Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

BACKGROUND: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known. METHODS: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point. RESULTS: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib. CONCLUSIONS: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).

Early life adversity predicts an accelerated cellular aging phenotype through early timing of puberty.

BACKGROUND: The current study examined if early adversity was associated with accelerated biological aging, and if effects were mediated by the timing of puberty. METHODS: In early mid-life, 187 Black and 198 White (Mage = 39.4, s.d.age = 1.2) women reported on early abuse and age at first menstruation (menarche). Women provided saliva and blood to assess epigenetic aging, telomere length, and C-reactive protein. Using structural equation modeling, we created a latent variable of biological aging using epigenetic aging, telomere length, and C-reactive protein as indicators, and a latent variable of early abuse using indicators of abuse/threat events before age 13, physical abuse, and sexual abuse. We estimated the indirect effects of early abuse and of race on accelerated aging through age at menarche. Race was used as a proxy for adversity in the form of systemic racism. RESULTS: There was an indirect effect of early adversity on accelerated aging through age at menarche (b = 0.19, 95% CI 0.03-0.44), in that women who experienced more adversity were younger at menarche, which was associated with greater accelerated aging. There was also an indirect effect of race on accelerated aging through age at menarche (b = 0.25, 95% CI 0.04-0.52), in that Black women were younger at menarche, which led to greater accelerated aging. CONCLUSIONS: Early abuse and being Black in the USA may both induce a phenotype of accelerated aging. Early adversity may begin to accelerate aging during childhood, in the form of early pubertal timing.

Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial.

BACKGROUND: In the CheckMate 9ER trial, patients with advanced renal cell carcinoma who received first-line nivolumab plus cabozantinib had significantly better progression-free survival compared with those given sunitinib. In this study, we aimed to describe the patient-reported outcome (PRO) results from CheckMate 9ER. METHODS: In this open-label, randomised, phase 3 trial done in 125 cancer centres, urology centres, and hospitals across 18 countries, patients aged 18 years or older with previously untreated advanced renal cell carcinoma with a clear-cell component, a Karnofsky performance status of 70% or more, and available tumour tissue were randomly assigned (1:1) via interactive response technology to nivolumab 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg per day, or oral sunitinib 50 mg per day monotherapy for 4 weeks in 6-week cycles. The primary endpoint of progression-free survival was reported previously. PROs were analysed as prespecified exploratory endpoints at common timepoints (at baseline and every 6 weeks) until week 115. Disease-related symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the three-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. PRO analyses were done in the intention-to-treat population. Change from baseline was assessed using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events. This study is registered with ClinicalTrials.gov, NCT03141177, and is closed to recruitment. FINDINGS: Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to nivolumab plus cabozantinib and 328 to sunitinib. Median follow-up was 23·5 months (IQR 21·0-26·5). At baseline, patients in both groups reported low symptom burden (FKSI-19 disease-related symptoms version 1 mean scores at baseline were 30·24 [SD 5·19] for the nivolumab plus cabozantinib group and 30·06 [5·03] for the sunitinib group). Change from baseline in PRO scores indicated that nivolumab plus cabozantinib was associated with more favourable outcomes versus sunitinib (treatment difference 2·38 [95% CI 1·20-3·56], nominal p<0·0001, effect size 0·33 [95% CI 0·17-0·50] for FKSI-19 total score; 1·33 [0·84-1·83], nominal p<0·0001, 0·45 [0·28-0·61] for FKSI-19 disease-related symptoms version 1; 3·48 [1·58-5·39], nominal p=0·0004, 0·30 [0·14-0·47] for EQ-5D-3L VAS; and 0·04 [0·01-0·07], nominal p=0·0036, 0·25 [0·08-0·41] for EQ-5D-3L UK utility index), reaching significance at most timepoints. Nivolumab plus cabozantinib was associated with decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib (first deterioration event hazard ratio 0·70 [95% CI 0·56-0·86], nominal p=0·0007; confirmed deterioration event 0·63 [0·50-0·80], nominal p=0·0001). INTERPRETATION: PROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma. FUNDING: Bristol Myers Squibb.

Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial.

BACKGROUND: In the primary analysis of CheckMate 9ER, nivolumab plus cabozantinib showed superior progression-free survival, overall survival, and objective response over sunitinib in patients with previously untreated advanced renal cell carcinoma (median follow-up of 18·1 months). Here, we report extended follow-up of overall survival and updated efficacy and safety. METHODS: This open-label, randomised, phase 3 trial was done in 125 hospitals and cancer centres across 18 countries. We included patients aged 18 years or older with previously untreated advanced or metastatic clear-cell renal cell carcinoma, a Karnofsky performance status of 70% or higher, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by the investigator, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumour tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily (4 weeks per 6-week cycle). Randomisation, stratified by IMDC risk status, tumour PD-L1 expression, and geographical region, was done by permuted block within each stratum using a block size of four, via an interactive response system. The primary endpoint was progression-free survival by blinded independent central review. Overall survival was a secondary endpoint (reported here as the preplanned final analysis according to the protocol). Efficacy was assessed in all randomly assigned patients; safety was assessed in all patients who received at least one dose of any study drug. This ongoing study, closed to recruitment, is registered with ClinicalTrials.gov, NCT03141177. FINDINGS: Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to the nivolumab plus cabozantinib group and 328 to the sunitinib group. With an extended follow-up (data cutoff of June 24, 2021; median 32·9 months [IQR 30·4-35·9]), median overall survival was 37·7 months (95% CI 35·5-not estimable) in the nivolumab plus cabozantinib group and 34·3 months (29·0-not estimable) in the sunitinib group (hazard ratio [HR] 0·70 [95% CI 0·55-0·90], p=0·0043) and updated median progression-free survival was 16·6 months (12·8-19·8) versus 8·3 months (7·0-9·7; HR 0·56 [95% CI 0·46-0·68], p<0·0001). Grade 3-4 treatment-related adverse events occurred in 208 (65%) of 320 patients with nivolumab plus cabozantinib versus 172 (54%) of 320 with sunitinib. The most common grade 3-4 treatment-related adverse events were hypertension (40 [13%] of 320 patients in the nivolumab plus cabozantinib group vs 39 [12%] of 320 in the sunitinib group), palmar-plantar erythrodysaesthesia (25 [8%] vs 26 [8%]), and diarrhoea (22 [7%] vs 15 [5%]). Grade 3-4 treatment-related serious adverse events occurred in 70 (22%) of 320 patients in the nivolumab plus cabozantinib group and 31 (10%) of 320 in the cabozantinib group. One additional treatment-related death occurred with sunitinib (sudden death). INTERPRETATION: With extended follow-up and preplanned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated improved efficacy versus sunitinib, further supporting the combination in the first-line treatment of advanced renal cell carcinoma. FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.

Safety and efficacy of nivolumab plus ipilimumab in patients with advanced renal cell carcinoma with brain metastases: CheckMate 920.

BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long-term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954) evaluated the safety and efficacy of NIVO + IPI in a cohort that included patients with aRCC and brain metastases, as reported here. METHODS: Patients with previously untreated aRCC and asymptomatic brain metastases received NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × 4 followed by NIVO 480 mg every 4 weeks. The primary end point was the incidence of grade ≥3 immune-mediated adverse events (imAEs) within 100 days of the last dose of study drug. Key secondary end points were progression-free survival and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (both determined by the investigator). Exploratory end points included overall survival, among others. RESULTS: After a minimum follow-up of 24.5 months (N = 28), no grade 5 imAEs occurred. The most common grade 3 and 4 imAEs were diarrhea/colitis (n = 2; 7%) and hypophysitis, rash, hepatitis, and diabetes mellitus (n = 1 each; 4%). The objective response rate was 32% (95% CI, 14.9%-53.5%) with a median duration of response of 24.0 months; 4 of 8 responders remained without reported progression. Seven patients (25%) had intracranial progression. The median progression-free survival was 9.0 months (95% CI, 2.9-12.0 months), and the median overall survival was not reached (95% CI, 14.1 months to not estimable). CONCLUSIONS: In patients who had previously untreated aRCC and brain metastases-a population with a high unmet medical need that often is underrepresented in clinical trials-the approved regimen of NIVO + IPI followed by NIVO showed encouraging antitumor activity and no new safety signals.

A phase 2 study of glembatumumab vedotin, an antibody-drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma.

BACKGROUND: Glembatumumab vedotin is an antibody-drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma. METHODS: This single-arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry. RESULTS: In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6-5.5 months), and the median OS was 9.0 months (95% CI, 6.1-11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB-positive epithelial cells. CONCLUSIONS: Glembatumumab vedotin had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Treatment-related rash may be associated with response.

MT-PCR panel detection of canine parvovirus (CPV-2): Vaccine and wild-type CPV-2 can be difficult to differentiate in canine diagnostic fecal samples.

Canine parvovirus (CPV-2) remains an important cause of devastating enteritis in young dogs. It can be successfully prevented with live attenuated CPV-2 vaccines when given at the appropriate age and in the absence of maternal antibody interference. Rapid diagnosis of parvoviral enteritis in young dogs is essential to ensuring suitable barrier nursing protocols within veterinary hospitals. The current diagnostic trend is to use multiplexed PCR panels to detect an array of pathogens commonly responsible for diarrhea in dogs. The multiplexed PCR assays do not distinguish wild from vaccine CPV-2. They are highly sensitive and detect even a low level of virus shedding, such as those caused by the CPV-2 vaccine. The aim of this study was to identify the CPV-2 subtypes detected in diagnostic specimens and rule out occult shedding of CPV-2 vaccine strains. For a total of 21 samples that tested positive for CPV-2 in a small animal fecal pathogens diagnostic multiplexed tandem PCR (MT-PCR) panel during 2014-2016 we partially characterized the VP2 gene of CPV-2. Vaccine CPV-2 strain, wild type CPV-2a subtypes and vaccine-like CPV-2b subtypes were detected. High copy number was indicative of wild-type CPV-2a presence, but presence of vaccine-like CPV-2b had a variable copy number in fecal samples. A yardstick approach to a copy number or Ct-value to discriminate vaccine strain from a wild type virus of CPV-2 can be, in some cases, potentially misleading. Therefore, discriminating vaccine strain from a wild type subtype of CPV-2 remains ambitious.

Robot-navigated pedicle screw insertion can reduce intraoperative blood loss and length of hospital stay: analysis of 1,633 patients utilizing propensity score matching.

BACKGROUND CONTEXT: Navigation and robotic technologies have emerged as an alternative option to conventional freehand techniques for pedicle screw insertion. However, the effectiveness of these technologies in reducing the perioperative complications of spinal fusion surgery remains limited due to the small cohort size in the existing literature. PURPOSE: To investigate whether utilization of robotically navigated pedicle screw insertion can reduce the perioperative complications of spinal fusion surgery-including reoperations-with a sizeable cohort. STUDY DESIGN: Retrospective study. PATIENT SAMPLE: Patients who underwent primary lumbar fusion surgery between 2019 and 2022. OUTCOME MEASURES: Perioperative complications including readmission, reoperation, its reasons, estimated blood loss, operative time, and length of hospital stay. METHODS: Patients' data were collected including age, sex, race, body mass index, upper-instrumented vertebra, lower-instrumented vertebra, number of screws inserted, and primary procedure name. Patients were classified into the following two groups: freehand group and robot group. The variable-ratio greedy matching was utilized to create the matched cohorts by propensity score and compared the outcomes between the two group. RESULTS: A total of 1,633 patients who underwent primary instrumented spinal lumbar fusion surgery were initially identified (freehand 1,286; robot 347). After variable ratio matching was performed with age, sex, body mass index, fused levels, and upper instrumented vertebrae level, 694 patients in the freehand group and 347 patients in robot groups were selected. The robot group showed less estimated blood loss (418.9±398.9 vs 199.2±239.6 ml; p<.001), shorter LOS (4.1±3.1 vs 3.2±3.0 days; p<.001) and similar operative time (212.5 vs 222.0 minutes; p=.151). Otherwise, there was no significant difference in readmission rate (3.6% vs 2.6%; p=.498), reoperation rate (3.2% vs 2.6%; p=.498), and screw malposition requiring reoperation (five cases, 0.7% vs one case, 0.3%; p=1.000). CONCLUSIONS: Perioperative complications requiring readmission and reoperation were similar between fluoroscopy guided freehand and robotic surgery. Robot-guided pedicle screw insertion can enhance surgical efficiency by reducing intraoperative blood loss and length of hospital stay without extending operative time.

Decreased but persistent epigenetic age acceleration is associated with changes in T-cell subsets after initiation of highly active antiretroviral therapy in persons living with HIV.

Introduction: Persons living with HIV (PLWH) experience the early onset of age-related illnesses, even in the setting of successful human immunodeficiency virus (HIV) suppression with highly active antiretroviral therapy (HAART). HIV infection is associated with accelerated epigenetic aging as measured using DNA methylation (DNAm)-based estimates of biological age and of telomere length (TL). Methods: DNAm levels (Infinium MethylationEPIC BeadChip) from peripheral blood mononuclear cells from 200 PLWH and 199 HIV-seronegative (SN) participants matched on chronologic age, hepatitis C virus, and time intervals were used to calculate epigenetic age acceleration, expressed as age-adjusted acceleration residuals from 4 epigenetic clocks [Horvath's pan-tissue age acceleration residual (AAR), extrinsic epigenetic age acceleration (EEAA), phenotypic epigenetic age acceleration (PEAA), and grim epigenetic age acceleration (GEAA)] plus age-adjusted DNAm-based TL (aaDNAmTL). Epigenetic age acceleration was compared for PLWH and SN participants at two visits: up to 1.5 years prior and 2-3 years after HAART (or equivalent visits). Flow cytometry was performed in PLWH and SN participants at both visits to evaluate T-cell subsets. Results: Epigenetic age acceleration in PLWH decreased after the initiation of HAART but remained greater post-HAART than that in age-matched SN participants, with differences in medians of 6.6, 9.1, and 7.7 years for AAR, EEAA, and PEAA, respectively, and 0.39 units of aaDNAmTL shortening (all p < 0.001). Cumulative HIV viral load after HAART initiation was associated with some epigenetic acceleration (EEAA, PEAA, and aaDNAmTL), but even PLWH with undetectable HIV post-HAART showed persistent epigenetic age acceleration compared to SN participants (p < 0.001). AAR, EEAA, and aaDNAmTL showed significant associations with total, naïve, and senescent CD8 T-cell counts; the total CD4 T-cell counts were associated with AAR, EEAA, and PEAA (p = 0.04 to <0.001). In an epigenome-wide analysis using weighted gene co-methylation network analyses, 11 modules demonstrated significant DNAm differences pre- to post-HAART initiation. Of these, nine were previously identified as significantly different from pre- to post-HIV infection but in the opposite direction. Discussion: In this large longitudinal study, we demonstrated that, although the magnitude of the difference decreases with HAART is associated with the cumulative viral load, PLWH are persistently epigenetically older than age-matched SN participants even after the successful initiation of HAART, and these changes are associated with changes in T-cell subsets.

Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV.

Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood. Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2-3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT). Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10-7) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis. Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.

Level-specific Comparison of 3D Navigated and Robotic Arm-Guided Screw Placement: An Accuracy Assessment of 1210 Pedicle Screws in Lumbar Surgery.

BACKGROUND CONTEXT: Robotic spine surgery, utilizing 3D imaging and robotic arms, has been shown to improve the accuracy of pedicle screw placement compared to conventional methods, although its superiority remains under debate. There are few studies evaluating the accuracy of 3D navigated versus robotic-guided screw placement across lumbar levels, addressing anatomical challenges to refine surgical strategies and patient safety. PURPOSE: This study aims to investigate the pedicle screw placement accuracy between 3D navigation and robotic arm-guided systems across distinct lumbar levels. STUDY DESIGN: A retrospective review of a prospectively collected registry PATIENT SAMPLE: Patients undergoing fusion surgery with pedicle screw placement in the prone position, using either via 3D image navigation only or robotic arm guidance OUTCOME MEASURES: Radiographical screw accuracy was assessed by the postoperative computed tomography (CT) according to the Gertzbein-Robbins classification, particularly focused on accuracy at different lumbar levels. METHODS: Accuracy of screw placement in the 3D navigation (Nav group) and robotic arm guidance (Robo group) was compared using Chi-squared test/Fisher's exact test with effect size measured by Cramer's V, both overall and at each specific lumbosacral spinal level. RESULTS: A total of 321 patients were included (Nav, 157; Robo, 189) and evaluated 1210 screws (Nav, 651; Robo 559). The Robo group demonstrated significantly higher overall accuracy (98.6 vs. 93.9%; P<0.001, V=0.25). This difference of no breach screw rate was signified the most at the L3 level (No breach screw: Robo 91.3 vs. 57.8%, P<0.001, V=0.35) followed by L4 (89.6 vs. 64.7%, P<0.001, V=0.28), and L5 (92.0 vs. 74.5%, P<0.001, V=0.22). However, screw accuracy at S1 was not significant between the groups (81.1 vs. 72.0%, V=0.10). CONCLUSION: This study highlights the enhanced accuracy of robotic arm-guided systems compared to 3D navigation for pedicle screw placement in lumbar fusion surgeries, especially at the L3, L4, and L5 levels. However, at the S1 level, both systems exhibit similar effectiveness, underscoring the importance of understanding each system's specific advantages for optimization of surgical complications.

Epigenetic predictors of species maximum life span and other life-history traits in mammals.

By analyzing 15,000 samples from 348 mammalian species, we derive DNA methylation (DNAm) predictors of maximum life span (R = 0.89), gestation time (R = 0.96), and age at sexual maturity (R = 0.85). Our maximum life-span predictor indicates a potential innate longevity advantage for females over males in 17 mammalian species including humans. The DNAm maximum life-span predictions are not affected by caloric restriction or partial reprogramming. Genetic disruptions in the somatotropic axis such as growth hormone receptors have an impact on DNAm maximum life span only in select tissues. Cancer mortality rates show no correlation with our epigenetic estimates of life-history traits. The DNAm maximum life-span predictor does not detect variation in life span between individuals of the same species, such as between the breeds of dogs. Maximum life span is determined in part by an epigenetic signature that is an intrinsic species property and is distinct from the signatures that relate to individual mortality risk.

Impact of Preoperative Symptom Duration on Patient-Reported Outcomes Following Cervical Disc Replacement for Cervical Radiculopathy.

STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To determine the impact of preoperative symptom duration on postoperative functional outcomes following cervical disc replacement (CDR) for radiculopathy. SUMMARY OF BACKGROUND DATA: CDR has emerged as a reliable and efficacious treatment option for degenerative cervical spine pathologies. The relationship between preoperative symptom duration and outcomes following CDR is not well established. METHODS: Patients with radiculopathy without myelopathy who underwent primary 1- or 2-level CDRs were included and divided into shorter (<6 mo) and prolonged (≥6 mo) cohorts based on preoperative symptom duration. Patient-reported outcome measures (PROMs) included Neck Disability Index (NDI), Visual Analog Scale (VAS) Neck and Arm. Change in PROM scores and minimal clinically important difference (MCID) rates were calculated. Analyses were conducted on the early (within 3 mo) and late (6 mo-2 y) postoperative periods. RESULTS: A total of 201 patients (43.6±8.7 y, 33.3% female) were included. In both early and late postoperative periods, the shorter preoperative symptom duration cohort experienced significantly greater change from preoperative PROM scores compared to the prolonged symptom duration cohort for NDI, VAS-Neck, and VAS-Arm. The shorter symptom duration cohort achieved MCID in the early postoperative period at a significantly higher rate for NDI (78.9% vs. 54.9%, P=0.001), VAS-Neck (87.0% vs. 56.0%, P<0.001), and VAS-Arm (90.5% vs. 70.7%, P=0.002). Prolonged preoperative symptom duration (≥6 mo) was identified as an independent risk factor for failure to achieve MCID at the latest timepoint for NDI (OR: 2.9, 95% CI: 1.2-6.9, P=0.016), VAS-Neck (OR: 9.8, 95% CI: 3.7-26.0, P<0.001), and VAS-Arm (OR: 7.5, 95% CI: 2.5-22.5, P<0.001). CONCLUSIONS: Our study demonstrates improved patient-reported outcomes for those with shorter preoperative symptom duration undergoing CDR for radiculopathy, suggesting delayed surgical intervention may result in poorer outcomes and greater postoperative disability. LEVEL OF EVIDENCE: III.

Morbidly Obese Patients Have Similar Clinical Outcomes and Recovery Kinetics After Minimally Invasive Decompression.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To study the impact of class 2/3 obesity (body mass index, BMI >35) on outcomes following minimally invasive decompression. SUMMARY OF BACKGROUND DATA: No previous study has analyzed the impact of class 2/3 obesity on outcomes following minimally invasive decompression. METHODS: Patients who underwent primary minimally invasive decompression were divided into 4 cohorts based on their BMI: normal (BMI 18.5 to <25), overweight (25 to <30), class 1 obesity (30 to <35), and class 2/3 obesity (BMI >35). Outcome measures were: 1) intraoperative variables: operative time, estimated blood loss (EBL); 2) patient reported outcome measures (PROMs) (Oswestry Disability Index, ODI; Visual Analog Scale, VAS back and leg; 12-Item Short Form Survey Physical Component Score, SF-12 PCS); 3) global rating change (GRC), minimal clinically important difference (MCID), and patient acceptable symptom state (PASS) achievement rates; 4) return to activities; and 5) complication and reoperation rates. RESULTS: 838 patients were included (226 normal, 357 overweight, 179 class 1 obesity, 76 class 2/3 obesity). Class 1 and 2/3 obesity groups had significantly greater operative times compared to the other groups. Class 2/3 obesity group had worse ODI, VAS back and SF-12 PCS preoperatively, worse ODI, VAS back, VAS leg and SF-12 PCS at <6 months, and worse ODI and SF-12 PCS at >6 months. However, they had significant improvement in all PROMs at both postoperative timepoints and the magnitude of improvement was similar to other groups. No significant differences were found in MCID and PASS achievement rates, likelihood of betterment on the GRC scale, return to activities, and complication/reoperation rates. CONCLUSIONS: Class 2/3 obese patients have worse PROMs pre- and post-operatively. However, they show similar improvement in PROMs, MCID and PASS achievement rates, likelihood of betterment, recovery kinetics, and complication/reoperation rates as other BMI groups following minimally invasive decompression.

Temporal Trends of Improvement After Minimally Invasive Transforaminal Lumbar Interbody Fusion.

STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To analyze temporal trends in improvement after minimally invasive transforaminal lumbar interbody fusion (MIS TLIF). SUMMARY OF BACKGROUND DATA: Although several studies have shown that patients improve significantly after MIS TLIF, evidence regarding the temporal trends in improvement is still largely lacking. METHODS: Patients who underwent primary single-level MIS TLIF for degenerative conditions of the lumbar spine and had a minimum of 2-year follow-up were included. Outcome measures were: 1) patient reported outcome measures (PROMs) (Oswestry Disability Index, ODI; Visual Analog Scale, VAS back and leg; 12-Item Short Form Survey Physical Component Score, SF-12 PCS); 2) global rating change (GRC); 3) minimal clinically important difference (MCID); and 4) return to activities. Timepoints analyzed were preoperative, 2 weeks, 6 weeks, 3 months, 6 months, 1 year, and 2 years. Trends across these timepoints were plotted on graphs. RESULTS: 236 patients were included. VAS back and VAS leg were found to have statistically significant improvement compared to the previous timepoint up to 3 months after surgery. ODI and SF-12 PCS were found to have statistically significant improvement compared to the previous timepoint up to 6 months after surgery. Beyond these timepoints, there was no significant improvement in PROMs. 80% of patients reported feeling better compared to preoperative by 3 months. >50% of patients achieved MCID in all PROMs by 3 months. Most patients returned to driving, returned to work, and discontinued narcotics at an average of 21, 20, and 10 days, respectively. CONCLUSIONS: Patients are expected to improve up to 6 months after MIS TLIF. Back pain and leg pain improve up to 3 months and disability and physical function improve up to 6 months. Beyond these timepoints, the trends in improvement tend to reach a plateau. 80% of patients feel better compared to preoperative by 3 months after surgery.

Predictors for Failure to Respond to Erector Spinae Plane Block Following Minimally Invasive Transforaminal Lumbar Interbody Fusion.

STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To identify the risk factors associated with failure to respond to erector spinae plane (ESP) block following minimally invasive transforaminal lumbar interbody fusion (MI-TLIF). SUMMARY OF BACKGROUND DATA: ESP block is an emerging opioid-sparing regional anesthetic that has been shown to reduce immediate postoperative pain and opioid demand following MI-TLIF-however, not all patients who receive ESP blocks perioperatively experience a reduction in immediate postoperative pain. METHODS: This was a retrospective review of consecutive patients undergoing 1-level MI-TLIF who received ESP blocks by a single anesthesiologist perioperatively at a single institution. ESP blocks were administered in the OR following induction. Failure to respond to ESP block was defined as patients with a first numerical rating scale (NRS) score post-surgery of >5.7 (mean immediate postoperative NRS score of control cohort undergoing MI TLIF without ESP block). Multivariable logistic regressions were performed to identify predictors for failure to respond to ESP block. RESULTS: A total of 134 patients were included (mean age 60.6 years, 43.3% females). The median and interquartile range (IQR) first pain score post-surgery was 2.5 (0.0-7.5). Forty-nine (36.6%) of patients failed to respond to ESP block. In the multivariable regression analysis, several independent predictors for failure to respond to ESP block following MI TLIF were identified: female sex (OR 2.33, 95% CI 1.04-5.98, P=0.040), preoperative opioid use (OR 2.75, 95% CI 1.03- 7.30, P=0.043), anxiety requiring medication (OR 3.83, 95% CI 1.27-11.49, P=0.017), and hyperlipidemia (OR 3.15, 95% CI 1.31-7.55, P=0.010). CONCLUSIONS: Our study identified several predictors for failure to respond to ESP block following MI TLIF including female sex, preoperative opioid pain medication use, anxiety, and hyperlipidemia. These findings may help inform the approach to counseling patients on perioperative outcomes and pain expectations following MI-TLIF with ESP block. LEVEL OF EVIDENCE: III.

Limited Improvement with Minimally Invasive Lumbar Decompression Alone for Degenerative Scoliosis with Cobb Angle over 20 Degrees: The Impact of Decompression Location.

STUDY DESIGN: Retrospective review of a prospectively collected multi-surgeon registry. OBJECTIVE: To evaluate the outcomes of minimally invasive (MI) decompression in patients with severe degenerative scoliosis (DS) and identify factors associated with poorer outcomes. SUMMARY OF BACKGROUND CONTEXT: MI decompression has gained widespread acceptance as a treatment option for patients with lumbar canal stenosis and DS. However, there is a lack of research regarding the clinical outcomes and the impact of MI decompression location in patients with severe DS exhibiting a Cobb angle exceeding 20 degrees. MATERIALS AND METHODS: Patients who underwent MI decompression alone were included and categorized into the DS or control groups based on Cobb angle (>20 degrees). Decompression location was labeled as "scoliosis-related" when the decompression levels were across or between end vertebrae, and "outside" when the operative levels did not include the end vertebrae. The outcomes including Oswestry Disability Index (ODI) were compared between the propensity score-matched groups for improvement and minimal clinical importance difference (MCID) achievement at ≥1 year postoperatively. Multivariable regression analysis was conducted to identify factors contributing to the non-achievement of MCID in ODI of the DS group at the ≥1 year timepoint. RESULTS: A total of 253 patients (41 DS) were included in the study. Following matching for age, gender, osteoporosis status, psoas muscle area, and preoperative ODI, the DS groups exhibited a significantly lower rate of MCID achievement in ODI (DS: 45.5% vs. control 69.0%, P=0.047). The "scoliosis-related" decompression (Odds ratio: 9.9, P=0.028) was an independent factor of non-achievement of MCID in ODI within the DS group. CONCLUSION: In patients with a Cobb angle>20 degrees, lumbar decompression surgery, even in the MI approach, may result in limited improvement of disability and physical function. Caution should be exercised when determining a surgical plan, especially when decompression involves the level between or across the end vertebrae. LEVEL OF EVIDENCE: 3.

Practical Answers to Frequently Asked Questions in Anterior Cervical Spine Surgery for Degenerative Conditions.

INTRODUCTION: Surgical counseling enables shared decision making and optimal outcomes by improving patients' understanding about their pathologies, surgical options, and expected outcomes. Here, we aimed to provide practical answers to frequently asked questions (FAQs) from patients undergoing an anterior cervical diskectomy and fusion (ACDF) or cervical disk replacement (CDR) for the treatment of degenerative conditions. METHODS: Patients who underwent primary one-level or two-level ACDF or CDR for the treatment of degenerative conditions with a minimum of 1-year follow-up were included. Data were used to answer 10 FAQs that were generated from author's experience of commonly asked questions in clinic before ACDF or CDR. RESULTS: A total of 395 patients (181 ACDF, 214 CDR) were included. (1, 2, and 3) Will my neck/arm pain and physical function improve? Patients report notable improvement in all patient-reported outcome measures. (4) Is there a chance I will get worse? 13% (ACDF) and 5% (CDR) reported worsening. (5) Will I receive a significant amount of radiation? Patients on average received a 3.7 (ACDF) and 5.5 mGy (CDR) dose during. (6) How long will I stay in the hospital? Most patients get discharged on postoperative day one. (7) What is the likelihood that I will have a complication? 13% (8% minor and 5% major) experienced in-hospital complications (ACDF) and 5% (all minor) did (CDR). (8) Will I need another surgery? 2.2% (ACDF) and 2.3% (CDR) of patients required a revision surgery. (9 & 10) When will I be able to return to work/driving? Most patients return to working (median of 16 [ACDF] and 14 days [CDR]) and driving (median of 16 [ACDF] and 12 days [CDR]). CONCLUSIONS: The answers to the FAQs can assist surgeons in evidence-based patient counseling.

The Impact of Posterior Intervertebral Osteophytes on Patient-Reported Outcome Measures After L5-S1 Anterior Lumbar Interbody Fusion and Transforaminal Lumbar Interbody Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: (1) To develop a reliable grading system to assess the severity of posterior intervertebral osteophytes and (2) to investigate the impact of posterior intervertebral osteophytes on clinical outcomes after L5-S1 decompression and fusion through anterior lumbar interbody fusion (ALIF) and minimally-invasive transforaminal lumbar interbody fusion (MIS-TLIF). BACKGROUND: There is limited evidence regarding the clinical implications of posterior lumbar vertebral body osteophytes for ALIF and MIS-TLIF surgeries and there are no established grading systems that define the severity of these posterior lumbar intervertebral osteophytes. PATIENTS AND METHODS: A retrospective analysis of patients undergoing L5-S1 ALIF or MIS-TLIF was performed. Preoperative and postoperative patient-reported outcome measures of the Oswestry Disability Index (ODI) and leg Visual Analog Scale (VAS) at 2-week, 6-week, 12-week, and 6-month follow-up time points were assessed. Minimal clinically important difference (MCID) for ODI of 14.9 and VAS leg of 2.8 were utilized. Osteophyte grade was based on the ratio of osteophyte length to foraminal width. "High-grade" osteophytes were defined as a maximal osteophyte length >50% of the total foraminal width. RESULTS: A total of 70 consecutive patients (32 ALIF and 38 MIS-TLIF) were included in the study. There were no significant differences between the two cohorts in patient-reported outcome measures or achievement of MCID for Leg VAS or ODI preoperatively or at any follow-ups. On multivariate analysis, neither the surgical approach nor the presence of high-grade foraminal osteophytes was associated with leg VAS or ODI scores at any follow-up time point. In addition, neither the surgical approach nor the presence of high-grade foraminal osteophytes was associated with the achievement of MCID for leg VAS or ODI at 6 months. CONCLUSION: ALIF and MIS-TLIF are both valid options for treating degenerative spine conditions and lumbar radiculopathy, even in the presence of high-grade osteophytes that significantly occupy the intervertebral foramen. LEVEL OF EVIDENCE: 3.

Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope (Review).

Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in solid tumors. More than 90% of pancreatic ductal adenocarcinoma (PDAC) are driven by mutations in the KRAS gene, suggesting the importance of targeting this oncogene in PDAC. Initial efforts to target KRAS have been unsuccessful due to its small size, high affinity for guanosine triphosphate/guanosine diphosphate, and lack of distinct drug­binding pockets. Therefore, much of the focus has been directed at inhibiting the activation of major signaling pathways downstream of KRAS, most notably the PI3K/AKT and RAF/MAPK pathways, using tyrosine kinase inhibitors and monoclonal antibodies. While preclinical studies showed promising results, clinical data using the inhibitors alone and in combination with other standard therapies have shown limited practicality, largely due to the lack of efficacy and dose­limiting toxicities. Recent therapeutic approaches for KRAS­driven tumors focus on mutation­specific drugs such as selective KRASG12C inhibitors and son of sevenless 1 pan­KRAS inhibitors. While KRASG12C inhibitors showed great promise against patients with non­small cell lung cancer (NSCLC) harboring KRASG12C mutations, they were not efficacious in PDAC largely because the major KRAS mutant isoforms in PDAC are G12D, G12V, and G12R. As a result, KRASG12D and pan­KRAS inhibitors are currently under investigation as potential therapeutic options for PDAC. The present review summarized the importance of KRAS oncogenic signaling, challenges in its targeting, and preclinical and clinical targeted agents including recent direct KRAS inhibitors for blocking KRAS signaling in PDAC.