancer center were reviewed. In addition to the Wells score, other clinical variables known to increase the risk of PE were analyzed. RESULTS: A total of 778 adult cancer patients were treated at King Hussein Cancer Center (Amman, Jordan) and were included in this study; the majority of patients (64.2%) had stage 4 disease. Overall, 129 (16.6%) patients had positive scans for PE, while alternative diagnoses were made in 308 (39.6%) patients. Cancer stage and anticancer treatment had no impact on positive PE rates. However, Wells criteria classified patients into three risk groups with PE rates of 10.2%, 16.1%, and 62.5% among the patients with low, moderate, and high risk, respectively (P < 0.0001). Duration of cancer diagnosis (<12 months versus >12 months) had a significant impact on positive PE studies (22.0% versus 12.4%, respectively, P = 0.007). CONCLUSION: The rate of positive PE studies in cancer patients is higher than previously reported in noncancer patients. Positivity for PE was higher during the first 12 months of cancer diagnosis and in those with high probability score according to the Wells criteria. Factors like primary tumor stage and anticancer therapy had no significant impact on PE-positive studies.

Dealing with thrombocytopenia during anticoagulation with heparins for active venous thromboembolism: a play-it-safe practical approach.

PURPOSE: Thrombocytopenia is not uncommonly encountered following active anticoagulation of thromboembolism with unfractionated or even low-molecular-weight heparins. In this report, and utilizing a case study, we will address issues related to the diagnosis and treatment of heparin-induced thrombocytopenia (HIT) in a community-based clinical practice. METHODS: The case of a 73-year-old female patient who was recently diagnosed with gastroesophageal junction cancer and who developed left lower extremity deep vein thrombosis (DVT) while on active chemotherapy is presented. Following the initiation of anticoagulation, a significant drop in platelet counts was noted and a clinical diagnosis of HIT was made. Articles published in English addressing issues related to anticoagulation and thrombocytopenia were accessed from PubMed and are discussed. RESULTS: HIT is not uncommon, but its diagnosis can occasionally be difficult to confirm. Alternative anticoagulants might not be available for immediate use and many require special expertise for appropriate use. Fondaparinux, a synthetic pentasaccharide, is approved for active anticoagulation of DVT and pulmonary embolism and can be given once daily subcutaneously at a fixed dose with no need for monitoring. Many recent reports described the successful use of this agent in the treatment of HIT. CONCLUSION: HIT can be difficult to diagnose; diagnostic tests are generally not available in most hospitals and the available ones lack the sensitivity and specificity needed to confirm such diagnosis. Additionally, the alternative anticoagulants are not widely available. In such circumstances, fondaparinux can be used as an alternative anticoagulant.

Inferior vena cava filters in cancer patients: to filter or not to filter.

PURPOSE: Cancer and its treatment are recognized risk factors for venous thromboembolism (VTE); active cancer accounts for almost 20% of all newly diagnosed VTE. Inferior vena cava (IVC) filters are utilized to provide mechanical thromboprophylaxis to prevent pulmonary embolism (PE) or to avoid bleeding from systemic anticoagulation in high-risk situations. In this report, and utilizing a case study, we will address the appropriate utilization of such filters in cancer patients. METHODS: The case of a 43-year-old female patient with rectal cancer, who developed deep vein thrombosis following a complicated medical course, will be presented. The patient was anticoagulated with a low molecular weight heparin, but a few months later and following an episode of bleeding, an IVC filter was planned. Using the PubMed database, articles published in English language addressing issues related to IVC filters in cancer patients were accessed and will be presented. RESULTS: Many recent studies questioned the need to insert IVC filters in advanced-stage cancer patients, particularly those whose anticipated survival is short and prevention of PE may be of little clinical benefit and could be a poor utilization of resources. CONCLUSION: Systemic anticoagulation can be safely offered for the majority of cancer patients. When the risk of bleeding or pulmonary embolism is high, IVC filters can be utilized. However, placement of such filters should take into consideration the stage of disease and life expectancy of such patients.

Incidental pulmonary embolism in cancer patients: clinical characteristics and outcome--a comprehensive cancer center experience.

BACKGROUND AND OBJECTIVES: Cancer patients undergo routine imaging studies much more than others. The widespread use of the recently introduced multi-detector CT scanners has resulted in an increasing number of incidentally diagnosed pulmonary embolism (PE) in asymptomatic cancer patients. The significance and clinical outcome of such incidental PE is described. METHODS: Both radiology department and hospital databases were searched for all cancer patients with a diagnosis of incidental PE. CT scans were performed using a 64-slice scanner with a 5.0 mm slice thickness. RESULTS: During the study period, 34 patients with incidental PE were identified. The mean age (±SD) was 57.7 (±12.4) years. All patients had active cancer, gastric, lung, colorectal, and lymphomas being the most frequent. Most patients had advanced-stage disease at the time of PE diagnosis; 26 (77%) patients had stage IV, whereas only 3 patients had stages I or II disease. Twenty-seven (79%) patients had their PE while undergoing active treatment with chemotherapy (68%) or radiotherapy (12%); none, however, were on hormonal therapy. Most (74%) patients had their PE diagnosed without history of recent hospital admission. Except for 5 (15%), all other patients were anticoagulated. With follow-up, 2 patients developed recurrent PE, 2 others had clinical and echocardiographic evidence of pulmonary hypertension, and 9 (26%) died suddenly within 30 days of the diagnosis of incidental PE; 2 of these where among the 5 patients who were not anticoagulated. CONCLUSION: Incidental PE in cancer patients is increasingly encountered. Similar to symptomatic PE, many were diagnosed in patients with advanced stage disease and while undergoing active anti-cancer therapy. A significant percentage of patients had recurrent emboli, pulmonary hypertension, and sudden death.

Novel drugs to treat hemophilia.

IMPORTANCE OF THE FIELD: Hemophilia management requires replacement of the deficient clotting factor. Inhibitor development complicates treatment, and the implementation of and adherence to prophylaxis, considered the standard of care for severe hemophilia, is hampered by the high cost and the need for frequent intravenous infusions. New, less expensive therapies are needed to reduce morbidities, enhance convenience and improve outcomes. AREAS COVERED IN THIS REVIEW: We conducted a search of the Medline database from 1990 to 2010 for English language articles pertaining to hemophilia drug therapy. More than 4000 citations were obtained and examined for topic relevance. Additionally, proceedings from the American Society of Hematology, International Society on Thrombosis and Hemostasis, World Federation of Hemophilia, National Hemophilia Foundation and European Association for Haemophilia and Allied Disorders and the ClinicalTrials.gov website were reviewed for relevant publications and information. WHAT THE READER WILL GAIN: This article summarizes current research efforts focused on developing less immunogenic and more potent and/or longer-acting clotting factor concentrates that uniquely promote hemostasis, are more affordable and do not require intravenous administration. TAKE HOME MESSAGE: The availability of orally administered clotting factors will truly transform the lives of hemophilia patients and their families and caregivers.