Rao, Amulya Nageswara

Abstract Diffuse intrinsic pontine glioma (DIPG) is a rare pediatric brainstem tumor that is the leading cause of death among pediatric brain malignancies. Despite over 200 clinical trials, no significant progress has been made, leading our lab to consider suicide gene therapy. The brainstem has particularly sensitive anatomy, creating the potential for toxic inflammation. Furthermore, the clinical standard of care for DIPG includes conventional radiation therapy (RT) followed by dexamethasone (DEX), each of which can alter the efficacy of gene therapy. In this study we found that a variety of gliomas, including human DIPG and murine glioma cell lines, are infectable in vitro with a replication-competent Moloney murine leukemia virus (MoMLV) (currently in Phase 2/3 clinical trials) and susceptible to ganciclovir (GCV)-mediated killing via the HSV thymidine kinase (tk) suicide gene. A B16 melanoma cell line expressing HSV tk implanted into the brainstem of mice, extended median survival with GCV therapy from 13 days to 38.5 days (p=.0006) with no signs of toxic inflammation. Pre-treatment with RT and DEX did not affect therapeutic efficacy. We have shown that GCV/TK therapy is mediated by NK and CD8 cells in subcutaneous tumors, and we are investigating whether a similar immunologic mechanism is involved in this brainstem model. These preclinical data will pave the way for novel clinical trials for the treatment of DIPG.

Myxopapillary ependymomas (MPEs) have an indolent clinical course, corresponding to World Health Organization Grade I. A total of 13 pediatric MPEs have been reported in the literature with “anaplastic features,” including elevated proliferative activity (≥5 mitoses/10 high-power fields), necrosis, and microvascular proliferation. No consensus exists regarding the prognostic significance of such features. A retrospective clinicopathologic review of pediatric MPEs diagnosed between 1996 and 2018 at Mayo Clinic was performed. Totally, 8 pediatric MPEs (6 male; age: 7.52 to 16.88 y) were identified. Totally, 3 had disseminated disease at presentation. All patients underwent surgical resection (7 gross total; 1 subtotal). Totally, 5 cases harbored ≥5 mitoses/10 high-power fields (range: 5 to 9), 3 of which showed necrosis (2 with disseminated disease). Postsurgery, 2 patients received radiation; one with disseminated disease and another with increased mitotic activity/necrosis; neither has recurred (follow-up: 1.18 and 3.19 y). In all, 2 patients with disseminated disease, elevated mitotic activity, and necrosis had new metastatic disease/progression of nonresected metastatic foci (2.6 and 26.8 mo), received radiation therapy, and remain progression free (3.01 and 9.34 y). All patients are alive (median follow-up 1.31 y, range: 0.66 to 11.75). Among pediatric MPEs, the concurrent presence of elevated mitotic activity and necrosis may be associated with an aggressive clinical course, warranting closer surveillance and consideration of adjuvant therapies.

Abstract Introduction May–Thurner syndrome (MTS) is a vascular anatomic variant resulting in compression of the left common iliac vein by the right common iliac artery, affecting approximately 22% of the population. In adults, following acute deep vein thrombosis (DVT) of the iliofemoral veins, the incidence of postthrombotic syndrome (PTS) and recurrent DVT are high if treated with anticoagulation alone, warranting adjunctive treatment with thrombolysis and stent placement. However, there is paucity of literature documenting the course of treatment and associated outcomes in pediatric patients with MTS. Methods A retrospective chart review of pediatric patients (≤ 18 years of age) with radiologic confirmation of MTS with or without DVT evaluated and/or treated at our institution from January 1, 2005 through December 31, 2015 was conducted. Results Seventeen patients (4 male; 13 female) were identified. Median age was 15.4 years (range 8.8–17.1 years) with a median follow-up of 1.2 years (range 0.4–7.5 years). Thirteen (76.5%) patients presented with left lower extremity DVT. Management included catheter-directed thrombolysis (n = 5), systemic thrombolysis (n = 1), and mechanical thrombectomy (n = 1). Fifteen patients were treated with anticoagulation including two patients with endovascular stents without DVT. Median duration of anticoagulation was 6.3 months (range 3.2–18.7 months). Ten patients (59%) underwent stent placements.Complete and partial thrombus resolution was noted in six patients each and no resolution in one patient. Four patients had recurrence/progression of thrombus (n = 3 with stents) at a median time of 29 days (range 12–495 days). No bleeding complications were observed. Clinically documented or self-reported PTS was noted in 8 patients (62%). Conclusion There are no clear guidelines for MTS management in children and adolescents. In our cohort, thrombolysis, anticoagulation, or stent placements were not associated with bleeding risks, with recurrence/progression of DVT and signs and symptoms of PTS noted in 30 and 62%, respectively. Further studies are needed to determine a standardized treatment approach of the pediatric patient with MTS with or without thrombosis.

The risk of viral infections and reactivation occurring in the setting of pediatric allogeneic hematopoietic stem cell transplantation is a concern in the pediatric patient, especially with the use of Alemtuzumab (Campath) as a conditioning agent. The purpose of this study was to determine the incidence of Epstein-Barr virus posttransplant lymphoproliferative disorder (EBV-PTLD), cytomegalovirus (CMV), and adenovirus among pediatric recipients of alemtuzumab at our institution. We found that EBV-PTLD occurred in 2.1% of transplants (1 matched unrelated donor [MUD] recipient), CMV reactivation occurred in 12.5% of transplants (4 MUD and 2 matched related donor [MRD] recipients) with disseminated CMV in 2.1% of cases (1 MRD recipient), and adenovirus infection occurred in 8.3% of the total transplants (2 MUD and 2 MRD recipients). Alemtuzumab continues to be used as a method of graft-versus-host disease and graft failure prevention among pediatric recipients of hematopoietic stem cell transplantation and seems to be safer than previously reported. At our institution, alemtuzumab has not increased the risk for EBV-PTLD, CMV infection, or adenovirus.

AbstractPurposeTo evaluate patterns of failure after multimodality treatment of nongerminomatous germ cell tumors (NGGCTs).Materials and methodsWe retrospectively reviewed records of 34 patients diagnosed with primary intracranial NGGCT between 1988 and 2014.ResultsThirty‐four patients received induction chemotherapy followed by radiation with or without surgery. Median follow‐up was 11.1 years (0.8–23.3). Outcomes were significantly improved in these 34 patients (5‐year overall survival [OS]: 88% versus 50%, P = 0.0092), so analysis is restricted to that subset. Disease‐free survival (DFS) was 67, 60, and 54% at 5, 10, and 15 years, respectively. Elevated cerebrospinal fluid–α‐fetoprotein (CSF–AFP) at diagnosis was associated with poorer DFS (37 vs. 89% at 10 years; P = 0.01). There was no statistically significant difference in OS, or DFS, or patterns of failure for limited radiotherapy volumes versus larger volumes; however, patients receiving initial local radiotherapy had 32% distant central nervous system (CNS) recurrence at 10 years compared to 0% for those receiving initial larger field irradiation (P = 0.09). Fifteen patients recurred. All four patients who relapsed in the spine had received local radiotherapy and had elevated serum and CSF‐AFP at baseline. All three patients with ventricular relapse received local radiation therapy.ConclusionsNGGCT patients continue to relapse beyond 5 years. Late ventricular relapse occurred even in patients without clear evidence of germinoma component. Elevated CSF‐AFP at diagnosis is associated with poor DFS and risk for distant CNS relapse. Patients with residual radiographic disease after chemotherapy or residual malignant histologies after second‐look surgery have inferior outcomes. Our data support consideration of treatment intensification for these patients.

AbstractBackgroundEducators in pediatric hematology–oncology lack rigorously developed instruments to assess fellows’ skills in humanism and professionalism.ProcedureWe developed a novel 15‐item self‐assessment instrument to address this gap in fellowship training. Fellows (N = 122) were asked to assess their skills in five domains: balancing competing demands of fellowship, caring for the dying patient, confronting depression and burnout, responding to challenging relationships with patients, and practicing humanistic medicine. An expert focus group predefined threshold scores on the instrument that could be used as a cutoff to identify fellows who need support. Reliability and feasibility were assessed and concurrent validity was measured using three established instruments: Maslach Burnout Inventory (MBI), Flourishing Scale (FS), and Jefferson Scale of Physician Empathy (JSPE).ResultsFor 90 participating fellows (74%), the self‐assessment proved feasible to administer and had high internal consistency reliability (Cronbach's α = 0.81). It was moderately correlated with the FS and MBI (Pearson's r = 0.41 and 0.4, respectively) and weakly correlated with the JSPE (Pearson's r = 0.15). Twenty‐eight fellows (31%) were identified as needing support. The self‐assessment had a sensitivity of 50% (95% confidence interval [CI]: 31–69) and a specificity of 77% (95% CI: 65–87) for identifying fellows who scored poorly on at least one of the three established scales.ConclusionsWe developed a novel assessment instrument for use in pediatric fellowship training. The new scale proved feasible and demonstrated internal consistency reliability. Its moderate correlation with other established instruments shows that the novel assessment instrument provides unique, nonredundant information as compared to existing scales.

BackgroundHumanism and professionalism are virtues intrinsic to the practice of medicine, for which we lack a standard, evidence‐based approach for teaching and evaluation. Pediatric hematology‐oncology (PHO) fellowship training brings new and significant stressors, making it an attractive setting for innovation in humanism and professionalism training.ProcedureWe electronically surveyed a national sample of PHO fellows to identify fellows' educational needs in humanism and professionalism. Next, we developed a case‐based, faculty‐facilitated discussion curriculum to teach this content within pilot fellowship programs. We assessed whether fellowships would decide to offer the curriculum, feasibility of administering the curriculum, and satisfaction of fellow and faculty participants.ResultsSurveys were completed by 187 fellows (35%). A minority (29%) reported that their training program offers a formal curriculum in humanism and/or professionalism. A majority desires more formal teaching on balancing clinical practice and research (85%), coping with death/dying (85%), bereavement (78%), balancing work and personal life (75%), navigating challenging relationships with patients (74%), and depression/burn out (71%). These six topics were condensed into four case‐based modules, which proved feasible to deliver at all pilot sites. Ten fellowship programs agreed to administer the novel curriculum. The majority (90%) of responding fellows and faculty reported the sessions touched on issues important for training, stimulated reflective communication, and were valuable.ConclusionsPediatric hematology‐oncology fellows identify numerous gaps in their training related to humanism and professionalism. This curriculum offers an opportunity to systematically address these educational needs and can serve as a model for wider implementation. Pediatr Blood Cancer 2015;62:335–340. © 2014 Wiley Periodicals, Inc.