Citations

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.

Background: Diagnosis of foveal triangular fibrocartilage complex (TFCC) tears remains difficult. The purpose of this study was to evaluate whether dynamic computed tomography (CT) of the distal radioulnar joint (DRUJ) has a higher sensitivity in detecting foveal tears of the TFCC when compared with magnetic resonance imaging (MRI). Methods: A database query identified all patients above the age of 18 years with suspected foveal TFCC injuries who underwent bilateral dynamic CT imaging of the DRUJ, static 3T MRI, and subsequent wrist arthroscopy. All patients had evidence of foveal tenderness on clinical examination. The imaging results were validated with wrist arthroscopy. Results: Twelve patients with a mean age of 31 years (range, 18-53 years) were identified. Eight patients were diagnosed with a complete foveal detachment of the TFCC on wrist arthroscopy. Of the 8 patients with a foveal tear on DRUJ arthroscopy, only 3 had a preoperative physical examination suggestive of DRUJ instability. Magnetic resonance imaging identified foveal injuries in 4 of these 8 patients (sensitivity, 50%), and 3 of these were identified as only partial tears. Dynamic CT identified instability of DRUJ in 6 of 8 patients (sensitivity, 75%). Seven of 8 patients had imaging findings suggestive of a foveal tear when including either MRI or CT imaging (sensitivity, 88%). Of the 4 patients with an intact foveal attachment on arthroscopy, 3 (specificity, 75%) had a stable DRUJ on CT and all 4 (specificity, 100%) had an intact foveal attachment on MRI. Conclusion: Sixty-two percent of patients with foveal tears on arthroscopy have a stable DRUJ on clinical examination. When combining MRI and dynamic CT imaging of the DRUJ, the sensitivity of detecting a foveal TFCC tear approaches 88% compared with a gold standard of wrist arthroscopy.

Superior mesenteric artery syndrome (SMAS) is a rare and potentially life-threatening cause of small bowel obstruction in which the superior mesenteric artery impinges on the third portion of the duodenum. SMAS is typically encountered in patients with low body fat and a history of rapid weight loss and is often diagnosed as a chronic or subacute condition. Here, we describe a case of a healthy adolescent boy without typical SMAS prodromal symptoms presenting with a severe, hyperacute proximal small bowel obstruction due to SMAS. Complications arising from massive gastric and duodenal distension, including gastric, pancreatic and renal ischaemia, necessitated emergent surgical intervention consisting of the duodenojejunostomy bypass with partial gastric resection. The patient recovered without significant lasting consequences.

BACKGROUND AND OBJECTIVES: Enhanced recovery after surgery (ERAS) protocols aim to optimize patient outcomes by reducing the surgical stress response, expediting recovery, and reducing care costs. We aimed to evaluate the impact of implementing ERAS protocols on the perioperative surgical outcomes and financial implications associated with spine surgeries. METHODS: A systematic review and meta-analysis of peer-reviewed studies directly comparing outcome differences between spine surgeries performed with and without utilization of ERAS pathways was conducted along Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of 676 unique articles identified, 59 with 15 198 aggregate patients (7748 ERAS; 7450 non-ERAS) were included. ERAS-treated patients had shorter operative times (mean difference [MD]: 10.2 mins; P < .01), shorter hospitalizations (MD: 1.41 days, P < .01), fewer perioperative complications (relative risk [RR] = 0.64, P < .01), lower postoperative opioid use (MD of morphine equivalent dose: 164.36 mg; P < .01), and more rapid mobilization/time to first out-of-bed ambulation (MD: 0.92 days; P < .01). Spine surgeries employing ERAS were also associated with lower total costs (MD: $1140.26/patient; P < .01), especially in the United States (MD: $2869.11/patient, P < .01) and lower postoperative visual analog pain scores (MD = 0.56, P < .01), without any change in odds of 30-day readmission (RR: 0.80, P = .13) or reoperation (RR: 0.88, P = .60). Subanalyses based on the region of spine showed significantly lower length of stay in both cervical and lumbar surgeries implementing ERAS. Type of procedure showed a significantly lesser time-to-initiate mobilization in fusion surgeries using ERAS protocols compared with decompression. CONCLUSION: The present meta-analysis indicates that current literature supports ERAS implementation as a means of reducing care costs and safely accelerating hospital discharge for patients undergoing spine surgery.

ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G 0 -G 1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53 -mutant tumors but not in TP53 -WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53 -mutant, but not in TP53 -WT, PDXs. In plasmid-based reporter assays, GBM43 ( TP53 -mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53 -mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53 -mutant cells to ATM inhibitor–mediated radiosensitization.

Abstract The loss of skeletal muscle mass during aging is a significant health concern linked to adverse outcomes in older individuals. Understanding the molecular basis of age‐related muscle loss is crucial for developing strategies to combat this debilitating condition. Long noncoding RNAs (lncRNAs) are a largely uncharacterized class of biomolecules that have been implicated in cellular homeostasis and dysfunction across a many tissues and cell types. To identify lncRNAs that might contribute to skeletal muscle aging, we screened for lncRNAs whose expression was altered in vastus lateralis muscle from older compared to young adults. We identified FRAIL1 as an aging‐induced lncRNA with high abundance in human skeletal muscle. In healthy young and older adults, skeletal muscle FRAIL1 was increased with age in conjunction with lower muscle function. Forced expression of FRAIL1 in mouse tibialis anterior muscle elicits a dose‐dependent reduction in skeletal muscle fiber size that is independent of changes in muscle fiber type. Furthermore, this reduction in muscle size is dependent on an intact region of FRAIL1 that is highly conserved across non‐human primates. Unbiased transcriptional and proteomic profiling of the effects of FRAIL1 expression in mouse skeletal muscle revealed widespread changes in mRNA and protein abundance that recapitulate age‐related changes in pathways and processes that are known to be altered in aging skeletal muscle. Taken together, these findings shed light on the intricate molecular mechanisms underlying skeletal muscle aging and implicate FRAIL1 in age‐related skeletal muscle phenotypes.

Abstract Advances in genetic technology have led to the increasing use of genomic panels in precision oncology practice, with panels ranging from a couple to hundreds of genes. However, the clinical utilization and utility of oncology genomic panels, especially among vulnerable populations, is unclear. We examined the association of panel size with socioeconomic status and clinical trial matching. We retrospectively identified 9,886 eligible adult subjects in the Mayo Clinic Health System who underwent genomic testing between January 1, 2016 and June 30, 2020. Patient data were retrieved from structured and unstructured data sources of institutional collections, including cancer registries, clinical data warehouses, and clinical notes. Socioeconomic surrogates were approximated using the Area Deprivation Index (ADI) corresponding to primary residence addresses. Logistic regression was performed to analyze relationships between ADI or rural/urban status and (i) use of genomic test by panel size; (ii) clinical trial matching status. Compared with patients from the most affluent areas, patients had a lower odds of receiving a panel test (vs. a single-gene test) if from areas of higher socioeconomic deprivation [OR (95% confidence interval (CI): 0.71 (0.61–0.83), P &lt; 0.01] or a rural area [OR (95% CI): 0.85 (0.76–0.96), P &lt; 0.01]. Patients in areas of higher socioeconomic deprivation were less likely to be matched to clinical trials if receiving medium panel tests [(OR) (95% CI): 0.69 (0.49–0.97), P = 0.03]; however, there was no difference among patients receiving large panel tests (P &gt; 0.05) and rural patients were almost 2x greater odds of being matched if receiving a large panel test [(OR) (95% CI): 1.76 (1.21–2.55), P &lt; 0.01]. Significance: We identified socioeconomic and rurality disparities in the use of genomic tests and trial matching by panel size, which may have implications for equal access to targeted therapies. The lack of association between large panel tests and clinical trial matching by socioeconomic status, suggests a potential health equity impact, while removing barriers in access to large panels for rural patients may improve access to trials. However, further research is needed.

Background: Approximately 90% of patients who undergo arthroscopic rotator cuff repair (RCR) are satisfied with their pain levels and function after surgery. However, a subset of patients experience continued symptoms that warrant revision surgery. Preoperative risk factors for RCR failure requiring revision surgery have not been clearly defined. Purpose: To (1) determine the rate of RCR failure requiring revision surgery and (2) identify risk factors for revision surgery, which will help surgeons to determine patients who are at the greatest risk for RCR failure. Study Design: Systematic review and meta-analysis; Level of evidence, 4. Methods: A systematic review and meta-analysis in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were performed. The initial search resulted in 3158 titles, and 533 full-text articles were assessed for eligibility. A total of 10 studies met the following inclusion criteria: (1) human clinical studies, (2) arthroscopic RCR, (3) original clinical research, and (4) evaluation of preoperative risk factors for revision. Results: After a full-text review, a total of 16 risk factors were recorded and analyzed across 10 studies. Corticosteroid injection was the most consistent risk factor for revision surgery, reaching statistical significance in 4 of 4 studies, followed by workers’ compensation status (2/3 studies). Patients with corticosteroid injections had a pooled increased risk of revision surgery by 47% (odds ratio, 1.44 [95% CI, 1.36-1.52]). Patients with workers’ compensation had a pooled increased risk of revision surgery by 133% (odds ratio, 2.33 [95% CI, 2.09-2.60]). Age, smoking status, diabetes, and obesity were found to be risk factors in half of the analyzed studies. Conclusion: Corticosteroid injections, regardless of the frequency of injections, and workers’ compensation status were found to be significant risk factors across the literature based on qualitative analysis and pooled analysis. Surgeons should determine ideal candidates for arthroscopic RCR by accounting for corticosteroid injection history, regardless of the frequency, and insurance status of the patient.

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

Background:Ibrutinib is approved in Europe and the US for the treatment of Waldenstrom macroglobulinemia (WM) with a median progression‐free survival (PFS) measured on several years. As PFS is commonly used for drug approval by regulatory entities, there is an unmet need of reliable surrogate markers for PFS that could help accelerating such process. This is of importance with novel BTK inhibitors currently in clinical trials.Aims:We hypothesized that the depth of response at 6 months can be predictive of PFS in patients with WM treated with the BTK inhibitor ibrutinib.Methods:We evaluated our hypothesis in two separate cohorts of WM patients treated with ibrutinib. The learning cohort was composed by participants of two prospective clinical trials at Dana‐Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center and Stanford Cancer Center. The validation cohort was composed by consecutive WM patients treated with ibrutinib off clinical trial at DFCI and Mayo Clinic. Categorical responses at 6 months were assessed based on criteria from the 6thInternational Workshop for WM. PFS6 was defined as the time from the 6‐month response assessment until progression of disease or death from any cause. PFS6 curves were generated using the Kaplan‐Meier method and compared using the log‐rank test. Cox proportional hazard regression models were fitted for PFS6. Pvalues <0.05 were considered statistically significant.Results:The learning and validation cohorts were composed by 92 and 190 WM patients treated with ibrutinib, repsectively. There were no statistical differences between cohorts with regards to age, sex, serum IgM level, hemoglobin level, bone marrow involvement, prior treatment status, and MYD88 and CXCR4 mutational status (p>0.05 for all variables). The rates of partial response (PR) or better at 6 months in the learning and validation cohorts were 63% (54/86) and 72% (114/159), respectively (p = 0.15). The median PFS6 was not reached in the learning cohort and was 53 months (95% CI 44‐not reached) in the validation cohort. In the learning cohort, the median PFS6 for patients who attained a PR or better at 6 months was not reached, while for the patients who did not attained PR at 6 months was 48 months (95% CI 33‐not reached). The 3‐year PFS rate for patients who attained a PR or better at 6 months was 83% (95% CI 68–91%), while for patients who did not attained PR at 6 months was 58% (95% CI 33–76%) (Figure, left, log‐rank p = 0.02). Attaining PR or better at 6 months was associated with a hazard ratio (HR) or progressing or dying of 0.37 (95% CI 0.16–0.87; p = 0.02).In the validation cohort, the median PFS6 for patients who attained a PR or better at 6 months was 53 months (95% CI 44‐not reached), while for the patients who did not attained PR at 6 months was 32 months (95% CI 22‐not reached). The 3‐year PFS rate for patients who attained a PR or better at 6 months was 79% (95% CI 67–87%), while for patients who did not attained PR at 6 months was 50% (95% CI 26–70%) (Figure, right, log‐rank p = 0.04). Attaining PR or better at 6 months was associated with a hazard ratio (HR) or progressing or dying of 0.46 (95% CI 0.22–0.98; p = 0.04). Age, sex, serum IgM level, hemoglobin level, bone marrow involvement and prior treatment status were not prognostic of PFS6 in both cohorts.Summary/Conclusion:Attaining a PR or better at 6 months to ibrutinib is associated with longer median PFS and higher rates of 3‐year PFS in WM patients. Depth of response at 6 months could serve as a surrogate for PFS in clinical trials evaluating BTK inhibitors in WM patients.image