Mark Ranalli

Fracture Prevalence and Relationship to Endocrinopathy in Iron Overloaded Patients with Sickle Cell Disease and Thalassemia

Transfusional iron overload leads to gonadal failure and low bone mass in patients with thalassemia (Thal). However, gonadal failure is rarely reported in transfused patients with sickle cell disease (SCD) and the literature regarding fracture prevalence in SCD is limited. The objective of this study was to assess self-reported fracture prevalence and its relationship to endocrinopathy in transfused Thal or SCD subjects and compare to non-transfused subjects with SCD (NonTxSCD). Eligibility was based on age> or =12 years and liver iron concentration> or =10 mg/g dry wt or serum ferritin> or =2000 ng/mL (Thal or TxSCD) or for NonTxSCD, ferritin<500 ng/mL. Data were collected by patient interview and chart review at 31 clinical centers in the U.S., Canada and the U.K. 152 subjects with Thal (52% Male; 25.6+/-0.7 years), 203 subjects with TxSCD (44% Male, 24.7+/-0.9 years: Mean+/-SE), and 65 NonTxSCD (50% Male, 22.2+/-1.3 years) were enrolled. Overall, male subjects with Thal were more likely to have sustained a fracture in their lifetime (51%) compared to TxSCD (28%) or NonTxSCD (32%) (p=0.005). There was no difference in fracture prevalence among women (Thal: 26%, TxSCD 17%, NonTxSCD: 16%). Fracture was most frequently reported in the upper extremities (53.3% of all fractures) while spine and pelvic fractures were relatively common for such a young cohort: 10.6%. Though overall fracture prevalence was not distinctly different from published healthy cohorts, fewer fractures occurred during the adolescent years. In multivariate analysis, the significant predictors of fracture prevalence were Thal diagnosis (Odds Ratio: 2.3; 1.2-4.6; 95%CI), male gender (OR: 2.6; 1.5-4.5), hypothyroidism (OR: 3.3; 1.1-9.8) and age (OR: 1.1; 1.03-1.08). These data suggest that despite similar iron burden, transfused patients with Thal are at greater risk for fracture than subjects with SCD. Male subjects with Thal and hypothyroidism are at particular risk for fracture, in contrast, transfused subjects with SCD had no greater risk of fracture compared to non-transfused SCD. Though ethnic differences in fracture risk cannot be ignored, endocrinopathy is rare in TxSCD which may also provide some protection from fracture.

Prognostic significance of interleukin-6 single nucleotide polymorphism genotypes in neuroblastoma: rs1800795 (promoter) and rs8192284 (receptor).

Purpose: Neuroblastoma is a childhood cancer of the sympathetic nervous system and many patients present with high-risk disease. Risk stratification, based on pathology and tumor-derived biomarkers, has improved prediction of clinical outcomes, but overall survival (OS) rates remain unfavorable and new therapeutic targets are needed. Some studies suggest a link between interleukin (IL)-6 and more aggressive behavior in neuroblastoma tumor cells. Therefore, we examined the impact of two IL-6 single nucleotide polymorphisms (SNP) on neuroblastoma disease progression. Experimental Design: DNA samples from 96 high-risk neuroblastoma patients were screened for two SNP that are known to regulate the serum levels of IL-6 and the soluble IL-6 receptor, rs1800795 and rs8192284, respectively. The genotype for each SNP was determined in a blinded fashion and independent statistical analysis was done to determine SNP-related event-free survival (EFS) and OS rates. Results: The rs1800795 IL-6 promoter SNP is an independent prognostic factor for EFS and OS in high-risk neuroblastoma patients. In contrast, the rs8192284 IL-6 receptor SNP revealed no prognostic value. Conclusions: The rs1800795 SNP [−174 IL-6 (G > C)] represents a novel and independent prognostic marker for both EFS and OS in high-risk neuroblastoma. Because the rs1800795 SNP [−174 IL-6 (G > C)] has been shown to correlate with production of IL-6, this cytokine may represent a target for development of new therapies in neuroblastoma. (Clin Cancer Res 2009;15(16):5234–9)

Disparity in the management of iron overload between patients with sickle cell disease and thalassemia who received transfusions.

BACKGROUND: Transfusion therapy is frequently used to prevent morbidity in sickle cell disease (SCD), and subsequent iron overload is common. The objective of this study was to evaluate the current standard of care in monitoring iron overload and related complications in patients with SCD compared to thalassemia (Thal).

Busulfan and melphalan as consolidation therapy with autologous peripheral blood stem cell transplantation following Children's Oncology Group (COG) induction platform for high-risk neuroblastoma: early results from a single institution.

Bu‐Mel as preparative therapy prior to autologous stem cell rescue was recently shown to be superior to the conventional CEM regimen for HR NBL in Europe. There are no data available on the feasibility and toxicity of Bu‐Mel as consolidation therapy following the COG‐type induction regimens used in North America. We report early complications and outcomes of patients with HR NBL who received Bu‐Mel for consolidation following COG‐based induction. Retrospective analysis of all patients who had received Bu‐Mel as preparative regimen prior to stem cell rescue for HR NBL was carried out. Toxicity, outcomes, and any delays to receiving radiation or anti‐GD2 antibody therapy were analyzed. Six patients undergoing PBSCT had received Bu‐Mel. The treatment was well tolerated. Mucositis was the main toxicity; three patients had developed neutropenia fever and none developed pulmonary toxicity. One patient had developed moderate SOS that responded to conservative management. All patients were able to receive and tolerate post‐transplant local radiotherapy and ch.14.18 anti‐GD2 antibody therapy without any delays. All patients are alive with no disease recurrence. The Bu‐Mel regimen is well tolerated and is feasible post‐COG‐type induction platform.

Treatment of refractory pemphigus erythematosus with rituximab

XXX Correspondence Treatment of refractory pemphigus erythematosus with rituximab Pemphigus erythematosus is an autoimmune disease with combined features of pemphigus foliaceus and lupus erythematosus. The disease manifests itself on sun-exposed skin as small, flaccid bullae with scaling and crusting. Generally the scalp, face, upper chest, and back are involved, with lesions of the face presenting in the typical butterfly distribution seen in systemic lupus erythematosus (SLE). An 18-year-old female presented in November 2004 for evaluation of keratotic hyperpigmented papules and plaques on the face, upper trunk, and proximal extremities (Fig. 1). Biopsy of the lesions revealed acantholysis within the granular cell layer with concomitant interface dermatitis. DIF showed intercellular deposits of IgG and C3 along with an interrupted band of +1/3 granular deposition of IgM along the dermal epidermal junction. The findings were consistent with the diagnosis of pemphigus erythematosus. Our patient showed no response to several months of dapsone plus topical corticosteroids (at escalating doses). She responded to high dose prednisone (60 mg/d), but flared upon tapering to 20 mg/d. She also had failed mycophenolate mofetil (Cellcept) and cyclosporine as steroid sparing agents. In February 2006 she was started on 40 mg of prednisone plus weekly infusions of 375 mg/m rituximab, and showed significant reduction in her symptoms by June 2006. On exam she showed regression of the majority of her skin lesions, leaving post-inflammatory hyperpigmentation (Fig. 2). The patient’s desmoglein 1 antibody level had decreased from 336.9 prior to treatment to 147 by the end of her 12-week course. According to a search of English literature, our case represents the first case of pemphigus erythematosus treated successfully with rituximab. Pemphigus erythematosus is an antibody-mediated autoimmune disease directed at desmoglein 1, a desmosomal protein important in keratinocyte adhesion, resulting in intraepidermal bullae. Treatment for pemphigus erythematosus has relied heavily on the use of systemic steroids, with some reports of use of dapsone, azathioprine, and cytotoxic agents such as cyclophosphamide and methotrexate. Rituximab is indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20positive, B cell non-Hodgkin lymphoma. It is a promising agent for the treatment of diseases mediated by B cells, and has been reported to be effective in pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, as well as refractory pediatric SLE. Rituximab is a chimeric murine/human monoclonal antibody. This IgG1 targets the CD20 antigen expressed by pre-B, immature and mature B cells and regulates early steps in the activation and differentiation of these cells. The binding of rituximab to CD20 results in cell lysis via complementand antibody-dependent cytotoxicity. CD20 is not expressed on stem cells or plasma cells and hence depletion of the B cell subpopulation is transient and does not affect immunoglobulin production. We believe that rituximab with its anti-B cell activities, namely activation and proliferation, has led to suppression of antidesmoglein antibody production leading to remission in our patient. The side-effects of rituximab are frequent but usually not serious. These include night sweats, hypersensitivity reactions, pruritus, urticaria, bacterial infections, and shivering during infusion. Uncommon cutaneous side-effects include Stevens–Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, toxic epidermal necrolysis, serum sickness, vasculitis, and severe mucocutaneous reactions, some with fatal outcome. Non-cutaneous side-effects include fatal infusion reactions, hepatitis B reactivation with related fulminant hepatitis and serious or life threatening cardiac arrhythmias. In conclusion, Rituximab is a novel alternative treatment for pemphigus erythematosus, especially recalcitrant cases or Figure 1 Pre-treatment lesions Figure 2 Post-treatment chest lesions

Primary testicular presentation of ALK-1-negative anaplastic large cell lymphoma in a pediatric patient.

Anaplastic large cell lymphoma is a heterogeneous group of malignant non-Hodgkin lymphomas that occurs in up to 15% of all pediatric non-Hodgkin lymphomas. It is characterized by B-symptoms and involvement of extranodal sites such as skin, bone, and soft tissue. This brief report describes first reported case of pediatric primary testicular anaplastic large cell lymphoma in a 14-year–old boy. The presentation included acute testicular pain, fever, and vomiting. After chemotherapy and unilateral radical orchiectomy, patient continues in complete remission.

Global microRNA profiling for diagnostic appraisal of melanocytic Spitz tumors

BACKGROUNDnMelanoma skin cancer remains the leading cause of skin cancer-related deaths. Spitz lesions represent a subset of melanocytic skin lesions characterized by epithelioid or spindled melanocytes organized in nests. These lesions occupy a spectrum ranging from benign Spitz and atypical Spitz lesions all the way to malignant Spitz tumors. Appropriate management is reliant on accurate diagnostic classification, yet this effort remains challenging using current light microscopic techniques. The discovery of novel biomarkers such as microRNAs (miR) may ultimately be a useful diagnostic adjunct for the evaluation of Spitz lesions. miR expression profiles have been suggested for non-Spitz melanomas but have yet to be ascribed to Spitz lesions. We hypothesized that distinct miR expression profiles would be associated with different lesions along the Spitz spectrum.nnnMATERIALS AND METHODSnRNAs extracted from paraffin-embedded, formalin-fixed tissues of 11 resected skin lesions including benign nevi (nxa0=xa02), benign Spitz lesions (nxa0=xa03), atypical Spitz lesions (nxa0=xa03), and malignant Spitz tumors (nxa0=xa03) were analyzed by the NanoString platform for simultaneous evaluation of over 800 miRs in each patient sample.nnnRESULTSnBenign Spitz lesions had increased expression of miR-21-5p and miR-363-3p compared with those of benign nevi. Malignant Spitz lesions exhibited overexpression of miR-21-5p, miR-155-5p, and miR-1283 relative to both benign nevi and benign Spitz tumors. Notably, atypical Spitz tumors had increased expression of miR-451a and decreased expression of miR-155-5p expression relative to malignant Spitz lesions. Conversely, atypical Spitz lesions had increased expression of miR-21-5p, miR-34a-5p, miR-451a, miR-1283, and miR-1260a relative to benign Spitz tumors.nnnCONCLUSIONSnOverall, distinct miR profiles are suggested among Spitz lesions of varying malignant potential with some similarities to non-Spitz melanoma tumors. This work demonstrates the feasibility of this analytic method and forms the basis for further validation studies.

Classification of Indeterminate Melanocytic Lesions by MicroRNA Profiling.

PurposeIdentification of indeterminate melanocytic skin lesions capable of neoplastic progression is suboptimal and may potentially result in unnecessary morbidity from surgery. MicroRNAs (miRs) may be useful in classifying indeterminate Spitz tumors as having high or low risk for malignant behavior.MethodsRNA was extracted from paraffin-embedded tissues of benign nevi, benign Spitz tumors, indeterminate Spitz tumors, and Spitzoid melanomas in adults (nxa0=xa062) and children (nxa0=xa028). The expression profile of 12 miRs in adults (6 miRs in children) was analyzed by real-time polymerase chain reaction.ResultsBenign Spitz lesions were characterized by decreased expression of miR-125b and miR-211, and upregulation of miR-22, compared with benign nevi (pxa0<xa00.05). A comparison of Spitzoid melanomas to benign nevi revealed overexpression of miR-21, miR-150, and miR-155 in the malignant primaries (pxa0<xa00.05). In adults, Spitzoid melanomas exhibited upregulation of miR-21, miR-150, and miR-155 compared with indeterminate Spitz lesions. Indeterminate Spitz lesions with low-risk pathologic features had lower miR-21 and miR-155 expression compared with Spitzoid melanoma tumors in adults (pxa0<xa00.05), while pathologic high-risk indeterminate Spitz lesions had increased levels of miR-200c expression compared with low-risk indeterminate lesions (pxa0<xa00.05). Pediatric Spitzoid melanomas exhibited increased miR-21 expression compared with indeterminate Spitz lesions (pxa0<xa00.05). Moreover, miR-155 expression was increased in indeterminate lesions with mitotic counts >1 and depth of invasion >1xa0mm, suggesting miR-155 expression is associated with histological characteristics.ConclusionsmiR expression profiles can be measured in indeterminate Spitz tumors and correlate with markers of malignant potential.

Fatal extraintestinal adrenal malignancy in a 12-year-old girl with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is a disease of significant morbidity and risk of early mortality caused by colorectal or periampullary cancer, or noncancerous desmoid tumors. In the pediatric and adolescent FAP population, precancerous and cancerous tumors of the colon, thyroid, liver, and cen

Renal Tumors in Children Younger Than 12 Months of Age: A 65-year Single Institution Review

Wilms tumor (WT) is the most prevalent pediatric renal tumor and most commonly occurs between ages 1 and 5 years. Data are lacking on children younger than 12 months with renal tumors. The cancer registry at the authors’ institution was queried to identify patients 12 months and younger with renal masses. Demographics, clinical presentation, histopathology, stage, and survival outcomes were reviewed. The most common presenting symptoms included an asymptomatic abdominal mass (73%) and hematuria (9%). Histopathology revealed WT in 73% of patients, mesoblastic nephroma in 20%. Of those infants younger than 1 month of age, mesoblastic nephroma was the most common histopathology (68%). The 5-year overall survival (OS) was 93%, and 5-year event-free survival (EFS) was 93% for the entire group. For patients with WT, 5-year OS was 88% and 5-year EFS was 83%. Outcomes for congenital mesoblastic nephroma were excellent with 5-year OS and EFS of 100%. Reasons for good prognosis may be multifactorial and may include frequent well child checks in the first year of life and favorable histology. Patients in this age group are more likely to be classified as very low risk and may be treated with surgical resection alone.