Citations

Abstract Background Unresectable hepatocellular carcinoma (uHCC) is a leading cause of cancer death. FDA-approved first-line systemic therapies include atezolizumab/bevacizumab (atezo/bev) and durvalumab/tremelimumab (durva/treme); however, there is a lack of comparative data. Methods We reviewed outcomes of patients with uHCC who initiated atezo/bev or durva/treme between 2017 and 2024, across six institutions. Overall survival (OS) and time to treatment discontinuation (TTD) were analyzed using the Kaplan–Meier and Cox models, adjusting for baseline characteristics. Results Four hundred fifty-two uHCC pts were included. Median age: 68 years; 77% male; 81% white. Most common etiologies were viral hepatitis (38.9%) and metabolic dysfunction-associated steatohepatitis (19.5%). Disease progression was the primary reason for treatment discontinuation, atezo/bev (56%) and durva/treme (42%). Outcomes were not statistically significant (median OS [month, m]: 14.0 vs 14.6 [P = .66]; median TTD [m]: 4.9 vs 3.9 [P = .42] for atezo/bev vs durva/treme). Outcomes were significantly different between Child-Pugh classes (CP: A, B7, B8/9, C) respectively, median OS(m): 19.0, 6.1, 5.1, 2.0 (P < .001); median TTD(m): 6.1, 2.3, 3.0, 1.3 (P < .001). Conclusions In this real-world study of uHCC, no significant difference in clinical outcomes was observed between atezo/bev and durva/treme in the first-line setting. CP scores were a key prognostic variable with both regimens.

Background: Particulated juvenile articular cartilage (PJAC) implantation has demonstrated promising early results in the treatment of symptomatic articular cartilage defects of the patella. However, some uncertainty exists regarding the stability of this cell-based technique in lesions that are not well contained or shouldered. Purpose: To compare clinical and magnetic resonance imaging (MRI) outcomes of PJAC treatment in shouldered versus unshouldered full-thickness cartilage defects of the patella. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review of prospectively collected data from an institutional knee registry was conducted to identify patients treated with PJAC for full-thickness symptomatic patellar cartilage lesion between January 2009 and August 2017. Cartilage defects were graded arthroscopically according to the Outerbridge classification and characterized as shouldered or unshouldered. For the primary outcome, postoperative MRI studies were read by a musculoskeletal fellowship-trained radiologist who characterized the percentage of fill based on both coronal and sagittal images. Patient-reported outcome measures (PROMs) were obtained at baseline and 2-year follow-up. MRI and PROM results were compared between the shouldered and unshouldered cohorts. Results: A total of 64 knees in 60 patients (mean age, 26.3 ± 7.6 years) were identified, of which 62 (97%) knees underwent a concomitant patellar stabilization or offloading procedure. There were 32 (50%) shouldered and 32 (50%) unshouldered defects. On postoperative MRI, 68.8% of shouldered lesions demonstrated 67% to 100% fill, compared with 59.4% of unshouldered lesions; 12.5% of shouldered lesions and 15.6% of unshouldered lesions demonstrated 34% to 66% fill; and 18.8% of shouldered lesions and 25.0% of unshouldered lesions demonstrated 0% to 33% fill ( P = .604). At 2 years, significant improvements were observed in Knee Injury and Osteoarthritis Outcome Score (KOOS) Quality of Life (QOL) (23.1 to 65.3; P < .001), International Knee Documentation Committee (IKDC) (41.2 to 76.0; P < .001), KOOS Physical Function Shortform (PS) (34.8 to 13.9; P < .001), Kujala (52.0 to 87.5; P < .001), 12-Item Short Form Survey (SF-12) Physical Health (39.5 to 51.5; P < .001), Veterans Rand 12 Item Health Survey (VR-12) Physical Health (40.7 to 52.8; P < .001), Veterans Rand 6D (0.66 to 0.79; P < .001), SF-12 Mental Health (48.9 to 53.4; P = .015), and VR-12 Mental Health (49.4 to 54.0; P = .019) values. No significant change was observed in Pediatric Functional Activity Brief Scale score (9.1 to 10.3; P = .384). All PROMs were equivalent between shouldered and unshouldered defects at the 2-year follow-up ( P = .318-.980). There was a greater improvement in both KOOS PS (27.2 vs 10.7; P = .015) and Kujala (44.3 vs 26.9; P = .039) values from baseline to the 2-year follow-up in the shouldered group. Conclusion: PJAC implantation with concomitant patellar stabilization led to significantly improved PROMs for both shouldered and unshouldered patellar cartilage lesions over time. Additionally, minimal differences were observed between shouldered and unshouldered defects treated with PJAC at the 2-year follow-up.

PURPOSE Preclinical studies suggest the combination of the poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) inhibitor olaparib and the ataxia telangiectasia–mutated and Rad3-related (ATR) inhibitor ceralasertib has synergistic antitumor activity in homologous recombination proficient (HRP) and homologous recombination repair gene mutation (HRRm) patients. This study aims to determine the efficacy of olaparib plus ceralasertib in metastatic castration-resistant prostate cancer (mCRPC) with and without HRRm. PATIENTS AND METHODS Thirty-five HRP and 12 HRRm PARP inhibitor–naïve patients with mCRPC progressing on ≥1 line of therapy or previous androgen receptor pathway inhibitor were enrolled. Patients received olaparib (300 mg twice daily) and ceralasertib (160 mg once daily, days 1-7) in 28-day cycles. HRRm was defined as biallelic inactivation of BRCA2 or BRCA1 , monoallelic inactivation of ATM , or germline inactivation of any of these genes. The primary end point was disease response rate (dRR; confirmed prostate-specific antigen decline ≥50% and/or complete/partial radiographic response by RECIST v1.1) in HRP patients. Secondary end points included dRR in HRRm patients, progression-free survival (PFS), and safety/toxicity. Two-stage designs were used. RESULTS Four of 35 (11%; 95% CI, 3.2 to 26.7) HRP and four of 12 HRRm patients responded. Median PFS was 8.2 months (95% CI, 5.3 to not reached) for HRP patients. Thirty-six percent of patients had ≥grade 3 toxicity, most commonly from anemia. Limitations include small, single-arm, nonrandomized trial design. CONCLUSION Combining ceralasertib with olaparib had limited activity in patients with HRP mCRPC. HRRm response rate was not greater than previous single-agent PARP inhibitor clinical trials.

Background: Patients with acute ischemic stroke secondary to distal and medium vessel occlusion (AIS-DMVO) and minor strokes present a challenge in determining the most appropriate emergent treatment. Factors leading to early neurological deterioration (END) in this patient population are understudied, but END is known to result in poor functional outcomes. Therefore, we aimed to investigate the factors contributing to END in minor AIS-DMVO cases. Methods: We included patients with AIS-DMVO and minor strokes from 37 sites across North America, Asia, and Europe. Minor stroke was defined as a baseline National Institutes of Health Stroke Scale (NIHSS) score of ⩽5. The primary outcome measure, END, was defined as a shift of ⩾4 points in the NIHSS score at day one after treatment compared to baseline. Univariable and multivariable logistic regression analyses were performed to identify factors associated with END. Results: Among 559 consecutive patients with DMVO and minor strokes, END was reported in 68 patients. In multivariable analysis, mechanical thrombectomy (MT) was independently associated with higher odds of END (adjusted odds ratio [aOR] 2.37, 95% CI 1.12–5.02, p = 0.02), while intravenous thrombolysis (IVT) was associated with lower odds of END (aOR 0.46, 95% CI 0.26–0.81, p = 0.008). However, the association between MT and END was no longer statistically significant in the IPTW-adjusted analysis (OR 1.65, 95% CI 0.69–3.98, p = 0.26). Hypertension and antiplatelet use at baseline were also independently associated with END. Among MT-treated patients, successful and excellent recanalization and first-pass effect were protective against END. Conclusion: MT was associated with END in patients with minor AIS-DMVO, although this association was not significant after IPTW adjustment. IVT was independently associated with reduced risk of END. These findings support careful patient selection and further study in randomized trials.

Importance The prognosis of advanced pancreaticobiliary tumors is poor. Next-generation sequencing (NGS) of tissue samples is utilized to identify actionable alterations, but there are occasional limitations due to inadequate tissue acquisition. Circulating tumor DNA (ctDNA) is an alternative method, but its correlation with tissue-based NGS remains unexplored. Objectives To assess the mutation concordance (mCR) rates between ctDNA and tissue testing for patients with pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CC) and to evaluate how ctDNA performs as a treatment response biomarker. Design, Setting, and Participants This retrospective cohort study was conducted among patients with PDAC and CC treated at academic institutions from January 2014 to January 2025. Patients underwent ctDNA testing using 1 platform and tissue NGS testing using 2 platforms. Main Outcomes and Measures mCR, which measures the shared gene alterations observed by both ctDNA and tissue-based NGS testing, was calculated using the Spearman correlation for PDAC and CC. The performance of ctDNA as a treatment response biomarker was assessed by comparing serial ctDNA data with restaging scans and cancer antigen 19-9 levels in patients with PDAC. Results Our cohort included 790 patients: 570 with advanced PDAC (265 [46.5%] female; median [IQR] age, 64 [33-84] years) and 220 with advanced CC (95 [43.2%] female; median [IQR] age, 66 [42-88] years). Overall, 461 patients with PDAC (80.9%) and 192 patients with CC (87.2%) underwent ctDNA testing, while 239 patients with PDAC (41.9%) and 70 patients with CC (31.8%) had tissue NGS testing. Among patients with PDAC, 85 of 130 patients (65.4%) showed shared specific gene alterations between ctDNA and tissue testing; there was a significant mCR, with a Spearman correlation of 0.47 (95% CI, 0.28-0.62; P &amp;lt; .001). For patients with CC, 32 of 48 (66.7%) had shared alterations between ctDNA and tissue testing; there was a significant mCR, with a Spearman correlation of 0.56 (95% CI, 0.35-0.70; P &amp;lt; .001). A subgroup analysis of patients with PDAC who underwent serial ctDNA testing suggested that new TP53 subclones and increased ctDNA variant allele frequency levels of TP53 and KRAS were associated with higher odds of progressive disease (eg, increased TP53 frequency: odds ratio, 7.28; 95% CI, 2.15-24.66; P = .001). Conclusions and Relevance In this cohort study of patients with pancreaticobiliary tumors, there was a significant mCR between ctDNA and tissue NGS testing. Additionally, results suggest that ctDNA might detect resistant clones and enable assessment of treatment response.

OBJECTIVE The purpose of this study was to evaluate whether level selection for a three-column osteotomy (3CO) impacts cervical deformity correction outcomes, including neurological, radiographic, and patient-reported outcomes. METHODS A retrospective review was performed of patients who underwent a cervical or upper thoracic 3CO for cervical deformity correction by the senior author from 2008 to 2024. Collected outcome measures included neurological outcomes, mechanical complication rates, spinopelvic alignment, and patient-reported outcomes. The minimum follow-up was 1 year. RESULTS One hundred fifteen patients were identified who underwent a cervical or upper thoracic 3CO for cervical deformity correction, of whom 77 met inclusion criteria for this study with a minimum follow-up of 1 year. The median age was 66 years, the median BMI was 27, and 43% of patients were male. Sixteen patients underwent a 3CO at the C7–T1 levels and 61 patients at T2–6 levels. Patients who underwent C7–T1 3CO were more likely to experience a new postoperative neurological deficit compared with those who underwent T2–6 3CO (56% vs 18%, p = 0.004), had less correction in their T1 slope (6° vs 18°, p = 0.027), had less correction in C2–T4 sagittal vertical axis (2.8 cm vs 4.9 cm, p = 0.043), and had a worse Neck Disability Index (NDI) score at 1 year compared with baseline (an increase of 7 vs a decrease of 12, p = 0.033). CONCLUSIONS Cervical deformity patients who underwent a 3CO at C7–T1 had a higher rate of postoperative neurological deficits, less radiographic correction, and worse NDI scores at 1 year compared with patients who underwent a 3CO from T2 to T6. Although 3CO level selection is multifactorial and patient specific, surgeons should consider a 3CO level caudal to T1 when feasible.

Background: A 21-question Lifestyle Medicine Assessment (LMA) tool was recently developed to quickly evaluate the lifestyle medicine domains (Avoidance of Substance Use, Nutrition, Connection, Movement, and Recovery). In this study, we used the LMA tool to complete a preliminary analysis of family medicine providers, a group that is known to face challenging lifestyle demands and burnout. Objective: The primary purpose was to assess the LMA domain scores and determine if significant differences exist (among the domains). The secondary purpose was to complete a correlation matrix for the LMA domain scores to better understand the strength of the relationships (among domains). Methods: The participants were 35 family medicine providers and all completed the LMA. The maximum LMA score is 50 (each of the five domains is scored 0-10 points). Pairwise comparisons were used to determine if there were significant differences among the five domain scores (P < .05) and Pearson correlation was used to assess correlations between domains. Results: The overall LMA score was moderate (34.68 ± 6.26). The Recovery domain score (4.71 ± 2.91) was significantly lower (P < 0.01) than the other domains (Connection = 6.94 ± 2.16; Nutrition = 7.41 ± 2.00; Movement = 6.26 ± 2.94; Avoidance of Substance Use = 9.35 ± 1.28). The Avoidance of Substance Use score was significantly higher than the other domains ( P < .01). Overall, the correlation scores among the domains were weak (all r-scores were ≤0.34). Conclusions: For this group of providers, there appears to be substantial room for improvement in four of the five domains. The domain of greatest concern appears to be Recovery. The weak correlation scores suggest that domain scores tend to be independent of each other, and that assessment results are unique to the individual.

Our study examined healthy human MASH and MASH-associated hepatocellular carcinoma (MASH-HCC) livers using bulk and scRNA sequencing, spatial transcriptomics, and immunohistochemistry. We found that ACSLs displayed differential and spatially heterogeneous expression. ACSL4 was abundant in tumor tissues, whereas ACSL5 was elevated in noncancerous MASH tissues. ACSL4 was mainly found in immune cells like natural killer cells and natural killer T cells in murine MASH-HCC, suggesting its role in tumor immune microenvironment modulation.