Joanna Weinstein

Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab

Hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyperinflammatory syndrome that remains difficult to treat. Even with current standard HLH therapy, only approximately half of patients will experience complete resolution of disease, and early mortality remains a significant problem. Salvage therapies have been described only in limited case reports, and there are no large studies of second‐line therapies.

Differentially expressed miRNAs in retinoblastoma

MicroRNAs (miRNAs) are short non-coding RNA transcripts that have the ability to regulate the expression of target genes, and have been shown to influence the development of various tumors. The purpose of our study is to identify aberrantly expressed miRNAs in retinoblastoma for the discovery of potential therapeutic targets for this disease, and to gain a greater understanding of the mechanisms driving retinoblastoma progression. We report 41 differentially expressed miRNAs (p<0.05) in 12 retinoblastomas as compared to three normal human retinae. Of these miRNAs, many are newly identified as being differentially expressed in retinoblastoma. Further, we report the validations of five of the most downregulated miRNAs in primary human retinoblastomas (p<0.05), human retinoblastoma cell lines, and mouse retinoblastoma cell lines. This serves as the largest and most comprehensive retinoblastoma miRNA analysis to date with corresponding clinical and pathological characteristics. This is an essential step in the discovery of miRNAs associated with retinoblastoma progression, and in the identification of potential therapeutic targets for this disease.

MicroRNAs-449a and -449b exhibit tumor suppressive effects in retinoblastoma

Retinoblastoma is the most common pediatric cancer of the eye. Currently, the chemotherapeutic treatments for retinoblastoma are broad-based drugs such as vincristine, carboplatin, or etoposide. However, therapies targeted directly to aberrant signaling pathways may provide more effective therapy for this disease. The purpose of our study is to illustrate the relationship between the expressions of miRs-449a and -449b to retinoblastoma proliferation and apoptosis. We are the first to confirm an inhibitory effect of miR-449a and -449b in retinoblastoma by demonstrating significantly impaired proliferation and increased apoptosis of tumor cells when these miRNAs are overexpressed. This study suggests that these miRNAs could serve as viable therapeutic targets for retinoblastoma treatment.

Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1 mutation

Although ionizing radiation induces germline mutations in animals, human studies of radiation‐exposed populations have not detected an effect. We conducted a case‐control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their childs conception. Parents of 206 cases from nine North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower gastrointestinal (GI) series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child [matched odds ratio (OR) = 3.6, 95% confidence interval (CI) = 1.2–11.2, two‐sided p = 0.02], as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI = 1.2–14.4, p = 0.02). Maternal history of lower GI series was also associated with increased risk (OR = 7.6, 95% CI = 2.8–20.7, p < 0.001) as was the estimated total dose (OR for highest dose = 3.0, 95% CI = 1.4–7.0, p = 0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.

Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma

Retinoblastoma is the most common intraocular tumor of childhood. Vision salvage rates in advanced cases are less than ideal, and the optimal treatment for intraocular retinoblastoma has not been established. We report the results of an institutional retinoblastoma treatment trial to determine the vision salvage rates and toxicity of a regimen combining carboplatin and etoposide with focal retinal therapy.

Novel miRNA-31 and miRNA-200a-Mediated Regulation of Retinoblastoma Proliferation.

Retinoblastoma is the most common intraocular tumor in children. Current management includes broad-based treatments such as chemotherapy, enucleation, laser therapy, or cryotherapy. However, therapies that target specific pathways important for retinoblastoma progression could provide valuable alternatives for treatment. MicroRNAs are short, noncoding RNA transcripts that can regulate the expression of target genes, and their aberrant expression often facilitates disease. The identification of post-transcriptional events that occur after the initiating genetic lesions could further define the rapidly aggressive growth displayed by retinoblastoma tumors. In this study, we used two phenotypically different retinoblastoma cell lines to elucidate the roles of miRNA-31 and miRNA-200a in tumor proliferation. Our approach confirmed that miRNAs-31 and -200a expression is significantly reduced in human retinoblastomas. Moreover, overexpression of these two miRNAs restricts the expansion of a highly proliferative cell line (Y79), but does not restrict the growth rate of a less aggressive cell line (Weri1). Gene expression profiling of miRNA-31 and/or miRNA-200a-overexpressing cells identified differentially expressed mRNAs associated with the divergent response of the two cell lines. This work has the potential to enhance the development of targeted therapeutic approaches for retinoblastoma and improve the efficacy of treatment.

Rechallenging With Intrathecal Methotrexate After Developing Subacute Neurotoxicity in Children With Hematologic Malignancies

Methotrexate is associated with neurologic side effects. It is recommended that patients who developed neurotoxicity be rechallenged with methotrexate, but little is known about the safety of this approach. We performed a chart review to identify patients who received high‐dose or intrathecal (IT) methotrexate. Twenty‐one of 298 patients (7%) experienced neurologic symptoms attributed to methotrexate treatment in the premaintenance phase. Seventeen of these patients were rechallenged with IT methotrexate and 13 (76%) had no further neurotoxic events. No patients rechallenged during maintenance (n = 9) experienced recurrence of neurotoxic events. It is safe to rechallenge with IT methotrexate in maintenance.

Successful treatment with rituximab of an epstein-barr virus-associated leiomyosarcoma occurring after liver transplantation

E pstein-Barr virus (EBV)–associated smooth muscle tumors (SMTs) have increasingly been recognized in children (1), typically following solid organ and stem cell transplantation, chemotherapy for malignancies, and in immunosuppressed states such as acquired immunodeficiency syndrome (1–3). We report a case of successful treatment of an EBV-associated SMT with rituximab, in a 2.5-year-old girl, 15 months following liver transplantation for biliary cirrhosis. To the best of our knowledge, this is the first report of rituximab used in the treatment of EBV-associated SMT. The patient was born full term following an uneventful pregnancy and delivery. She was diagnosed as having cryptogenic cirrhosis at 7 months of age and rapidly progressed to end-stage liver disease. She underwent an orthotopic liver transplant without complications and received a whole organ from a deceased male donor. Her initial immunosuppressive regimen included cyclosporine, 10 mg kg 1 dose 1 twice daily, prednisone, 0.3 mg/kg daily, and azathioprine, 1 mg/kg daily. One month posttransplant, she developed steroid-resistant acute cellular rejection, which was treated with an 8-day course of thymoglobulin, 1.5 mg/kg daily, methylprednisolone, 10 mg/kg daily for 4 days, and her calcineurin inhibitor was switched to tacrolimus, 0.2 mg kg 1 dose 1 twice daily, and adjusted to maintain goal levels between 10 and 12 ng/dL. Given her episode of steroid-resistant acute rejection, she was maintained at this goal until 12 months posttransplant, at which time her goal levels decreased to 8 and 10 ng/dL. Her antimetabolite was continued. Thirteen months posttransplant, she developed elevated aminotransferases with a markedly elevated EBV level, as detected

Sudden Dispersion of Retinoblastoma Shortly after Initial Chemotherapy Treatment

PURPOSE To present 3 cases of unilateral retinoblastoma that demonstrated unusual tumor dispersion shortly after initial chemotherapy treatment. DESIGN Observational case series. METHODS Review of medical records of patients in whom intraocular dissemination of retinoblastoma occurred after initial treatment with chemotherapy. RESULTS Three patients demonstrated an atypical response with intraocular dissemination of retinoblastoma shortly after 1 cycle of chemotherapy. All cases had unilateral retinoblastoma with no vitreous seeding or subretinal fluid at presentation. In 2 cases (Cases 2 and 3), there were a few distant subretinal seeds. Per the International Classification of Retinoblastoma, 1 tumor was group E (Case 1), and the other 2 tumors were group D1 (Cases 2 and 3). In 2 cases (Cases 1 and 2), chemotherapy included a 2-drug regimen of carboplatin and etoposide; in the third case, a 3-drug regimen of carboplatin, etoposide, and vincristine was used. In each case, the retinoblastoma dispersed with tumor cells in the vitreous shortly after initial chemotherapy treatment, leading to subsequent enucleation of the eye. CONCLUSIONS Retinoblastoma can exhibit an unexpected and sudden dispersion of the tumor shortly after chemotherapy is initiated.

Deconstructing the diagnosis of hemophagocytic lymphohistiocytosis using illustrative cases

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of extreme inflammation occurring in association with genetic defects involving the granule-dependent cytotoxic pathway of CD8+ T cells or NK cells and/or a wide variety of triggers including infections, malignancies, and rheumatologic disorders. Because of its relative rarity and the non-specific nature of the individual clinical and laboratory abnormalities comprising the characteristic “pattern” of HLH, the diagnosis can be elusive. Furthermore, some of the laboratory tests included in the diagnostic criteria are time-consuming or not widely available, and since many of these patients are critically ill, HLH must be considered early on so that the diagnosis can be established and potentially life-saving treatment initiated. Since the diagnosis of HLH is truly a clinicopathologic correlation, in this article, we as a team of pediatric clinical and laboratory physicians will use exemplary cases from our own institution with a variety of clinical presentations to illustrate the many “faces” of HLH; deconstruct the diagnosis; point out some of the challenges, limitations, pearls and pitfalls; and make it easier to understand the pathophysiology in context. However, while we may see relatively more cases working in a tertiary care children’s hospital, HLH is a disease of both children and adults.