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BACKGROUND: Substernal lead placement of the extravascular implantable cardioverter defibrillator (EV ICD) permits both defibrillation at thresholds similar to those seen with transvenous implantable cardioverter defibrillators and effective anti-tachycardia pacing (ATP) while avoiding the vasculature and associated complications. The global Pivotal study has shown the EV ICD system to be safe and effective through 6 months, but long-term experience has yet to be published. Our aim was to report the performance and safety of the EV ICD system throughout the study. METHODS: The EV ICD Pivotal study was a prospective, global, single-arm, premarket clinical study. Individuals with a Class I or IIa indication for a single-chamber implantable cardioverter defibrillator per guidelines were enrolled. Freedom from major system- or procedure-related complications and appropriate and inappropriate therapy rates were assessed through 3 years with the Kaplan-Meier method. ATP success was calculated from simple proportions. RESULTS: An implantation was attempted in 316 patients (25.3% female; 53.8±13.1 years of age; 81.6% primary prevention; left ventricular ejection fraction, 38.9±15.4%). Of 299 patients with a successful implantation, 24 experienced 82 spontaneous arrhythmic episodes that were appropriately treated with ATP only (38, 46.3%), shock only (34, 41.5%), or both (10, 12.2%) for a Kaplan-Meier–estimated rate of first any appropriate therapy of 9.2% at 3 years. ATP was successful in 77.1% (37/48) of episodes, and ATP use significantly increased from discharge to last follow-up visit ( P <0.0001). Shock therapy was successful in 100% (27/27) of discrete, spontaneous ventricular arrhythmias. The inappropriate shock rates at 1 and 3 years were 9.8% and 17.5%, respectively, with P-wave oversensing the predominant cause. No major intraprocedural complications were reported, and the estimated freedom from system- or procedure-related major complications was 91.9% at 1 year and 89.0% at 3 years. The most common major complications were lead dislodgement (10 events; n=9 patients, 2.8%), postoperative wound or device pocket infection (n=8, 2.5%), and device inappropriate shock delivery (n=4, 1.3%). Twenty-four system revisions were performed as a result of major complications related to the EV ICD system or procedure. CONCLUSIONS: From implantation to study completion, the EV ICD Pivotal study demonstrated that a single integrated system with an extravascular lead placed in the substernal space maintains high ATP success, effective defibrillation, and a consistent safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04060680.

Abstract Purpose: Mutations in hematopoietic progenitor cells accumulate with age leading to clonal expansion, termed clonal hematopoiesis (CH). CH in the general population is associated with hematopoietic neoplasms and reduced overall survival (OS), predominantly through cardiovascular adverse events (CVAE). Because androgen receptor pathway inhibitors (ARPI) used in metastatic castration-resistant prostate cancer (mCRPC) are also associated with CVAEs and because CH negatively impacted survival in an advanced solid tumor cohort, we hypothesized that CH in mCRPC may be associated with increased CVAEs and inferior survival. Experimental Design: A targeted DNA sequencing panel captured common CH mutations in pretreatment blood samples from 957 patients enrolled in Alliance A031201: a randomized trial of enzalutamide ± abiraterone/prednisone in the first-line mCRPC setting. The primary outcome was the impact of CH on OS; the secondary outcomes were progression-free survival (PFS) and CVAEs. Results: Baseline comorbidities were similar by CH status. No differences in OS/progression-free survival were detected regardless of treatment arm or the variant allele frequency threshold used to define CH [primary: 2% (normal-CH, N-CH); exploratory: 0.5% (low-CH) and 10% (high-CH, H-CH)]. Patients with H-CH (7.2%) and TET2-mutated N-CH (6.0%) had greater odds of any CVAE (14.5% vs. 4.0%; P = 0.0004 and 12.3% vs. 4.2%; P = 0.010, respectively). More major CVAEs were observed in patients with H-CH (5.8% vs. 1.9%; P = 0.042) and N-CH (3.4% vs. 1.8%; P = 0.147). Conclusions: CH did not affect survival in patients with mCRPC treated with ARPIs in A031201. H-CH and TET2-mutated CH were associated with more CVAEs. These findings inform the risk/benefit discussion about ARPIs in mCRPC.

OBJECTIVE The long-term effects of increased body mass index (BMI) on surgical outcomes are unknown for patients who undergo surgery for low-grade lumbar spondylolisthesis. The goal of this study was to assess long-term outcomes in obese versus nonobese patients after surgery for grade 1 spondylolisthesis. METHODS Patients who underwent surgery for grade 1 spondylolisthesis at the Quality Outcomes Database’s 12 highest enrolling sites (SpineCORe group) were identified. Long-term (5-year) outcomes were compared for patients with BMI ≥ 35 versus BMI < 35. RESULTS In total, 608 patients (57.6% female) were included. Follow-up was 81% (excluding patients who had died) at 5 years. The BMI ≥ 35 cohort (130 patients, 21.4%) was compared to the BMI < 35 cohort (478 patients, 78.6%). At baseline, patients with BMI ≥ 35 were more likely to be younger (58.5 ± 11.4 vs 63.2 ± 12.0 years old, p < 0.001), to present with both back and leg pain (53.8% vs 37.0%, p = 0.002), and to require ambulation assistance (20.8% vs 9.2%, p < 0.001). Furthermore, the cohort with BMI ≥ 35 had worse baseline patient-reported outcomes including visual analog scale (VAS) back (7.6 ± 2.3 vs 6.5 ± 2.8, p < 0.001) and leg (7.1 ± 2.6 vs 6.4 ± 2.9, p = 0.031) pain, disability measured by the Oswestry Disability Index (ODI) (53.7 ± 15.7 vs 44.8 ± 17.0, p < 0.001), and quality of life on EuroQol-5D (EQ-5D) questionnaire (0.47 ± 0.22 vs 0.56 ± 0.22, p < 0.001). Patients with BMI ≥ 35 were more likely to undergo fusion (85.4% vs 74.7%, p = 0.01). There were no significant differences in 30- and 90-day readmission rates (p > 0.05). Five years postoperatively, there were no differences in reoperation rates or the development of adjacent-segment disease for patients in either BMI < 35 or ≥ 35 cohorts who underwent fusion (p > 0.05). On multivariate analysis, BMI ≥ 35 was a significant risk factor for not achieving minimal clinically important differences (MCIDs) for VAS leg pain (OR 0.429, 95% CI 0.209–0.876, p = 0.020), but BMI ≥ 35 was not a predictor for achieving MCID for VAS back pain, ODI, or EQ-5D at 5 years postoperatively. CONCLUSIONS Both obese and nonobese patients benefit from surgery for grade 1 spondylolisthesis. At the 5-year time point, patients with BMI ≥ 35 have similarly low reoperation rates and achieve rates of satisfaction and MCID for back pain (but not leg pain), disability (ODI), and quality of life (EQ-5D) that are similar to those in patients with a BMI < 35.

OBJECTIVE The aim of this study was to compare the rate of achievement of the minimal clinically important difference (MCID) in patient-reported outcomes (PROs) and satisfaction between cervical spondylotic myelopathy (CSM) patients with and without class III obesity who underwent surgery. METHODS The authors analyzed patients from the 14 highest-enrolling sites in the prospective Quality Outcomes Database CSM cohort. Patients were dichotomized based on whether or not they were obese (class III, BMI ≥ 35 kg/m 2 ). PROs including visual analog scale (VAS) neck and arm pain, Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA), EQ-5D, and North American Spine Society patient satisfaction scores were collected at baseline and 24 months after cervical spine surgery. RESULTS Of the 1141 patients with CSM who underwent surgery, 230 (20.2%) were obese and 911 (79.8%) were not. The 24-month follow-up rate was 87.4% for PROs. Patients who were obese were younger (58.1 ± 12.1 years vs 61.2 ± 11.6 years, p = 0.001), more frequently female (57.4% vs 44.9%, p = 0.001), and African American (22.6% vs 13.4%, p = 0.002) and had a lower education level (high school or less: 49.1% vs 40.8%, p = 0.002) and a higher American Society of Anesthesiologists grade (2.7 ± 0.5 vs 2.5 ± 0.6, p < 0.001). Clinically at baseline, the obese group had worse neck pain (VAS score: 5.7 ± 3.2 vs 5.1 ± 3.3), arm pain (VAS score: 5.4 ± 3.5 vs 4.8 ± 3.5), disability (NDI score: 42.7 ± 20.4 vs 37.4 ± 20.7), quality of life (EQ-5D score: 0.54 ± 0.22 vs 0.56 ± 0.22), and function (mJOA score: 11.6 ± 2.8 vs 12.2 ± 2.8) (all p < 0.05). At the 24-month follow-up, however, there was no difference in the change in PROs between the two groups. Even after accounting for relevant covariates, no significant difference in achievement of MCID and satisfaction was observed between the two groups at 24 months. CONCLUSIONS Despite the class III obese group having worse baseline clinical presentations, the two cohorts achieved similar rates of satisfaction and MCID in PROs. Class III obesity should not preclude and/or delay surgical management for patients who would otherwise benefit from surgery for CSM.

Abstract Background: Medium vessel occlusion (MeVO) strokes, particularly affecting the M2 segment of the middle cerebral artery, represent a critical proportion of acute ischemic strokes, posing significant challenges in management and outcome prediction. The efficacy of mechanical thrombectomy (MT) in MeVO stroke may warrant reliable predictors of functional outcomes. This study aimed to investigate the prognostic value of follow-up infarct volume (FIV) for predicting 90-day functional outcomes in MeVO stroke patients undergoing MT. Methods: This multicenter, retrospective cohort study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, covering patients with acute ischemic stroke due to M2 segment occlusion treated with MT. We examined the relationship between 90-day functional outcomes, measured by the modified Rankin Scale (mRS), and follow-up infarct volume (FIV), assessed through CT or MRI within 12–36 h post-MT. Results: Among 130 participants, specific FIV thresholds were identified with high specificity and sensitivity for predicting outcomes. A FIV ⩽5 ml was highly specific for predicting favorable and excellent outcomes. The optimal cut-off for both prognostications was identified at ⩽15 ml by the Youden Index, with significant reductions in the likelihood of favorable outcomes observed above a 40 ml threshold. Receiver Operator Curve (ROC) analyses confirmed FIV as a superior predictor of functional outcomes compared to traditional recanalization scores, such as final modified thrombolysis in cerebral infarction score (mTICI). Multivariable analysis further highlighted the inverse relationship between FIV and positive functional outcomes. Conclusions: FIV within 36 h post-MT serves as a potent predictor of 90-day functional outcomes in patients with M2 segment MeVO strokes. Establishing FIV thresholds may aid in the prognostication of stroke outcomes, suggesting a role for FIV in guiding post intervention treatment decisions and informing clinical practice. Future research should focus on validating these findings across diverse patient populations and exploring the integration of FIV measurements with other clinical and imaging markers to enhance outcome prediction accuracy.

Abstract Objective To provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival outcomes. Design Systematic review and meta-analysis. Data sources Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to 23 October 2023). Study selection Included studies were randomised controlled trials focusing on conventional fractionation (CF; daily fractions of 1.8-2 Gy, reaching a total dose of 50-50.4 Gy over 5-6 weeks), moderate hypofractionation (MHF; fraction sizes of 2.65-3.3 Gy for 13-16 fractions over 3-5 weeks), and/or ultra-hypofractionation (UHF; schedule of only 5 fractions). Data extraction Two independent investigators screened studies and extracted data. Risk of bias and quality of evidence were assessed using the Cochrane Collaboration’s tool and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach, respectively. Data synthesis Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity was analysed using Cochran’s Q test and I 2 statistic. Network meta-analysis was used to integrate all available evidence. Main outcome measures The pre-specified primary outcome was grade ≥2 acute radiation dermatitis and late radiation therapy related side effects; secondary outcomes included cosmesis, quality of life, recurrence, and survival metrics. Results From 1754 studies, 59 articles representing 35 trials (20 237 patients) were assessed; 21.6% of outcomes showed low risk of bias, whereas 78.4% had some concerns or high risk, particularly in outcome measurement (47.4%). The RR for grade ≥2 acute radiation dermatitis for MHF compared with CF was 0.54 (95% CI 0.49 to 0.61; P<0.001) and 0.68 (0.49 to 0.93; P=0.02) following breast conserving therapy and mastectomy, respectively. Hyperpigmentation and grade ≥2 breast shrinkage were less frequent after MHF than after CF, with RRs of 0.77 (0.62 to 0.95; P=0.02) and 0.92 (0.85 to 0.99; P=0.03), respectively, in the combined breast conserving therapy and mastectomy population. However, in the breast conserving therapy only trials, these differences in hyperpigmentation (RR 0.79, 0.60 to 1.03; P=0.08) and breast shrinkage (0.94, 0.83 to 1.07; P=0.35) were not statistically significant. The RR for grade ≥2 acute radiation dermatitis for UHF compared with MHF was 0.85 (0.47 to 1.55; P=0.60) for breast conserving therapy and mastectomy patients combined. MHF was associated with improved cosmesis and quality of life compared with CF, whereas data on UHF were less conclusive. Survival and recurrence outcomes were similar between UHF, MHF, and CF. Conclusions MHF shows improved safety profile, cosmesis, and quality of life compared with CF while maintaining equivalent oncological outcomes. Fewer randomised controlled trials have compared UHF with other fractionation schedules, but its safety and oncological effectiveness seem to be similar with short term follow-up. Given the advantages of reduced treatment time, enhanced convenience for patients, and potential cost effectiveness, MHF and UHF should be considered as preferred options over CF in appropriate clinical settings, with further research needed to solidify these findings. Systematic review registration PROSPERO CRD42023460249.

OBJECTIVE Depression and anxiety are associated with poor outcomes following spine surgery. However, the influence of these conditions on achieving a minimal clinically important difference (MCID) following lumbar spine surgery, as well as the potential compounding effects of comorbid depression and anxiety, is not well understood. This study explores the impact of comorbid depression and anxiety on long-term clinical outcomes following surgical treatment for degenerative lumbar spondylolisthesis. METHODS This study was a retrospective analysis of the multicenter, prospectively collected Quality Outcomes Database (QOD). Patients with surgically treated grade 1 lumbar spondylolisthesis from 12 centers were included. Preoperative baseline characteristics and comorbidities were recorded, including self-reported depression and/or anxiety. Pre- and postoperative patient-reported outcomes (PROs) were recorded: the numeric rating scale (NRS) score for back pain (NRS-BP), NRS score for leg pain (NRS-LP), Oswestry Disability Index (ODI), and EQ-5D. Patients were grouped into 3 cohorts: no self-reported depression or anxiety (non-SRD/A), self-reported depression or anxiety (SRD/A), or presence of both comorbidities (SRD+A). Changes in PROs over time, satisfaction rates, and rates of MCID were compared. A multivariable regression analysis was performed to establish independent associations. RESULTS Of the 608 patients, there were 452 (74.3%) with non-SRD/A, 81 (13.3%) with SRD/A, and 75 (12.3%) with SRD+A. Overall, 91.8% and 80.4% of patients had ≥ 24 and ≥ 60 months of follow-up, respectively. Baseline PROs were universally inferior for the SRD+A cohort. However, at 60-month follow-up, changes in all PROs were greatest for the SRD+A cohort, resulting in nonsignificant differences in absolute NRS-BP, NRS-LP, ODI, and EQ-5D across the 3 groups. MCID was achieved for the SRD+A cohort at similar rates to the non-SRD/A cohort. All groups achieved > 80% satisfaction rates with surgery without significant differences across the cohorts (p = 0.79). On multivariable regression, comorbid depression and anxiety were associated with worse baseline PROs, but they had no impact on 60-month PROs or 60-month achievement of MCIDs. CONCLUSIONS Despite lower baseline PROs, patients with comorbid depression and anxiety achieved comparable rates of MCID and satisfaction after surgery for lumbar spondylolisthesis to those without either condition. This quality-of-life benefit was durable at 5-year follow-up. These data suggest that patients with self-reported comorbid depression and anxiety should not be excluded from consideration of surgical intervention and often substantially benefit from surgery.

OBJECTIVE Myelopathy in the cervical spine can present with diverse symptoms, many of which can be debilitating for patients. Patients with radiculopathy symptoms demonstrate added complexity because of the overlapping symptoms and treatment considerations. The authors sought to assess outcomes in patients with myelopathy presenting with or without concurrent radiculopathy. METHODS The Quality Outcomes Database, a prospectively collected multi-institutional database, was used to analyze demographic, clinical, and surgical variables of patients presenting with myelopathy or myeloradiculopathy as a result of degenerative pathology. Outcome measures included arm (VAS-arm) and neck (VAS-neck) visual analog scale (VAS) scores, modified Japanese Orthopaedic Association (mJOA) scale score, EuroQol VAS (EQ-VAS) score, and Neck Disability Index (NDI) at 3, 12, and 24 months compared with baseline. RESULTS A total of 1015 patients were included in the study: 289 patients with myelopathy alone (M0), 239 with myeloradiculopathy but no arm pain (MRAP−), and 487 patients with myeloradiculopathy and arm pain (MRAP+). M0 patients were older than the myeloradiculopathy cohorts combined (M0 64.2 vs MRAP− + MRAP+ 59.5 years, p < 0.001), whereas MRAP+ patients had higher BMI and a greater incidence of current smoking compared with the other cohorts. There were more anterior approaches used in in MRAP+ patients and more posterior approaches used in M0 patients. In severely myelopathic patients (mJOA scale score ≤ 10), posterior approaches were used more often for M0 (p < 0.0001) and MRAP+ (p < 0.0001) patients. Patients with myelopathy and myeloradiculopathy both exhibited significant improvement at 1 and 2 years across all outcome domains. The amount of improvement did not vary based on surgical approach. In comparing cohort outcomes, postoperative outcome differences were associated with patient-reported scores at baseline. CONCLUSIONS Patients with myelopathy and those with myeloradiculopathy demonstrated significant and similar improvement in arm and neck pain scores, myelopathy, disability, and quality of life at 3 months that was sustained at 1- and 2-year follow-up intervals. More radicular symptoms and arm pain increased the likelihood of a surgeon choosing an anterior approach, whereas more severe myelopathy increased the likelihood of approaching posteriorly. Surgical approach itself was not an independent predictor of outcome.

Abstract Background In the TOPAZ-1, patients with biliary tract cancers (BTC) and recurrence within 6 months after surgery were excluded, even if this event is frequently observed in clinical practice. Our study aimed to assess if the efficacy of cisplatin-gemcitabine-durvalumab (CGD) in this population is comparable to that reported in the phase 3 trial. Methods The study cohort included patients with BTC who underwent surgery on the primary tumor, experienced disease recurrence occurring ≤6 months or &gt;6 months after surgery or after the end of adjuvant therapy and started CGD. The primary objectives were overall survival (OS) and progression free survival (PFS). Results A total of 178 patients were enrolled. No significant differences were observed between early and late relapse groups in OS (23.4 months vs not reached; HR 1.26; 95% CI, 0.67-2.37; P = .45) and PFS [7.0 months vs 9.8 months; HR 1.3(95% CI, 0.9-2.1) P = .13]. Overall response rate and disease control rate (P = .33 and P = .62) were comparable between the 2 groups, as the overall safety profile. In addition, we compared survival outcomes between the selected population and a historical cohort of patients with BTC treated with cisplatin-gemcitabine (CG) and found that despite the absence of statistical significance, CGD showed an outcome trend compared with CG regardless of the time of recurrence after surgery or adjuvant chemotherapy [(CG ≤ 6 vs CGD ≤ 6 months: HR 0.59, 95%CI, 0.35-1.01, P = .05; HR 0.70; 95%CI, 0.46-1.06, P = .09, OS and PFS, respectively) and (CG &gt; 6 vs. CGD &gt; 6 months: HR 0.50; 95%CI, 0.29-0.88, P = 0.0165; HR 0.54; 95%CI, 0.35-0.84, P = .0068, OS and PFS, respectively)]. Conclusion Our analysis suggests that CGD retains its efficacy independently of the timing of relapse after surgery or completion of adjuvant treatment in patients with advanced BTC.