Challenging the Standard Immunogenicity Assessment Approach: 1-Tiered ADA Testing Strategy in Clinical Trials.

The ADA testing strategy for protein therapeutics was established almost two decades ago when assay methodologies were rudimentary, and serious immunogenicity-related safety issues had recently been observed with some biotherapeutics. The current testing paradigm employs multiple tiers and stringent cut points to minimize false negatives, reflecting a conservative stance towards ADA analysis. The development of highly sensitive ADA assay platforms and technologies such as humanized or fully human monoclonal antibody (mAb) drugs has put the traditional, resource-intensive 3-tiered testing approach under scrutiny.

Functional MRI Assessment of Brain Activity Patterns Associated with Reading in Medulloblastoma Survivors.

Medulloblastoma, a malignant brain tumor primarily affecting children, poses significant challenges to patients and clinicians due to its complex treatment and potential long-term cognitive consequences. While recent advancements in treatment have significantly improved survival rates, survivors often face cognitive impairments, particularly in reading, impacting their quality of life. According to the double deficit theory, reading impairments are caused by deficits in one or both of two independent reading-related functions: phonological awareness and rapid visual naming.

Using Hypothetical Scenarios to Address Social Desirability Bias: Investigating Student Perceptions, Evaluations, and Motivations of Cheating and Academic Integrity in the General Chemistry Laboratory.

Supporting students with upholding the principles of academic integrity is an important aspect of teaching. Academic integrity is especially important in chemistry laboratory classrooms, where students gain hands-on experience related to research and scientific practices. Prior literature on academic integrity largely focuses on catching and preventing cheating, describing various factors commonly associated with cheating behaviors.

Cerebellar Mutism Syndrome and Dentato-Thalamo-Cortical Tract Disruption in Diffusion Tractography Following Surgery for Medulloblastoma.

Background Cerebellar mutism syndrome (CMS), a complication following medulloblastoma surgery, has been linked to dentato-thalamo-cortical tract (DTCT) injury; the association of the degree of DTCT injury with severity of CMS-related symptoms has not been investigated. Purpose To investigate the association between severity of CMS-related symptoms and degree and patterns of DTCT injury with use of diffusion tensor imaging (DTI), and if laterality of injury influences neurologic symptoms. Materials and Methods This retrospective case-control study used prospectively collected clinical and DTI data on patients with medulloblastoma enrolled in a clinical trial (between July 2016 and February 2020) and healthy controls (between April and November 2017), matched with the age range of the participants with medulloblastoma.

Outcomes of a Formal Hematopoietic Cell Transplantation Survivorship Program on Screening for Late Effects.

Allogeneic hematopoietic cell transplantation (HCT) survivors may benefit from routine screening for post-transplant complications. However, the impact of formal survivorship efforts to promote screening adherence is uncertain. The effect of a formal HCT survivorship program to promote screening adherence was evaluated.

Secondary cerebro-cerebellar and intra-cerebellar dysfunction in cerebellar mutism syndrome.

Background: Cerebellar mutism syndrome (CMS) is characterized by deficits of speech, movement, and affect that can occur following tumor removal from the posterior fossa. The role of cerebro-cerebellar tract injuries in the etiology of CMS remains unclear, with recent studies suggesting that cerebro-cerebellar dysfunction may be related to chronic, rather than transient, symptomatology.

Methods: We measured functional connectivity between the cerebellar cortex and functional nodes throughout the brain using fMRI acquired after tumor removal but prior to adjuvant therapy in a cohort of 70 patients diagnosed with medulloblastoma.

Third-party fecal microbiota transplantation for high-risk treatment-naïve acute GVHD of the lower GI tract.

Disruption of the intestinal microbiome is observed with acute graft-versus-host disease (GVHD) of the lower gastrointestinal (LGI) tract, and fecal microbiota transplantation (FMT) has successfully cured steroid-refractory cases. In this open-label, single-arm, pilot study, third-party, single-donor FMT was administered in combination with systemic corticosteroids to participants with high-risk acute LGI GVHD, with a focus on treatment-naïve cases. Participants were scheduled to receive 1 induction dose (15 capsules per day for 2 consecutive days), followed by 3 weekly maintenance doses, consisting of 15 capsules per dose.

Immunogenicity of Cemiplimab: Low Incidence of Antidrug Antibodies and Cut-Point Suitability Across Tumor Types.

The immunogenicity of cemiplimab, a fully human immunoglobulin G4 monoclonal antibody directed against programmed cell death 1, was assessed in patients across multiple tumor types. The development of antidrug antibodies (ADAs) against cemiplimab was monitored using a validated bridging immunoassay. To identify ADA-positive samples in the assay, statistically determined cut points were established by analyzing baseline clinical study samples from a mixed population of different tumor types, and this validation cut point was used to assess immunogenicity in all subsequent studies.

Cerebellar mutism is linked to midbrain volatility and desynchronization from speech cortices.

Cerebellar mutism syndrome is a disorder of speech, movement and affect that can occur after tumour removal from the posterior fossa. Projections from the fastigial nuclei to the periaqueductal grey area were recently implicated in its pathogenesis, but the functional consequences of damaging these projections remain poorly understood. Here, we examine functional MRI data from patients treated for medulloblastoma to identify functional changes in key brain areas that comprise the motor system for speech, which occur along the timeline of acute speech impairment in cerebellar mutism syndrome.

Statistical Approaches for Establishing Appropriate Immunogenicity Assay Cut Points: Impact of Sample Distribution, Sample Size, and Outlier Removal.

The statistical assessments needed to establish anti-drug antibody (ADA) assay cut points (CPs) can be challenging for bioanalytical scientists. Poorly established CPs that are too high could potentially miss treatment emergent ADA or, when set too low, result in detection of responses that may have no clinical relevance. We evaluated 16 validation CP datasets generated with ADA assays at Regeneron's bioanalytical laboratory and compared results obtained from different CP calculation tools.

Multicenter Phase I Trial of Ivosidenib as Maintenance Treatment Following Allogeneic Hematopoietic Cell Transplantation for IDH1-Mutated Acute Myeloid Leukemia.

Purpose: Isocitrate dehydrogenase 1 (IDH1) mutations occur in 5% to 10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML.

Patients And Methods: We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML.

Automatic detection and segmentation of postoperative cerebellar damage based on normalization.

Background: Surgical resection is the gold standard in the treatment of pediatric posterior fossa tumors. However, surgical damage is often unavoidable and its association with postoperative complications is not well understood. A reliable localization and measure of cerebellar damage is fundamental to study the relationship between the damaged cerebellar regions and postoperative neurological outcomes.

Enasidenib as maintenance following allogeneic hematopoietic cell transplantation for IDH2-mutated myeloid malignancies.

IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies.

Fastigial nuclei surgical damage and focal midbrain disruption implicate PAG survival circuits in cerebellar mutism syndrome.

Background: Pediatric postoperative cerebellar mutism syndrome (CMS) is a rare but well-known complication of medulloblastoma (Mb) resection with devastating effects on expressive language, mobility, cognition, and emotional regulation that diminishes quality of life for many Mb survivors. The specific anatomical and neuronal basis of CMS remains obscure. We address this issue by identifying patterns of surgical damage and secondary axonal degeneration in Mb survivors with CMS.

Pre-existing Reactivity to an IgG4 Fc-Epitope: Characterization and Mitigation of Interference in a Bridging Anti-drug Antibody Assay.

Twenty percent of baseline patient samples exhibited a pre-existing response in a bridging anti-drug antibody (ADA) assay for a human IgG4 monoclonal antibody (mAb) therapeutic. In some cases, assay signals were more than 100-fold higher than background, potentially confounding detection of true treatment-emergent ADA responses. The pre-existing reactivity was mapped by competitive inhibition experiments using recombinant proteins or chimeric human mAbs with IgG4 heavy chain regions swapped for IgG1 sequences.

Chemotherapy Resistance in B-ALL with Cryptic NUP214-ABL1 Is Amenable to Kinase Inhibition and Immunotherapy.

BCR-ABL1 kinase inhibitors have improved the prognosis of Philadelphia-chromosome-positive (Ph+)-acute lymphoblastic leukemia (ALL). Ph-like (or BCR-ABL1-like) ALL does not express BCR-ABL1 but commonly harbors other genomic alterations of signaling molecules that may be amenable to therapy. Here, we report a case with a NUP214-ABL1 fusion detected at relapse by multiplexed, targeted RNA sequencing.

Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial.

CD19-directed chimerical antigen receptor T-cell (CAR-T) products have gained US Food and Drug Administration approval for systemic large B-cell lymphoma. Because of concerns about potential immune cell-associated neurotoxicity syndrome (ICANS), patients with primary central nervous system (CNS) lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. We conducted a phase 1/2 clinical trial of tisagenlecleucel in a highly refractory patients with PCNSL and significant unmet medical need.

Ixazomib in addition to chemotherapy for the treatment of acute lymphoblastic leukemia in older adults.

We sought to assess the safety of adding ixazomib, an oral proteasome inhibitor, to a multi-agent treatment regimen for older adults with acute lymphoblastic leukemia (ALL). Patients 51 to 75 years of age with newly diagnosed ALL were screened. Induction consisted of prednisone (P), vincristine (V), and doxorubicin (D).