Deconvolution of cell type-specific drug responses in human tumor tissue with single-cell RNA-seq.

BACKGROUND: Preclinical studies require models that recapitulate the cellular diversity of human tumors and provide insight into the drug sensitivities of specific cellular populations. The ideal platform would enable rapid screening of cell type-specific drug sensitivities directly in patient tumor tissue and reveal strategies to overcome intratumoral heterogeneity. METHODS: We combine multiplexed drug perturbation in acute slice culture from freshly resected tumors with single-cell RNA sequencing (scRNA-seq) to profile transcriptome-wide drug responses in individual patients. We applied this approach to drug perturbations on slices derived from six glioblastoma (GBM) resections to identify conserved drug responses and to one additional GBM resection to identify patient-specific responses. RESULTS: We used scRNA-seq to demonstrate that acute slice cultures recapitulate the cellular and molecular features of the originating tumor tissue and the feasibility of drug screening from an individual tumor. Detailed investigation of etoposide, a topoisomerase poison, and the histone deacetylase (HDAC) inhibitor panobinostat in acute slice cultures revealed cell type-specific responses across multiple patients. Etoposide has a conserved impact on proliferating tumor cells, while panobinostat treatment affects both tumor and non-tumor populations, including unexpected effects on the immune microenvironment. CONCLUSIONS: Acute slice cultures recapitulate the major cellular and molecular features of GBM at the single-cell level. In combination with scRNA-seq, this approach enables cell type-specific analysis of sensitivity to multiple drugs in individual tumors. We anticipate that this approach will facilitate pre-clinical studies that identify effective therapies for solid tumors.

High-frequency spinal cord stimulation causing cardiac paresthesias after lead migration: a case report.

INTRODUCTION: High-frequency (HF) spinal cord stimulation (SCS), a relatively new form of spinal cord stimulation, provides stimulation frequencies of up to 10 kHz and allows for paresthesia-free pain relief, an advantage that distinguishes it from traditional stimulation therapy. Without paresthesias, patients with HF SCS do not experience position-dependent painful stimulation and do not have to experience treatment interruption during sleep. Lead migration is a well-known complication of conventional spinal cord stimulation and usually results in a loss of efficacy along with other unpleasant sensory symptoms. In this case report, we present an incidence of lead migration in HF SCS that resulted in paresthesias, a symptom not expected to occur in this novel therapy. CASE: The patient, a 60-year-old female with post-laminectomy syndrome, underwent a trial of HF SCS with standard lead placement at T8-T9. She initially had pain relief, but returned to the office on post-operative day 2 complaining of left chest wall and cardiac paresthesias, without frank pain or palpitations, in addition to loss of efficacy for her back and leg pain. Imaging showed that the leads had migrated, with one lead reaching the levels of T1-T3. CONCLUSION: While HF SCS has emerged as an effective paresthesia-free means of reducing back and leg pain, we provide the first report of paresthesias occurring with the HF SCS system as a result of cephalad lead migration. As HF SCS is only now being utilized as a treatment modality, we must remain cautious of potential adverse outcomes in patients, in particular above T8.