Spinal cord stimulation for treatment of chronic neuropathic pain in adolescent patients: a single-institution series, systematic review, and individual participant data meta-analysis.

OBJECTIVE: Neuropathic pain is undertreated in children. Neurosurgical treatments of pediatric chronic pain are limited by the absence of both US Food and Drug Administration approval and pediatric-specific hardware, as well as weak referral patterns due to a lack of physician education. This study presents a single-institution retrospective case series of spinal cord stimulation (SCS) in children ≤ 19 years of age and a systematic review of SCS in children. The authors' findings may further validate the role of SCS as an effective treatment modality for varied neuropathic pain syndromes found in pediatric patients. METHODS: The study was a single-center, single-surgeon, retrospective case series of individuals treated between July 2017 and May 2022. The outcomes for pediatric patients with chronic neuropathic pain syndromes indicated by the multidisciplinary pain clinic for evaluation for SCS were cataloged. A systematic review and individual participant data (IPD) meta-analysis was performed for cases treated until May 2022, using PubMed, EMBASE, and Scopus to characterize outcomes of children with neuropathic pain treated with SCS. RESULTS: Twelve patients were evaluated and 9 were indicated for percutaneous or buried lead trials. Seven female and 2 male patients between the ages of 13 and 19 years were implanted with trial leads. Eight of 9 (89%) patients went on to receive permanent systems. The average trial length was 6 days, and the length of stay for both trial and implant was less than 1 day. Complication rates due to CSF leaks were 22% and 0% for trial and implant, respectively. Visual analog scale pain scores decreased from 9.2 to 2.9 (p = 0.0002) and the number of medications decreased from 4.9 to 2.1 (p = 0.0005). Functional status also improved for each patient. A systematic review identified 13 studies describing pediatric patients with SCS, including 12 providing IPD on 30 patients. In the IPD meta-analysis, pain was reduced in 16/16 (100%) of patients following surgery and in 25/26 (96.2%) at last follow-up. Medication use was decreased in 16/21 (76.2%), and functional outcomes were improved in 29/29 (100%). The complication rate was 5/30 (16.7%). CONCLUSIONS: SCS effectively decreases pain and medication use for pediatric neuropathic pain syndromes. Patients also report improved functional status, including improved matriculation, gainful employment, and physical activity. There is minimal high-quality literature describing neuromodulation for pain in children. Neuromodulation should be considered earlier as a viable alternative to escalating use of multiple drugs and as a potential mechanism to address tolerance, dependence, and addiction in pediatric patients.

Preoperative and Postoperative Gait Analysis and Video for Selective Dorsal Rhizotomy in Focal Hemiplegic Spasticity: 2-Dimensional Operative Video.

Selective dorsal rhizotomy (SDR) has been a well-established neurosurgical treatment option for ambulatory children with spastic diplegic cerebral palsy to reduce spasticity. Outcomes for SDR for spastic lower extremity hemiparesis has been less well described. In our experience, hemi-SDR has been an excellent intervention for children with suboptimal spasticity control despite maximizing pharmacologic and chemodenervation treatments. In Video 1, we demonstrate a focal segmental hemi-SDR at the L5-S1 level in a 7-year-old male patient with spastic hemiparesis secondary to a dysembryoplastic neuroepithelial tumor in the right inferior frontoparietal area. Rhizotomy was performed with identification and selective sectioning of dorsal nerve roots with abnormal stimulation patterns as determined by electrophysiology and clinical correlation. Dorsal nerve root fibers with unsustained discharges were spared. Postoperatively, the patient participated well in inpatient and outpatient therapies with significant progress in his mobility and activities of daily living. The patient showed improvement in gait velocity (51%), internal pressure ratio (+0.05), and step length (41% on the left and 27% on the right) 20 months after hemi-SDR. He also demonstrated a step length ratio closer to 1 (0.89) showing a more equal step length bilaterally and improved weight acceptance on the affected side. There were no changes observed on the left upper extremity. This positive outcome on spasticity control and function supports the need for further prospective studies for hemi-SDR as a treatment option for children with spastic hemiparesis.

HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma.

PURPOSE: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1ß, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients. PATIENTS AND METHODS: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies. RESULTS: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance. CONCLUSIONS: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).

Targeting renal cell carcinoma with a HIF-2 antagonist.

Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1ß) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1ß, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.

Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes.

To further understand the molecular distinctions between kidney cancer subtypes, we analyzed exome, transcriptome and copy number alteration data from 167 primary human tumors that included renal oncocytomas and non-clear cell renal cell carcinomas (nccRCCs), consisting of papillary (pRCC), chromophobe (chRCC) and translocation (tRCC) subtypes. We identified ten significantly mutated genes in pRCC, including MET, NF2, SLC5A3, PNKD and CPQ. MET mutations occurred in 15% (10/65) of pRCC samples and included previously unreported recurrent activating mutations. In chRCC, we found TP53, PTEN, FAAH2, PDHB, PDXDC1 and ZNF765 to be significantly mutated. Gene expression analysis identified a five-gene set that enabled the molecular classification of chRCC, renal oncocytoma and pRCC. Using RNA sequencing, we identified previously unreported gene fusions, including ACTG1-MITF fusion. Ectopic expression of the ACTG1-MITF fusion led to cellular transformation and induced the expression of downstream target genes. Finally, we observed upregulation of the anti-apoptotic factor BIRC7 in MiTF-high RCC tumors, suggesting a potential therapeutic role for BIRC7 inhibitors.

XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis.

Women are more susceptible to multiple sclerosis (MS) and have more robust immune responses than men. However, men with MS tend to demonstrate a more progressive disease course than women, suggesting a disconnect between the severity of an immune attack and the CNS response to a given immune attack. We have previously shown in an MS model, experimental autoimmune encephalomyelitis, that autoantigen-sensitized XX lymph node cells, compared with XY, are more encephalitogenic. These studies demonstrated an effect of sex chromosomes in the induction of immune responses, but did not address a potential role of sex chromosomes in the CNS response to immune-mediated injury. Here, we examined this possibility using XX versus XY bone marrow chimeras reconstituted with a common immune system of one sex chromosomal type. We found that experimental autoimmune encephalomyelitis mice with an XY sex chromosome complement in the CNS, compared with XX, demonstrated greater clinical disease severity with more neuropathology in the spinal cord, cerebellum, and cerebral cortex. A candidate gene on the X chromosome, toll-like receptor 7, was then examined. Toll-like receptor 7 expression in cortical neurons was higher in mice with XY compared with mice with XX CNS, consistent with the known neurodegenerative role for toll-like receptor 7 in neurons. These results suggest that sex chromosome effects on neurodegeneration in the CNS run counter to effects on immune responses, and may bear relevance to the clinical enigma of greater MS susceptibility in women but faster disability progression in men. This is a demonstration of a direct effect of sex chromosome complement on neurodegeneration in a neurological disease.

Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERα signaling on astrocytes but not through ERß signaling on astrocytes or neurons.

Estrogens can signal through either estrogen receptor α (ERα) or ß (ERß) to ameliorate experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model of multiple sclerosis (MS). Cellular targets of estrogen-mediated neuroprotection are still being elucidated. Previously, we demonstrated that ERα on astrocytes, but not neurons, was critical for ERα ligand-mediated neuroprotection in EAE, including decreased T-cell and macrophage inflammation and decreased axonal loss. Here, we determined whether ERß on astrocytes or neurons could mediate neuroprotection in EAE, by selectively removing ERß from either of these cell types using Cre-loxP gene deletion. Our results demonstrated that, even though ERß ligand treatment was neuroprotective in EAE, this neuroprotection was not mediated through ERß on either astrocytes or neurons and did not involve a reduction in levels of CNS inflammation. Given the differential neuroprotective and anti-inflammatory effects mediated via ERα versus ERß on astrocytes, we looked for molecules within astrocytes that were affected by signaling through ERα, but not ERß. We found that ERα ligand treatment, but not ERß ligand treatment, decreased expression of the chemokines CCL2 and CCL7 by astrocytes in EAE. Together, our data show that neuroprotection in EAE mediated via ERß signaling does not require ERß on either astrocytes or neurons, whereas neuroprotection in EAE mediated via ERα signaling requires ERα on astrocytes and reduces astrocyte expression of proinflammatory chemokines. These findings reveal important cellular differences in the neuroprotective mechanisms of estrogen signaling through ERα and ERß in EAE.