Deepti M. Warad

Intratumoral CD14+ Cells and Circulating CD14+HLA-DRlo/neg Monocytes Correlate with Decreased Survival in Patients with Clear Cell Renal Cell Carcinoma

Purpose: Immunotherapeutic strategies to treat patients with renal cell carcinoma (RCC) offer new opportunities for disease management. Further improvements to immunotherapy will require additional understanding of the host response to RCC development. Experimental Design: Using a novel approach to understanding the immune status of cancer patients, we previously showed that patients with a certain immune profile had decreased overall survival. Here, we examine in more detail the phenotypic changes in peripheral blood and the potential consequences of these changes in RCC patients. Results: We found that CD14+HLA-DRlo/neg monocytes were the most predominant phenotypic change in peripheral blood of RCC patients, elevated nearly 5-fold above the average levels measured in healthy volunteers. Intratumoral and peritumoral presence of CD14 cells was an independent prognostic factor for decreased survival in a cohort of 375 RCC patients. The amount of peripheral blood CD14+HLA-DRlo/neg monocytes was found to correlate with the intensity of CD14 staining in tumors, suggesting that the measurement of these cells in blood may be a suitable surrogate for monitoring patient prognosis. The interaction of monocytes and tumor cells triggers changes in both cell types with a loss of HLA-DR expression in monocytes, increases of monocyte survival factors such as GM-CSF in tumors, and increased production of angiogenic factors, including FGF2. Conclusions: Our results suggest a model of mutually beneficial interactions between tumor cells and monocytes that adversely affect patient outcome. Clin Cancer Res; 21(18); 4224–33. ©2015 AACR.

Lemierre Syndrome: A Retrospective Study of the Role of Anticoagulation and Thrombosis Outcomes

Lemierre syndrome (LS) is a multisystemic infection beginning in the oropharynx and leading to thrombosis of the internal jugular vein (IJV) with septic emboli and potential thrombotic extension to the central nervous system. Although patient outcomes have improved with early initiation of antimicrobial therapies, there is no consensus regarding the role of anticoagulation in LS. To better define the role of anticoagulation therapy in LS and determine whether anticoagulation improves thrombosis outcomes, we conducted a retrospective chart review of pediatric and adult patients diagnosed with LS and managed at our institution from January 1998 to December 2014. Eighteen patients (9 females and 9 males) were included in this analysis, 6 of whom received ≥4 weeks of anticoagulation therapy (median 23.1 weeks, range 6.9-32.9 weeks). Six patients were in the pediatric age group (<18 years). All patients received broad-spectrum antibiotics. All patients had improvement in their thrombi by 3 months (nonanticoagulated patient group: complete response [CR], n = 9; partial response [PR], n = 3; anticoagulated patient group: CR, n = 2; PR, n = 4). No patient developed recurrent thrombosis or progression during the follow-up period, regardless of anticoagulation status. Our study suggests that anticoagulation in LS may not affect thrombosis outcomes.

Haemorrhagic complications with adenotonsillectomy in children and young adults with bleeding disorders.

Haemorrhagic complications remain a challenge with surgical procedures in patients with bleeding disorders. In children and young adults, the most commonly performed surgeries are tonsillectomies and/or adenoidectomies. Adequate haemostasis in these patients with bleeding disorders is centred on comprehensive perioperative haemostatic support and dexterous surgical technique. The aim of this study was to assess postoperative bleeding complications with tonsillectomy and/or adenoidectomy in children and young adults with known bleeding disorders. Retrospective review of all patients aged <25 years with known bleeding disorders who underwent tonsillectomy and/or adenoidectomy at Mayo Clinic, Rochester MN between July 1992 and July 2012. In contrast to reported literature, we observed a higher rate of bleeding complications (10/19, 53%) despite aggressive haemostatic support and appropriate surgical techniques. Delayed bleeding (>24 h postoperatively) was more common than early bleeding; and recurrent bleeding was associated with older age. Children and young adults with haemorrhagic diatheses undergoing adenotonsillectomy are at a higher risk of delayed bleeding and require close monitoring with haemostatic support for a prolonged duration in the postoperative period. A uniform approach is needed to manage these patients perioperatively by establishing standard practice guidelines and ultimately reduce postsurgical bleeding complications.

A Retrospective Analysis of Outcomes of Dalteparin Use in Pediatric Patients: A Single Institution Experience

BACKGROUND Dalteparin is a commonly used low molecular weight heparin (LMWH) with extensive safety data in adults. With distinct advantages of once daily dosing and relative safety in renal impairment, it has been used off-label in pediatric practice; however, age-based dosing guidelines, safety and efficacy data in children are evolving. OBJECTIVES To report our institutional experience with the use of dalteparin in the treatment and prophylaxis of venous thromboembolism (VTE) in pediatric patients. PATIENTS/METHODS Retrospective chart review of all children (0-18years) that received dalteparin from December 1, 2000 through December 31, 2011. Doses per unit body weight per day (units/kg/day) were calculated for age-based group comparisons. RESULTS Of 166 patients identified, 116 (70%) received prophylactic doses while 50 (30%) received therapeutic doses of dalteparin. Infants (<1year) required significantly higher weight-based dosing to achieve therapeutic anti-Xa levels compared to children (1-10years) or adolescents (>10-18years) (mean dose units/kg/day; 396.6 versus 236.7 and 178.8 respectively, p<0.0001). Overall response rate, including complete and partial thrombus resolution, was 83%. Bleeding complications were minor and the rates were similar in therapeutic and prophylaxis patients. No significant differences in dosing or bleeding events were noted based on obesity or malignancy. CONCLUSIONS In our experience, dalteparin is effective for prophylaxis and therapy of VTE in pediatric patients. Dosing should be customized in an age-based manner with close monitoring of anti-Xa activity in order to achieve optimal levels, prevent bleeding complications, and to allow full benefit of prevention or therapy of thrombotic complications.

Diagnostic laboratory standardization and validation of platelet transmission electron microscopy

Abstract Platelet transmission electron microscopy (PTEM) is considered the gold standard test for assessing distinct ultrastructural abnormalities in inherited platelet disorders (IPDs). Nevertheless, PTEM remains mainly a research tool due to the lack of standardized procedures, a validated dense granule (DG) count reference range, and standardized image interpretation criteria. The aim of this study was to standardize and validate PTEM as a clinical laboratory test. Based on previously established methods, we optimized and standardized preanalytical, analytical, and postanalytical procedures for both whole mount (WM) and thin section (TS) PTEM. Mean number of DG/platelet (plt), percentage of plts without DG, platelet count (PC), mean platelet volume (MPV), immature platelet fraction (IPF), and plt light transmission aggregometry analyses were measured on blood samples from 113 healthy donors. Quantile regression was used to estimate the reference range for DG/plt, and linear regression was used to assess the association of DG/plt with other plt measurements. All PTEM procedures were standardized using commercially available materials and reagents. DG interpretation criteria were established based on previous publications and expert consensus, and resulted in improved operator agreement. Mean DG/plt was stable for 2 days after blood sample collection. The median within patient coefficient of variation for mean DG/plt was 22.2%; the mean DG/plt reference range (mid-95th %) was 1.2–4.0. Mean DG/plt was associated with IPF (p = .01, R2 = 0.06) but not age, sex, PC, MPV, or plt maximum aggregation or primary slope of aggregation (p > .17, R2 < 0.02). Baseline ultrastructural features were established for TS-PTEM. PTEM was validated using samples from patients with previously established diagnoses of IPDs. Standardization and validation of PTEM procedures and interpretation, and establishment of the normal mean DG/plt reference range and PTEM baseline ultrastructural features, will facilitate implementation of PTEM as a valid clinical laboratory test for evaluating ultrastructural abnormalities in IPDs.

Management of pediatric hepatocellular carcinoma: A multimodal approach

HCC is rare in the pediatric population, but is the second most common liver malignancy in children. Survival rates for primary unresectable HCC have been dismal. The objective of this study was to describe our experience with a multimodal approach for the management of unresectable HCC in two adolescent patients and to review the literature. Both patients are currently alive with no recurrence at 51 and 29 months post‐transplant. Multimodality treatment involving chemotherapy with doxorubicin, cisplatin, and sorafenib; TACE; timely liver transplantation; and post‐transplant therapy with sorafenib and mTOR inhibitors may help improve outcomes and prolong survival in pediatric patients with unresectable HCC.

Cross-Cultural Care Training for Pediatric Hematology/Oncology Fellows

Introduction Physicians are entrusted with the medical care of culturally and socially diverse patient populations. In addition, pediatric hematologists/oncologists are faced with the challenge of taking care of children with life-threatening and complex conditions. We implemented a cross-cultural care training curriculum for our pediatric hematology/oncology fellows with the goal of preparing them to handle complex clinical situations while navigating different social and cultural belief systems. Methods The curriculum includes a precourse self-reflection; a learning module with a review of published literature; faculty-facilitated small-group role-play simulations; interactive sessions with language interpreters and physicians from different cultural, ethnic, and religious belief systems; and a postcourse reflection. Results Fellows who participated in the curriculum strongly agreed that the module was helpful, indicating that it enhanced their communication skills, improved delivery of cross-cultural care, and had a sustained impact on their interaction with medical language interpreters. Discussion Cross-cultural care training should be integrated into any pediatric hematology/oncology training curriculum. Sessions directed at addressing the perceived gaps between physician awareness and the patients belief systems can increase awareness of personal biases in practice and improve interview techniques. Likewise, self-reflection can help physicians apply their medical knowledge and skills in the appropriate cultural and social context, thereby improving patient satisfaction, partnerships, and health care outcomes.

Pediatric Coagulation Disorders

1. Vilmarie Rodriguez, MD* 2. Deepti Warad, MBBS* 1. *Division of Pediatric Hematology-Oncology, Mayo Clinic Children’s Center, Mayo Clinic Comprehensive Hemophilia Center, Mayo Clinic, Rochester, MN. Clinicians are often challenged in primary practice with patients who present with potential hemostatic disorders. Determining which laboratory tests to order and when to refer a patient to a pediatric hematologist is of vital importance. After completing this article, the reader should be able to: 1. Describe the physiology of hemostasis in the pediatric patient. 2. List clinical signs and symptoms suggestive of a congenital or acquired bleeding disorder. 3. Understand laboratory testing and indications in the diagnosis of a bleeding disorder and timing of subspecialty referral. 4. Describe the clinical management of bleeding disorders. 5. Become familiar with congenital and acquired thrombophilic disorders and their diagnosis and management recommendations. Hemostasis in the pediatric patient evolves as the child grows and matures, and normal adult laboratory values are not often the norm for a child. This article provides a summary of the pathophysiology of hemostasis (eg, bleeding and thrombosis disorders) and reviews the basic principles of history and physical findings to provide the primary care practitioner with the necessary tools for initial evaluation of a pediatric patient with a suspected coagulation disorder. A basic understanding of when to test a patient for a coagulation disorder or make a proper referral to a pediatric hematologist will result in optimal care. Hemostasis is a complex process that requires a balance between maintaining blood in a fluid state and addressing areas of tissue injury in which a local response is generated at the site of vascular endothelial injury to promote healing and prevent hemorrhage. This process requires the interaction of the vascular endothelium, platelets, and coagulation factors. Diminished or dysfunctional activity of any of the components of the …

Hermansky-Pudlak syndrome subtype 5 (HPS-5) novel mutation in a 65 year-old with oculocutaneous hypopigmentation and mild bleeding diathesis: The importance of recognizing a subtle phenotype

Abstract Hermansky-Pudlak syndrome (HPS) − characterized by the distinct clinical phenotypes of both oculocutaneous albinism and mild bleeding diathesis–is caused by mutations in genes that have crucial roles in the assembly of cellular organelles (skin melanosomes, platelet delta [dense] granules, lung lamellar bodies, and cytotoxic T-cell lymphocyte granules). Immunodeficiency, pulmonary fibrosis and granulomatous colitis are associated with some, but not all subtypes of HPS, with varying degrees of clinical severity. We describe a patient diagnosed with platelet dense granule storage pool deficiency (DG-SPD) at age 38 years after he presented with spontaneous intracranial hemorrhage. His mild oculocutaneous hypopigmentation was subtle. In the following 27 years, he did not develop severe bleeding nor pulmonary or gastrointestinal complications. A novel homozygous c.1960A>T; p.Lys654* mutation in the HPS-5 protein gene (HPS5) was identified through next generation sequencing, (NGS) which is consistent with the patient’s clinical and laboratory phenotypes. This case underscores the importance of recognizing the mild clinical phenotype of HPS-5 and utilization of both laboratory and molecular testing for diagnosis, prognostication, and surveillance for end organ damage in patients affected with HPS.

Obesity, sedentary lifestyle, and video games: The new thrombophilia cocktail in adolescents

Rates of venous thromboembolism have increased in the adolescent population over the last two decades, likely due to advanced diagnostics, increased use of central venous catheters, chronic medical conditions, obesity, and oral contraceptive use. Of these factors, a modifiable risk factor for adolescents is obesity. Sedentary lifestyle and prolonged immobilization are additional prothrombotic risk factors that are often associated with obesity. With ever‐increasing screen time, sedentary behavior has risen accordingly, especially among gamers. We present four cases of adolescents who developed life‐threatening venous thromboembolic events in the setting of obesity, sedentary lifestyle and/or immobilization, and prolonged video game use.