Evaluation of Targets for Maytansinoid ADC Therapy Using a Novel Radiochemical Assay.

PURPOSE: Many antibody-drug conjugates (ADCs) become active only after antigen-mediated internalization and release of the cytotoxic agent via antibody degradation. Quantifying these processes can provide critical information on the suitability of a particular receptor target or antibody for ADC therapy by providing insight into the amount of cytotoxic agent released. We describe a simple and inexpensive radiolabel assay to monitor this process in cultured cancer cells. METHODS: Monoclonal antibodies were trace-labeled at their lysine residues by treatment with the N-hydroxysuccinimide ester of [(3)H]propionic acid. Human cancer cell cultures were treated with the labeled antibody at concentrations sufficient to saturate the targeted antigen. After washing to remove unbound antibody, cells were incubated and analyzed for antigen expression, conjugate degradation and catabolite formation. Results were compared with data obtained from similar assays run with radiolabeled antibody-[(3)H]maytansinoid conjugates ([(3)H]AMCs). To exemplify the method, studies were conducted with a panel of [(3)H]propionamide-antibodies to evaluate processing efficiency in EGFR-expressing SCCHN cell lines, and in NHL cell lines expressing the B-cell targets CD19, CD20, CD22 and CD37. RESULTS: Use of the [(3)H]propionamide-antibody assay yielded cell-mediated processing results similar to those obtained with corresponding maytansinoid ADCs. Further exploration allowed comparison of expression levels, antigen-dependent degradation, and catabolite formation across a panel of EGFR-expressing SCCHN cell lines, and for multiple targets in various B-cell cancer indications. CONCLUSIONS: The [(3)H]propionamide-antibody assay described here is a sensitive, facile method which enables rapid and robust assessment of relative antibody processing amounts for target, antibody, and cell line evaluation.

Sacral metastases in a patient with BRAF V600E+ papillary thyroid carcinoma.

Lack of consensus exists on an algorithm to screen for synchronous distant metastases in patients presenting with papillary thyroid carcinoma (PTC). A 68-year-old male presented with a 3 cm supraclavicular neck mass. Computed tomography (CT) scan revealed a 1.3 cm left thyroid lobe nodule and 3 cm left level 3 and 4 lymphadenopathy. Ultrasound-guided fine needle aspiration was positive for PTC. Patient underwent total thyroidectomy and lymph node dissection with molecular testing confirming BRAF V600E+ PTC. Six weeks post-operatively, he developed left hip pain and numbness. Magnetic resonance imaging (MRI) revealed a large sacral mass and multiple bony lesions confirmed to be osseous metastases. Given the relatively rapid report of hip pain after surgery, metastases were likely synchronous at presentation and may have been detected with earlier suspicion. Further investigation is necessary to systematically stratify risk of synchronous distant metastases in patients with metastatic PTC.

Drivers of vaccine hesitancy among vulnerable populations in India: a cross-sectional multi-state study.

Objectives: India's Covid-19 vaccination campaign engaged frontline workers (FLWs) to encourage vaccination among vulnerable segments of society. The FLWs report encountering a variety of barriers to vaccination and are often unsuccessful despite multiple visits to the same person. This cross-sectional study aims to pinpoint which of these barriers drive vaccine hesitancy among these segments, to help streamline vaccine communication, including FLW training, to better safeguard the population. Methods: Trained field enumerators contacted 893 individuals from five states across India and collected self-reported assessments of fifteen vaccination barriers (identified through discussions with FLWs), current vaccination status and future vaccination intentions, and covariates (demographics/comorbidities). Factor analysis of the fifteen barriers yielded two factors, one relating to fear of vaccine adverse effects and a second focused on peripheral concerns regarding the vaccine. The covariates significantly associated with current vaccination status were combined under a latent class regime to yield three cluster types (health access, financial strength, and demographics). The primary analysis examined the effect of the two barrier factors, the covariate clusters, and comorbidity, on current vaccination status and future vaccine intentions. Results: Fear of vaccine adverse effects was the primary driver of vaccine hesitancy; peripheral concerns frequently mentioned by the FLWs had no impact. Although cluster membership and the presence of comorbidities predicted vaccine uptake, neither of them materially altered the effect of fear of vaccine adverse effects with the following exception: fear of adverse effects was not associated with vaccination status among young Muslim men. Conclusion: Subject to limitations, these results indicate that interventions to decrease vaccine hesitancy should focus primarily on fear associated with vaccines rather than spend resources trying to address peripheral concerns.

Patient Safety and Quality for Office-Based Procedures in Otolaryngology.

Office-based procedures have increased in frequency with the recent changes in the current health care climate prioritizing improved efficiency and greater value in the care that is delivered. This article focuses on patient safety and quality issues that are specific to procedures in the office setting of an Otolaryngologist. Specific topics are categorized into preprocedure planning, procedural execution, and postprocedure follow-up. Several best practice recommendations are included to promote and simplify the integration of these quality and safety measures into every office setting.

The Antitumor Activity of IMGN529, a CD37-Targeting Antibody-Drug Conjugate, Is Potentiated by Rituximab in Non-Hodgkin Lymphoma Models.

Naratuximab emtansine (IMGN529) is an investigational antibody-drug conjugate consisting of a CD37-targeting antibody conjugated to the maytansine-derived microtuble disruptor, DM1. IMGN529 has shown promising preclinical and clinical activity in non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Due to the aggressive nature of the disease, DLBCL is often treated with combination therapies to maximize clinical outcomes; therefore, we investigated the potential of combining IMGN529 with both standard-of-care and emerging therapies against multiple oncology-relevant targets and pathways. The strongest enhancement in potency was seen with anti-CD20 antibodies, including rituximab. The combination of IMGN529 and rituximab was more potent than either agent alone, and this combinatorial benefit was associated with increased apoptotic induction and cell death. Additional studies revealed that rituximab treatment increased the internalization and degradation of the CD37-targeting antibody moiety of IMGN529. The combination of IMGN529 and rituximab was highly efficacious in multiple xenograft models, with superior antitumor efficacy seen compared to either agent alone or treatment with R-CHOP therapy. These findings suggest a novel mechanism whereby the potency of IMGN529 can be enhanced by CD20 binding, which results in the increased internalization and degradation of IMGN529 leading to the generation of greater amounts of cytotoxic catabolite. Overall, these data provide a biological rationale for the enhanced activity of IMGN529 in combination with rituximab and support the ongoing clinical evaluation of IMGN529 in combination with rituximab in patients with relapsed and/or refractory DLBCL.

The presentation and management of nasal dermoid: a 30-year experience.

OBJECTIVE: To review the presentation of nasal dermoid in children and present guidelines for its management. DESIGN: Retrospective study (January 1, 1970, through December 31, 2000). SETTING: Tertiary-care pediatric medical center. PATIENTS: Number of patients: 42 (28 boys and 14 girls). Intervention Extensive review of the initial presentation, significant family and medical history, workup, surgical approach, complication, and rate of recurrence. RESULTS: Mean age of presentation was 32 months. The most common presentation was a nasoglabellar mass, in 13 patients (31%). Five patients presented with an associated craniofacial abnormality. Thirty-nine patients (93%) underwent a preoperative imaging workup. Thirty-one (74%) did not show any clinical and/or radiographic indication of intracranial extension. Thirty-four (81%) underwent extracranial excision, and 8 (19%) underwent combined intracranial-extracranial excision. Five patients (12%) presented with recurrence, extracranially in 4 and intracranially in 1. No other complication was noted, with a mean follow-up of 7 years. CONCLUSIONS: Nasal dermoid is a rare congenital anomaly. Preoperative evaluation is essential to rule out intracranial extension. Surgical strategy depends on the location and extent of the lesion, ranging from local excision to a combined intracranial-extracranial approach. Recurrence is uncommon and often easily managed.