Citations

OBJECTIVE The principal tenet of minimally invasive neurosurgery is to limit approach-related tissue trauma, and a major assumption is that shorter incisions and smaller openings, in addition to protecting the brain, also have some perceptible benefits for the patient. This study tests the assumption of patient benefit and tries to define its significance. METHODS Procedures that fit the inclusion criteria of minimally invasive transcranial "keyhole" surgery were sought in the principal investigator’s archives. Each case was then paired with a classic procedure performed within the study time frame by the two senior authors, matched for pathology, size, location, and complexity. These pairs were then compared using a statistical tool (i.e., the Wilcoxon signed-rank test) designed for matched samples. Differences in estimated blood loss, duration of surgery, and length of hospital stay were examined. The narcotic needs during hospitalization were also examined as morphine milligram equivalent (MME). RESULTS Ninety patients were included in this study, evenly split between the minimally invasive surgery (MIS) and classic cohorts. Comparison of the 45 pairs showed no significant difference in estimated blood loss, though the operative times favored the MIS cohort significantly (mean ± SEM 310 ± 17 minutes vs 383 ± 24 minutes, p = 0.02). The length of stay was shorter for MIS, but the difference reached statistical significance only when cases with complications were excluded. The most important finding was that significantly less narcotic was needed during hospitalization in the MIS cohort (83 ± 15 MME vs 257 ± 47 MME). CONCLUSIONS The large difference in narcotic needs points to enhanced recovery from MIS techniques. While the difference in operative time did not lead to significantly shorter hospital stays, data suggest that minimally invasive technique may benefit the patient during recovery. This inspires further investigations to define the potentially positive impact on hospital and healthcare systems.

Objectives To compare electrical stimulation and speech perception in vestibular schwannoma (VS) patients across treatment modalities and standard cochlear implant (CI) patients. Study Design Retrospective review. Setting Tertiary academic center. Patients Sixty-seven CI ears consisting of 23 standard CI controls and 44 VS patients with ipsilateral CI. VS patients were separated by treatment modality: 24 microsurgical resection, 15 radiation therapy, and 5 observation. Eleven VS patients with CI did not receive auditory sensation from electrical stimulation. Interventions VS microsurgical resection, radiation therapy, and observation. Main Outcome Measures Threshold (T-levels), comfort (C-levels), consonant-nucleus-consonant (CNC) word score, and AzBio sentence recognition scores. Results Patients who underwent microsurgical resection required significantly higher (p < 0.001) T-levels and C-levels compared with the standard CI group. Stimulation levels in the VS radiation therapy and observation groups were higher but not significantly different compared with standard CI controls. Overall rate of CI nonstimulation across all VS patients was 25%: 38% for microsurgery and 13% for radiation. Average CNC score for microsurgery group was 18% compared with 44% for radiation, 55% for observation, and 68.5% for standard CI controls. CNC word and AzBio scores were significantly lower (p < 0.001) for the microsurgery group compared with standard CI group. Conclusions Resection may negatively affect auditory nerve function, leading to higher stimulation levels, increased risk of nonstimulation, and poorer postoperative CI speech outcomes compared with observation or radiosurgery. When medically appropriate, nonsurgical VS management may be used to allow for optimization of CI programming and postoperative hearing outcomes.

Abstract Most myelofibrosis (MF) drug approvals by Health Authorities are based on 1 or 2 outcome measures such as spleen volume reduction and/or improved quality-of-life. This 1–2 dimensional approach fails to capture the clinical complexity of MF. A European LeukemiaNet (ELN) taskforce developed a composite endpoint which allows multiple outcomes to be simultaneously measured. The panel used the Desirability-Of-Outcome-Ranking (DOOR) method to assign 25 outcomes into 4 quartiles based on a multi-dimensional desirability score and build a 5-layer composite outcome named Desirability-of-Myelofibrosis-Outcomes (DEMYO). Outcome operational definitions were tested by Delphi consensus and correlations with survival validated by a literature review. The outcomes assigned to the first two quartiles were negatively correlated with leukemia-free survival and survival. DEMYO comprehensively captures relevant MF clinical features and meaningful endpoints. Despite DEMYO requires validation based on available trial data, it is expected to improve the quality of Health Authority approvals for new drugs for MF.

Abstract TDP-43 pathology is a defining feature of Limbic-Predominant Age-Related TDP-43 Encephalopathy neuropathologic change (LATE-NC) and is frequently comorbid with Alzheimer’s disease neuropathologic change (ADNC). However, the molecular consequences of co-occurring LATE-NC and ADNC pathology (TDP-43, β-amyloid, and tau protein pathologies) remain unclear. Here, we conducted a comparative biochemical, molecular, and proteomic analysis of hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups to assess the impact of cryptic exon (CE) inclusion, phosphorylated TDP-43 pathology (pTDP-43), and AD-related pathologies (β-amyloid, and tau) on the proteome. ADNC+LATE-NC cases exhibited the highest burden of CE inclusion as quantified by measuring the levels of known TDP-43 regulated CEs within eight transcripts: STMN2, UNC13A, ELAVL3, KALRN, ARHGAP32, CAMK2B, PFKP, and SYT7 . While CE levels correlated with pTDP-43 pathology, they were more strongly correlated with each other, suggesting that the molecular signature of CE inclusion may serve as a more sensitive measure of TDP-43 dysfunction than pTDP-43 pathology alone. Unbiased classification based on the relative abundance of these eight CEs stratified individual cases into low, intermediate, and high CE burden subtypes, largely independent of β-amyloid and tau pathology. Proteome-wide correlation analysis revealed a bias toward reduced protein levels from genes harboring TDP-43-regulated CEs in cases with high cumulative CE burden. Notably, proteins significantly decreased under high CE burden included canonical STMN2, ELAVL3, and KALRN, as well as kinesin proteins that are genetically associated with amyotrophic lateral sclerosis. Co-expression network analysis identified both shared and distinct biological processes across CE subtypes and pathways associated with pTDP-43, tau, β-amyloid pathologies, and CE accumulation in the hippocampus. Protein modules associated with TDP-43 loss of function were prioritized by integrating proteomic data from TDP-43–depleted human neurons with the hippocampal co-expression network. Specifically, we observed decreased endosomal vesicle, microtubule-binding, and synaptic modules, alongside an increase in RNA-binding modules. These results provide new insights into the proteomic impact of CE burden across the spectrum of LATE and AD pathological severity, highlighting the molecular consequences of TDP-43 dysfunction in neurodegenerative disease

PURPOSE To report the results of the multicenter, open-label IRAKLIA trial (ClinicalTrials.gov identifier: NCT05405166 ) of isatuximab subcutaneous (SC) versus intravenous (IV), plus pomalidomide and dexamethasone, in relapsed/refractory multiple myeloma (MM), to our knowledge, the first phase III MM trial using an on-body injector (OBI). METHODS Patients with ≥1 prior line of therapy were randomly assigned 1:1 to Isa OBI (1,400 mg) or IV (10 mg/kg) once weekly in cycle (C)1 and then every 2 weeks, plus pomalidomide (4 mg once daily, day [D]1-21) and dexamethasone (40 mg once weekly [age ≥75: 20 mg]) and treated until progression, unacceptable toxicity, or patient request. Coprimary end points were overall response rate (ORR; noninferiority margin, 0.839) and Isa C trough (C6D1 predose; noninferiority margin, 0.8). Noninferiority of OBI versus IV was demonstrated if both coprimary end points achieved noninferiority. RESULTS IRAKLIA randomly assigned 531 patients (OBI, n=263; IV, n=268). After 12-month median follow-up, the ORR was 71.1% (OBI) and 70.5% (IV; relative risk, 1.008 [95% CI, 0.903 to 1.126]; lower CI exceeded noninferiority margin). The mean (standard deviation) C6D1 C trough was 499 (259) μg/mL (OBI) and 340 (169) μg/mL (IV). The C trough geometric mean ratio (90% CI) was 1.532 (1.316 to 1.784); lower CI exceeded noninferiority margin. Grade ≥3 treatment-emergent adverse event incidences were 81.7% (OBI) and 76.1% (IV); infusion reaction incidences were 1.5% and 25.0%. Injection site reactions occurred in 0.4% of OBI injections (all grade 1-2); 99.9% of injections completed without interruption. CONCLUSION IRAKLIA demonstrated efficacy and pharmacokinetic noninferiority between Isa OBI and IV. No unexpected safety signal was observed, with excellent local tolerability of Isa OBI. Efficacy and safety were comparable with Isa IV in ICARIA-MM, except the lower OBI infusion reaction rate. These results support potential use of the OBI, designed to improve practice efficiency.

CARTITUDE-1 evaluated ciltacabtagene autoleucel (cilta-cel) in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM). We describe overall survival (OS), ≥5-year progression-free outcomes, associated biomarkers, and safety, with a median study follow-up of 61.3 months. For the 97 treated patients, median OS was 60.7 months (95% CI, 41.9 to not estimable). One third (32/97) of patients remain alive and progression-free for ≥5 years after a single cilta-cel infusion, without maintenance treatment. Twelve of these patients treated at a single center underwent serial minimal residual disease (MRD) and positron emission tomography-computed tomography assessments, and all (100%) were MRD-negative (at least 10 −5 threshold) and imaging-negative at year 5 or later after cilta-cel. Baseline characteristics, including the presence of high-risk cytogenetics and extramedullary disease, were generally comparable for the 32 patients who were progression-free for ≥5 years versus patients who had progressive disease by year 5. A trend of lower baseline tumor burden, higher fraction of naïve T-cells in the cilta-cel drug product, higher T cell-to-neutrophil ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio were associated with ≥5-year progression-free status. The safety profile of cilta-cel remained consistent with previous reports. To our knowledge, our data provide the first evidence that cilta-cel is potentially curative in patients with RRMM.

OBJECTIVE While traditional literature in adult spinal deformity (ASD) examining mechanical complications has focused on proximal junctional kyphosis and failure, distal junctional failure (DJF) of constructs ending at the sacrum with or without spinopelvic fixation remains less explored. The current study sought to 1) propose a new DJF classification with a panel of experienced deformity surgeons, and 2) analyze intra- and interreliability of the novel classification. METHODS A prior review study was completed that identified all types of distal complications for lumbosacral fusions. A panel of 25 experienced spinal deformity surgeons used a modified Delphi approach with three rounds of review to create a classification system. Ten deformity surgeons then reviewed a representative series of 14 de-identified cases to assess the interrater reliability of the classification system using the intraclass correlation coefficient (ICC). A second round of review was conducted by each investigator to determine intrarater reliability using Cohen’s kappa coefficient. RESULTS Complications were classified as acute (< 90 days from the date of surgery) or chronic (≥ 3 months from the date of surgery). Acute failures included mechanical failure of the screws or screw-rod interface, such as pelvic set plug dissociation, tulip head dissociation, and fracture of the pelvic screw at any point along its trajectory. Fractures of the rod (proximal vs distal to S1) and distal bony anatomy (sacrum vs pelvis) were included, as was failure of the offset connector. Chronic failures also consisted of pseudarthrosis at distal levels, sacroiliac joint (SIJ) pain, screw halo formation, and painful screw prominence. The intrarater and interrater reliability were both high with Cohen’s kappa of 0.91 and an ICC of 0.98, respectively. CONCLUSIONS These data provide a comprehensive and systematic classification scheme of distal complications following long-segment ASD fusion to the sacrum. This new paradigm will allow for more detailed and consistent reporting of distal junctional complications following spinopelvic fusion, with or without supplemental pelvic fixation and/or concomitant SIJ fusion. This classification scheme resulted in high intra- and interrater reliability.

Abstract A variety of genetic diseases of the kidney tubule are amenable to correction via gene therapy. However, gene delivery to renal tubule epithelial cells mediated by viral vectors via the blood is inefficient due to the permselectivity of the glomerular barrier. We hypothesized that effacement of podocyte foot processes would disrupt typical glomerular limitations on filtration and make renal tubule epithelial cells susceptible to transduction from viral vectors delivered intravenously. We determined that adeno-associated virus serotype 8 (AAV8) transduced significantly more epithelial cells in the kidney under the conditions of LPS-induced proteinuria. Use of AAV1 in tandem with LPS-induced proteinuria yielded an ideal two-pronged effect of both partially detargeting the liver and transducing the kidney with a higher bioluminescent signal than AAV8 did, and at half of the dose. Using adenovirus serotype 5 (Ad5) in conjunction with LPS-induced proteinuria showed that kidney transduction was enhanced, but only in glomerular cells. These studies mechanistically test the efficacy of different viral vectors and demonstrate their capacity to transduce kidney epithelial cells. This is a fundamental step in designing future treatments for kidney gene therapy. Significance Statement The slit diaphragms in the glomerulus of the kidney are too narrow to allow most solute from the blood to enter the nephron. As a result, large particles such as viral vectors generally cannot access tubule epithelial cells necessary to correct genetic disorders. In this study, mice are induced into a state of proteinuria and subsequently administered viral vectors intravenously. This group of mice had higher levels of transduced kidney epithelial cells than the control (non-proteinuria) group. The induction of transient proteinuria before intravenous viral vector administration is a novel approach that could make tubulopathies treatable via gene therapy in both animal models and humans.