The impact of changes in gadolinium-enhancement on disease progression in children with neurofibromatosis type 1-associated optic pathway glioma: a retrospective analysis.

PURPOSE: There has been limited investigation of imaging features associated with visual acuity (VA) decline and initiation of treatment for patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). METHODS: To evaluate the association of increased gadolinium enhancement with decline in VA, initiation of chemotherapy, and tumor growth, we performed a retrospective cohort study of children diagnosed with NF1-OPG between January 2006 to June 2016. Two cohorts were defined: a new diagnosis and a longitudinal cohort. Outcomes were examined at 1 and 2 years from initial diagnosis, and 1 and 2 years from initial increase in enhancement in the longitudinal cohort. RESULTS: Eighty patients were eligible; all 80 contributed to the new diagnosis cohort and 73 to the longitudinal cohort. Fifty-six patients (70%) demonstrated enhancing NF1-OPG at diagnosis. 39% of patients in the new diagnosis cohort and 45% of those in the longitudinal cohort developed increased enhancement during the study period. There was no significant association between increases in enhancement and VA decline in the newly diagnosed or longitudinal cohorts, as well as with initiation of treatment in the longitudinal cohort. Although there was an association of enhancement increase with treatment in the new diagnosis cohort, this association was not maintained when stratified by concurrent change in tumor size. CONCLUSION: Increased gadolinium-enhancement independent of a concurrent increase in tumor size on MRI should not be used as a marker of NF1-OPG progression and does not appear to be associated with visual decline or initiation of chemotherapy.

Diagnostic Challenges in Pediatric Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune dysregulation that encompasses a broad range of underlying genetic diseases and infectious triggers. Monogenic conditions, autoimmune diseases, and infections can all drive the phenotype of HLH and associated immune hyperactivation with hypercytokinemia. A diagnosis of HLH usually requires a combination of clinical and laboratory findings; there is no single sensitive and specific diagnostic test, which often leads to "diagnostic dilemmas" and delays in treatment initiation. Ferritin levels, one of the most commonly used screening tests, were collected across a large tertiary care pediatric hospital to identify the positive predictive value for HLH. Herein, we present several cases that illustrate the clinical challenges of confirming an HLH diagnosis. Additionally, we report on the utility of establishing a formal multi-disciplinary group to aid the prompt diagnosis and treatment of patients presenting with HLH-like pathophysiologies.

High Expression of TIM 3 and Galectin 9 on Immunohistochemistry Staining of Tumor Specimen at Diagnosis in Pediatric Patients with Ewing Sarcoma.

Significant progress has been made in the advancement of immune system modulation for cancer treatment in recent years. In particular, immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy have demonstrated remarkable clinical benefit in relapsed/refractory cancers. However, our understanding of the immuno-oncologic landscape in pediatric solid tumors remains limited and is a barrier to continued progress. We examined the immunohistochemical expression of checkpoint receptors PD-1, TIM-3, LAG-3 and their respective ligands in various pediatric cancers at diagnosis and found high expression of TIM-3/Galectin-9 in the infiltrating cells of Ewing sarcoma. Location of checkpoint receptor/ligand expressions is important, as some staining patterns were only seen along tumor borders. Finally, peripheral T cell function varied significantly among different tumors supporting a complex relationship between the tumor microenvironment and the global immune system.

An Usual Presentation of Pneumocystis jirovecii Pneumonia in a Woman Treated With Immune Checkpoint Inhibitor.

We describe a case of Pneumocystis jirovecii pneumonia in an 18-year-old female individual with refractory primary mediastinal B-cell lymphoma treated with the immune checkpoint inhibitor pembrolizumab. She received 11 doses of pembrolizumab without immune-related adverse events (irAEs) before the diagnosis of P. jirovecii pneumonia. However, prophylactic trimethoprim/sulfamethoxazole was discontinued 6 months of postautologous stem cell transplant per standard guidelines. This case report highlights the importance of judicious infectious disease evaluation while on immune checkpoint inhibitor therapy as symptoms can often mimic irAEs. Furthermore, the benefits of immunosuppressive therapy for the treatment of presumptive irAEs must be weighed against the possible increased risk for opportunistic infections.

Spotlight on Tocilizumab in the Treatment of CAR-T-Cell-Induced Cytokine Release Syndrome: Clinical Evidence to Date.

Immune-based therapies such as chimeric antigen receptor (CAR)-T-cell therapy have revolutionized the landscape of cancer treatment in recent years. Although this class of therapy has demonstrated impressive clinical efficacy against cancers that were once thought to be incurable, its success is in part limited by unique toxicities which can be severe or even fatal. Cytokine release syndrome (CRS) is the most commonly observed toxicity and occurs as a result of non-antigen specific immune activation. Similar to macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH), CRS is associated with elevated levels of several cytokines including interleukin-6 (IL-6) that serve as a driver for host immune dysregulation. As a direct anti-cytokine drug, tocilizumab has been a cornerstone in the treatment of CAR-T-associated CRS through its ability to dampen CRS without compromising CAR-T-cell function. However, optimal timing of administration is yet unknown. Here, we review the use of tocilizumab in the management of CAR-T-associated CRS, emphasizing on the clinical efficacy across various CAR constructs and its role in current CRS management algorithms. We also discuss alternative therapies that may be considered for refractory CRS therapy and the use of tocilizumab in the current COVID-19 global pandemic.

Hearing loss among survivors of childhood brain tumors treated with an irradiation-sparing approach.

BACKGROUND: Intensive, irradiation-sparing chemotherapy regimens for malignant brain tumors have improved survival and neurocognitive outcomes in very young children. Platinum compounds are pivotal to this approach's success but are associated with hearing loss that markedly reduces quality of life for survivors. The purpose of this study was to determine the prevalence and severity of ototoxicity associated with Head Start and similar irradiation-sparing regimens. PROCEDURE: A retrospective cohort study was conducted of children treated for malignant brain tumors at Children's Hospital Los Angeles using irradiation-sparing regimens. Patient and treatment characteristics were ascertained. Primary outcomes were post-treatment hearing status, need for hearing aids, and hearing threshold change. RESULTS: Twenty-nine patients were evaluable. The most common diagnosis was medulloblastoma (n = 14). The median age at diagnosis was 2.0 years (range, 0.2-9.2). Median time from diagnosis to most recent hearing assessment was 1.1 years (mean 2.4; range, 0.2-17.5). Cumulative cisplatin and carboplatin dose was 281 ± 88 mg/m(2) and 1,205 ± 277 mg/m(2) , respectively. All patients had aminoglycoside exposure. Following treatment, 18 patients (62.1%) had abnormal hearing and 11 (37.9%) required hearing aids. At 4,000 Hz, statistically significant hearing loss was documented in the range of 30-40 dB. CONCLUSIONS: While eliminating cranial irradiation has dramatically improved survival and neurocognitive and neuroendocrine outcomes in this population, clinically significant hearing loss is now the leading late effect due to the necessity of platinum-based chemotherapy. Our results document the need for audiometric monitoring and developing otoprotective strategies in this vulnerable population.

Regression of primary central nervous system germinoma after dexamethasone administration: a case report.

Childhood central nervous system (CNS) germinoma are highly curable brain tumors characterized pathologically by varying degrees of lymphocytic infiltration. The authors present a case of a CNS germinoma with significant regression in size following surgery and administration of dexamethasone, prior to initiation of chemotherapy or irradiation. The authors speculate the possible mechanism involved in its occurrence. Perioperative corticosteroid administration in patients with CNS germinoma may obfuscate the increase in response demonstrated with various chemotherapy regimens or with irradiation in CNS germinomas.