Citations

Abstract Background Neuro-oncology education in American neurology departments is highly variable, with no clear guidelines on appropriate practices. To better understand its current state, we focus on the perspective of departmental Grand Rounds (GR), views of adult neurology residency program directors (ANRPD), neuro-oncologists, and residents. Methods First, we obtained GR series from academic years 2017–2018 and 2018–2019 via an online search and direct emails to neurology residency programs. Second, two online surveys were dispensed to ANRPD and neuro-oncologists. Third, a cohort of neurology residents completed surveys with pre/post-didactic tests. Results Neuro-oncology consisted of 7% (28/ 411) GR in 2017–2018 and 6% (29/463) in 2018–2019; approximately 20% of institutions had no neuro-oncology GR. Twenty neuro-oncologists and 25 of the 175 ANRPDs completed the surveys. Respondents thought 1-to-4 GR annually was adequate. Thirty-five residents completed the survey. Residents might consider neuro-oncology with more exposure (77%, 27/35) and a stronger knowledge base (57%, 20/35). After 8-hours of didactics, residents demonstrated significant (P = .019) pre-/post-test improvement. Conclusions Here, we begin to define the status of several aspects of neuro-oncology education: 1 in 5 academic institutions do not have any neuro-oncology GR lectures annually, and both ANRPDs and neuro-oncologists agree that 1-to-4 lectures annually are adequate. Residents overwhelmingly stated they would be more interested in neuro-oncology with more exposure, and a pilot study of 8 hours of didactic did show knowledge improvement. While these initial datasets require confirmation in larger studies, it suggests that small changes to the current state at some institutions could have a meaningful impact.

Abstract The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+.

Abstract Objectives IBM is characterized by slowly progressive muscle weakness making it challenging to detect significant changes in weakness during a clinical trial. Trial participants receiving placebo may behave differently from in natural history studies. We aimed to quantify the change in muscle strength and IBM Functional Rating Scale (IBMFRS) of IBM patients receiving placebo during clinical trials. Methods Several databases were searched. Randomized, double-blinded, placebo-controlled trials without treatment intervention on the placebo group were included. Standardized mean differences (SMD) for change in muscle strength and mean differences for IBMFRS were used to calculate pooled effects, using DerSimonian-Laird continuous random effect models. Meta-regression determined change in muscle strength. Heterogeneity was evaluated using the I2 indicator. Results Eleven eligible trials were identified with 257 participants receiving placebo and a low risk of bias per the Cochrane Collaboration Risk of Bias 2 (RoB2) tool. Participants receiving placebo on average had a measurable decline in muscle strength with a mean effect size of –0.398 (95% CI –0.652, –0.144) (P = 0.002). SMD changed by –0.009 (–0.016, –0.002) points per week (P = 0.015). Manual muscle testing was associated with higher heterogeneity (I2 = 67.68%) compared with quantitative muscle testing (I2 = 0%). Only three studies reported IBMFRS results. The pooled change in IBMFRS at 12 months was –2.189 points (–3.893, –0.485) on this 0 to 40-point scale (P = 0.012), with relatively high heterogeneity. Conclusion Participants with IBM displayed a measurable decline in their muscle strength and IBMFRS during clinical trials, in keeping with the disease’s slowly progressive nature. These estimates can inform sample size calculations in future studies.

Key Points The Standard versus Accelerated Initiation of Renal Replacement Therapy in AKI trial found that starting dialysis earlier for AKI resulted in a 74% higher risk of still receiving dialysis at 90 days. Among patients who likely would have started dialysis under usual practice, the risks of dialysis dependence were similar. This suggests much of the risk observed may have been due to starting dialysis (versus never starting) rather than starting slightly earlier. Background The Standard versus Accelerated Initiation of Renal Replacement Therapy in AKI Trial showed that among critically ill patients with AKI, an accelerated KRT initiation strategy resulted in more KRT dependence at 90 days, as compared with a standard strategy. However, it is unclear whether this difference exists among participants who likely would have been treated with KRT in usual practice. Methods Secondary analysis of the Standard versus Accelerated Initiation of Renal Replacement Therapy in AKI randomized controlled trial, analyzing participants who received more than the median number of days of KRT, which served as a proxy for high probability of requiring KRT under usual practice. Two sensitivity analyses redefined the cohort as ( 1 ) those with ≥24 hours of oliguria who received KRT and ( 2 ) those who received any KRT. Using the same statistical approach as the original trial, we calculated unadjusted relative risks with 95% confidence intervals (CIs) for the exposure of randomized KRT initiation strategy (accelerated versus standard) on the outcome of KRT dependence at 90 days among survivors. Results Among the 1184 participants who received ≥6 days of KRT (670 and 514 in the accelerated and standard arms, respectively), baseline characteristics remained balanced between treatment arms. The relative risk of KRT dependence at 90 days was attenuated and nonsignificant: 1.21 (95% CI, 0.84 to 1.78), compared with 1.74 (95% CI, 1.24 to 2.43) in the overall trial. The results were similar in sensitivity analyses. Conclusions Among patients who likely would have been treated with KRT in usual practice, there was no significant difference in 90-day KRT dependence among survivors between those randomized to the accelerated and standard KRT initiation strategies. These results suggest that the harm of long-term KRT dependence may be largely due to KRT initiation (versus never initiation) rather than earlier initiation. Clinical Trial registry name and registration number: NCT02568722.

OBJECTIVE Management of locally invasive colorectal carcinoma at any stage currently involves surgical excision followed by chemoradiotherapy; however, the prognosis is poor, with a 5-year overall survival (OS) of only 5%. Failure to achieve gross-total resection is associated with poorer OS, and patients with residual tumor postresection (R1 or R2 resection) have a median OS of 7 months compared with 23 months in those who undergo resection with negative margins (R0 resection). For tumors that have invaded the sacrum, sacrectomy becomes necessary to achieve R0 resection. The objective of this study was to provide a descriptive multicenter account of resection for locally invasive colorectal carcinoma with sacral invasion, focusing on the association of tumor morphometry with surgical planning and perioperative outcomes. METHODS Demographic, comorbidity, clinical, tumor-specific, operative characteristic, and outcome data were collected on all patients who underwent resection of colorectal carcinoma with concurrent sacral resection between January 2005 and May 2022. Patients were grouped into those having undergone surgery for purely palliative intent, or those with resection with attempt at local control and dichotomized into level of osteotomy (either proximal or distal to the S2–3 level). RESULTS Twenty-two patients (median age 50.5 [IQR 43.3–60.0] years, 54.5% female) underwent sacrectomy for colorectal carcinoma. Operative records indicated intent for local control in 14 patients and palliative in the remaining 8 patients. Palliative surgical intent was based primarily on the presence of distant metastases. There was no significant difference in median local progression-free survival between patients undergoing osteotomy proximal to the S2–3 level and those undergoing osteotomy distal to the S2–3 level. CONCLUSIONS En bloc resection is believed to offer the best local control in patients with locally invasive colorectal carcinoma. The present descriptive series highlights outcomes of en bloc resection with partial or full sacrectomy in patients with tumors showing local extension into the sacrum. Complications are common, most often in the form of wound dehiscence or infection, and many patients require placement in a rehabilitation or intermediate-care facility upon discharge. However, for those with stage III (locally aggressive) disease, median OS exceeds 16 years, suggesting that such aggressive management with en bloc resection may be warranted in properly selected patients.

Bacteriophage (phage) therapy has emerged as a promising solution to combat the growing crisis of multidrug-resistant (MDR) infections. There are several international centers actively engaged in implementation of phage therapy, and recent case series have reported encouraging success rates in patients receiving personalized, compassionate phage therapy for difficult-to-treat infections. Nonetheless, substantial hurdles remain in the way of more widespread adoption and more consistent success. This Review offers a comprehensive overview of current phage therapy technologies and therapeutic approaches. We first delineate the common steps in phage therapy development, from phage bank establishment to clinical administration, and examine the spectrum of therapeutic approaches, from personalized to fixed phage cocktails. Using the framework of a conventional drug development pipeline, we then identify critical knowledge gaps in areas such as cocktail design, formulation, pharmacology, and clinical trial design. We conclude that, while phage therapy holds promise, a structured drug development pipeline and sustained government support are crucial for widespread adoption of phage therapy for MDR infections.

In 2023, Faith Kipyegon set the female world record for running one mile (4:07.64). Here, we quantitatively explore if improved aerodynamic drafting could allow her to run just 3.19% faster and thus break the 4-minute mile barrier. Drafting involves other athletes (pacers) running in formation around a designated athlete to reduce the aerodynamic drag force acting on the designated runner. Drafting allows the designated athlete to run faster at the same rate of metabolic energy consumption. Our overall approach was to estimate Kipyegon’s metabolic energy consumption during her mile world record performance. Then, we used empirically established relationships between horizontal resistive force, running velocity and metabolic power to estimate how much faster she could run at the same metabolic power if the aerodynamic force was reduced via drafting. Our calculations suggest that Kipyegon could run ~3:59.37 with drafting provided by one pacer in front and one in back who change out with two other pacers at 800 m.

Abstract Background Inter‐fractional and intra‐fractional positioning and motion monitoring based on implanted fiducials through kilovoltage (kV) imaging is a cost‐effective approach to enhance intact prostate radiotherapy treatment accuracy. However, comprehensive studies for three‐dimensional (3D) position extraction and the corrective action threshold are lacking. Purpose To develop and verify a fiducial motion monitoring system with 3D position information based on triggered kV images taken during treatment delivery, and to comprehensively evaluate the recommended thresholds for corrective action during treatment. Methods An in‐house fiducial triangulation algorithm was developed to monitor fiducial positions using subsequent kV triggered images. The precision of fiducial triangulation and motion detection was validated on a pelvis phantom with four fiducial inserts. A retrospective study was conducted on prostate cancer patients who received either moderately hypofractionated radiotherapy (MHRT, n = 16) or stereotactic body radiotherapy (SBRT, n = 12), categorized by endo‐rectal balloon (ERB) use. Intra‐fractional positions relative to isocenter were computed, and these positions were analyzed in comparison to the original marker locations of the patient's treatment plan. A linear regression fit was used per fraction to determine correlation coefficients between motions in the left–right (LR), superior–inferior (SI), and anterior–posterior (AP) directions. Average fraction time (AFT) of treatment was reported based on the observed average time spent on steps in the workflow and the percentage of fiducials caught outside of the current two‐dimensional (2D) tolerance threshold of 5 mm. The observed 3D offsets were used to estimate AFT for various 3D tolerance thresholds. Results Overall, our triangulation method proved to be very precise for static cases, where phantom measurements revealed a fiducial position triangulation precision of mm for stationary targets, but had a spread of mm for targets with 1 mm of motion. Employing triangulation, true motion exceeding 5 mm was detected above 4.0 mm in magnitude 90.9% of the time, a noticeable improvement in comparison to the 28%–65% successful detection rate reported by 2D projection methods. Most detection errors were attributed to depth disparity. Similar to other reports, correlation coefficients for intra‐fractional motion generally indicated no LR/SI, no LR/AP, and weak positive SI/AP correlations for MHRT and SBRT patients. Offsets beyond a 3D tolerance threshold of 5 mm were observed at a rate of 4.25%–5.25%, while the 5 mm 2D out‐of‐tolerance catch‐rate was 1.6%. The AFT was 8.1–8.2 min using the 2D tolerance threshold of 5 mm. In comparison, the estimated AFT for the proposed 3D tolerance monitoring of offsets beyond 2–5 mm was slightly higher at 8.2–10.9 min due to the higher amount of out‐of‐tolerance instances for the higher precision intra‐fractional motion management. Conclusions Our study showcases a promising subsequent kV‐based triangulation method for intra‐fractional prostate motion monitoring. Acquiring 3D motion information results in higher out‐of‐tolerance catch‐rates particularly in the depth dimension of the kV images, which is perpendicular to the treatment beam. Failure to properly observe and catch these offsets would result in sub‐optimal conformality and accuracy of the dose delivery.

INTRODUCTION: Abdominal bloating is a difficult symptom to treat. Hypnotherapy and diaphragmatic intervention have separately shown benefit on bloating in prior work but have not been united into a single intervention. We aimed to obtain data on the potential therapeutic impact of a novel audio-recorded bloating treatment for bloating integrating hypnosis and diaphragmatic breathing, with proposed synergistic effect. METHODS: Patients with nonorganic bowel disorders with predominant bloating symptoms completed a digitally delivered 7-session audio-recorded hypnotherapy program without clinician involvement. The intervention combined bloating-targeted hypnotic suggestions and guided diaphragmatic breathing delivered under hypnosis, and was supplemented with interval self-guided breathing exercises. Participants completed online REDCap assessments at baseline, midtreatment, at end of treatment, and 3-month follow-up, evaluating symptom severity, gastrointestinal symptom-specific anxiety, overall anxiety/depression, and quality of life. Outcomes were assessed in an intention-to-treat manner with repeated measures analysis of variances (ANOVAs) with Bonferroni-adjusted pairwise post hoc tests. RESULTS: Of 23 patients who started treatment, 22 (95.6%) completed follow-up. Bloating severity on Irritable Bowel Syndrome-Symptom Severity Scale and Patient Assessment of Upper Gastrointestinal Symptom Severity Index showed reduction in bloating with large effect sizes (Cohen d of ∼0.8) at the end of treatment, as did Visceral Sensitivity Index bloating-related anxiety. At the end of treatment, 16 patients (69.6%) were Irritable Bowel Syndrome-Symptom Severity Scale treatment responders (≥30% symptom reduction) on bloating and 17 (73.9%) on overall bowel symptom severity. Anxiety, depression, and quality-of-life scores were unchanged. Outcome measures were fully maintained at the 3-month follow-up. DISCUSSION: Results suggest the therapeutic utility of a new cost-effective self-administered bloating intervention. A randomized controlled trial is planned to confirm these therapeutic effects.

16 Background: In PSMAfore (NCT04689828), [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) prolonged rPFS versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive adults with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) progressing once on an ARPI. Baseline circulating tumor DNA (ctDNA) fraction was associated with rPFS at the second interim analysis (IA) of OS (ASCO 24). Here, we assessed the association of baseline and cycle 2 day 1 (C2D1) ctDNA fraction, and early ctDNA and prostate-specific antigen (PSA) dynamics, with rPFS and OS at the third IA of OS. Methods: Patients were randomized 1:1 to 177 Lu-PSMA-617 (7.4 GBq Q6W; x6) or ARPI change. Endpoints included rPFS (primary) and OS (key secondary). Plasma ctDNA fraction was analyzed at baseline and at C2D1 using an in-house custom panel. Cox regression (adjusted for 3 risk classes based on clustering of 17 baseline clinical features) and random forest (adjusted for 15 baseline clinical features) modeling were used to assess the association of ctDNA fraction and PSA with clinical outcomes at the Feb-27-2024 data cutoff. Results: Patients with plasma samples at baseline and C2D1 were included ( 177 Lu-PSMA-617, n/N = 82/234; ARPI change, n/N = 91/234). Cox regression models adjusted for clinical features in the 177 Lu-PSMA-617 arm showed that higher ctDNA fraction was associated with shorter rPFS and OS (Table). These associations were stronger for C2D1 than baseline, both when comparing individual models and within a model including both timepoints (Table). In random forest models including clinical features and C2D1 ctDNA fraction, the total area under curves were not improved by addition of baseline ctDNA fraction (rPFS, 0.87; OS, 0.86). In the overall population, fractional decreases from baseline to C2D1 in ctDNA ( p = 0.0015) and PSA ( p < 0.0001) were strongly associated with longer rPFS, and were weakly correlated with one another (correlation coefficient, 0.26). In the 177 Lu-PSMA-617 arm, fractional decrease in ctDNA ( p = 0.002) was more strongly correlated with OS than was decrease in PSA ( p = 0.12). Conclusions: This exploratory analysis suggested that C2D1 ctDNA fraction was more strongly associated than baseline ctDNA fraction with rPFS and OS. Early ctDNA fraction dynamics contributed additional information in the prediction of rPFS and OS beyond PSA dynamics alone. Clinical trial information: NCT04689828 . Cox regression models. a rPFS OS Baseline model, HR (95% CI); p 6.0 (1.6–23.0); 0.0095 12.0 (3.0–48.7); 0.00052 C-index ± SE 0.69 ± 0.04 0.75 ± 0.04 C2D1 model, HR (95% CI); p 47.7 (10.1–226.0); < 0.0001 82.7 (16.4–417.0); < 0.0001 C-index ± SE 0.72 ± 0.03 0.77 ± 0.03 Baseline + C2D1 model Baseline, HR (95% CI); p 3.1 (0.7–14.0); 0.14 2.1 (0.4–12.7); 0.41 C2D1, HR (95% CI); p 35.9 (7.2–180.0); < 0.0001 52.5 (7.6–362.0); < 0.0001 C-index ± SE 0.72 ± 0.03 0.79 ± 0.03 a HRs correspond to 1 unit change in ctDNA fraction.