Multiparametric MRI of early tumor response to immune checkpoint blockade in metastatic melanoma.

BACKGROUND: Immune checkpoint inhibitors are now standard of care treatment for many cancers. Treatment failure in metastatic melanoma is often due to tumor heterogeneity, which is not easily captured by conventional CT or tumor biopsy. The aim of this prospective study was to investigate early microstructural and functional changes within melanoma metastases following immune checkpoint blockade using multiparametric MRI. METHODS: Fifteen treatment-naïve metastatic melanoma patients (total 27 measurable target lesions) were imaged at baseline and following 3 and 12 weeks of treatment on immune checkpoint inhibitors using: T2-weighted imaging, diffusion kurtosis imaging, and dynamic contrast-enhanced MRI. Treatment timepoint changes in tumor cellularity, vascularity, and heterogeneity within individual metastases were evaluated and correlated to the clinical outcome in each patient based on Response Evaluation Criteria in Solid Tumors V.1.1 at 1 year. RESULTS: Differential tumor growth kinetics in response to immune checkpoint blockade were measured in individual metastases within the same patient, demonstrating significant intertumoral heterogeneity in some patients. Early detection of tumor cell death or cell loss measured by a significant increase in the apparent diffusivity (Dapp) (p<0.05) was observed in both responding and pseudoprogressive lesions after 3 weeks of treatment. Tumor heterogeneity, as measured by apparent diffusional kurtosis (Kapp), was consistently higher in the pseudoprogressive and true progressive lesions, compared with the responding lesions throughout the first 12 weeks of treatment. These preceded tumor regression and significant tumor vascularity changes (Ktrans, ve, and vp) detected after 12 weeks of immunotherapy (p<0.05). CONCLUSIONS: Multiparametric MRI demonstrated potential for early detection of successful response to immune checkpoint inhibitors in metastatic melanoma.

Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.

Diagnosis in just over a minute: a case of chronic eosinophilic pneumonia.

Chronic eosinophilic pneumonia (CEP) is a rare interstitial lung disease characterized by subacute dyspnea, peripheral infiltrates on imaging, and pulmonary eosinophilia. We report a case of a 48-year-old man who presented to a "minute clinic" with cough and dyspnea. After improvement on a short course of steroids for a presumptive diagnosis of bronchospasm, he presented to our hospital with symptom recurrence. Computed tomography (CT) imaging revealed peripheral infiltrates and bronchoscopy confirmed pulmonary eosinophilia. In this clinical vignette, we review the typical presentation of chronic eosinophilic pneumonia, the differential diagnosis of pulmonary infiltrates with eosinophilia, and the challenges of diagnosing a rare condition that may mimic more common causes of dyspnea, especially in a "minute clinic" setting.