Citations

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non–muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)–unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

Abstract Aims Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials. Methods and results Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: < 1.8 mmol/L (< 70 mg/dL); ASCVD risk equivalent: < 2.6 mmol/L (< 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was −49.4% (95% CI: −50.4, −48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified. Conclusion In the largest and longest follow-up to date with >12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile. Trial Registration number ClinicalTrials.gov identifier: NCT03814187

Context: Elbow medial ulnar collateral ligament (UCL) injuries have become increasingly common in athletes. Despite this, rehabilitation protocols appear to vary drastically, which may explain the clinical equipoise regarding optimal management. Objective: This systematic review reports rehabilitation characteristics reported after UCL injuries and compares reported outcomes based on early versus delayed rehabilitation. Data Sources: Our search utilized PubMed/MEDLINE, Embase, Web of Science, and Cochrane to identify all articles on UCL rehabilitation published between January 1, 2002 and October 1, 2022. Study Selection: Studies in English with ≥5 patients that reported rehabilitation protocols for UCL injuries were evaluated. Study Design: Systematic review. Level of Evidence: Level 4. Data Extraction: Data included sample characteristics, time to achieve physical therapy milestones, outcome scores, and return-to-play (RTP) rate and timing. Results: Our review included 105 articles with a total of 15,928 elbows (98% male; weighted mean age, 23 years; follow-up, 47 months), with 15,077 treated operatively and 851 treated nonoperatively. The weighted mean time patients spent adhering to nonweightbearing status was 42 days. The mean time until patients were given clearance for active range of motion (ROM) 15 days, full ROM 40 days, and elbow strengthening exercises 32 days. The mean time until all restrictions were lifted was 309 days. The mean time to begin a throwing program was 120 days. Across all rehabilitation characteristics, protocols for patients undergoing nonoperative management started patients on rehabilitation earlier. After UCL reconstruction, earlier active ROM (≤14 days), elbow strengthening (≤30 days), no restrictions (≤180 days), and throwing (≤120 days) postoperatively led to earlier RTP without a negative effect on functional outcome scores. Conclusion: Current literature provides a spectrum of protocols for elbow UCL rehabilitation, regardless of management. Nonoperative patients began ROM activities, strengthening, and throwing programs sooner than operative patients, and earlier milestones led to earlier RTP.

Abstract Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements (“double hit”; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated. Here, we used custom targeted capture and/or whole-genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, although BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because 1 IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B-cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.

Abstract Background: Fibroblast growth factor receptor 1 (FGFR1) gene amplification and overexpression is associated with an adverse prognosis in hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) breast cancer and is observed in ~10% of all invasive breast cancers. The phase 2 FOENIX-MBC2 study (NCT04024436) was designed to evaluate the effect of futibatinib, a highly selective and potent irreversible covalent inhibitor of FGFR1–4 (FDA-approved for intrahepatic cholangiocarcinoma), used either alone or in combination with fulvestrant in patients with metastatic breast cancer. Here, we report final efficacy and safety data for the cohort of patients receiving futibatinib plus fulvestrant for HR+/HER2− breast cancer harboring high-level FGFR1 gene amplification. Methods: Patients were eligible if they had disease progression after prior therapy for advanced/metastatic disease, had measurable disease per RECIST v1.1, had an ECOG performance status of 0 or 1, were fulvestrant-naïve, and had previously received 1–2 endocrine-containing therapies, ≤1 chemotherapy regimen, and a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for advanced cancer (unless ineligible). High-level FGFR1 gene amplification, determined in tumor tissue using next-generation sequencing, fluorescence in situ hybridization (FISH), or similar assays, was defined as FGFR1/centromere 8 ratio ≥5 or FGFR1 copy number ≥10 signals per cell. Local FGFR1 determination results were confirmed in tumor tissue by a central laboratory using FISH. Patients received oral futibatinib 20 mg once daily and standard fulvestrant dosing until disease progression, unacceptable toxicity, or other discontinuation criteria were met. The primary endpoint was the 6-month progression-free survival (PFS) rate. Key secondary endpoints included objective response rate (ORR), PFS, and overall safety. Results: Overall, 22 female patients were enrolled in this cohort. Patients were a median age of 58 years, had received a median of 3 lines of any prior systemic anticancer therapy, and had all received CDK4/6 inhibitor pretreatment. PFS at 6 months was observed in 10 (45.5%) patients (95% CI: 24.4, 67.8) and the median PFS was 7.2 (95% confidence interval [CI]: 2.1, 7.6) months. Four patients had a confirmed partial response (ORR: 18.2%; 95% CI: 5.2, 40.3). The median duration of response was 6.3 (range: 3.3–12.8) months. All patients had ≥1 treatment-related adverse event (TRAE), the most common being hyperphosphatemia (95.5%), alopecia (54.5%), constipation (45.5%), and dry mouth (40.9%). There were 5 (22.7%) patients with a Grade 3 TRAE (no Grade 4 or 5). TRAEs leading to study treatment interruption or reduction were seen in 9 (40.9%) and 15 (68.2%) patients, respectively. There were 2 (9.1%) patients who had TRAEs leading to study treatment discontinuation. No treatment-related serious adverse events were reported. Conclusions: Futibatinib plus fulvestrant showed antitumor activity in patients with advanced HR+/HER2− breast cancer with FGFR1 amplification progressing on prior CDK4/6 inhibitors, with a numerically higher ORR and doubling in PFS relative to historical fulvestrant results in post-CDK4/6 patients. The safety profile was consistent with those of the individual study drugs. Further biomarker work is ongoing. Citation Format: Senthil Damodaran, Fabrice André, Nisha Unni, Marta Ferreira, Karthik Giridhar, Brooke Daniel, Marco Colleoni, Luis Costa, Thomas Bachelot, Ciara O’Brien, Gail Wright, Masashi Shimura, Gareth Tomlinson, Maciej Gil, Nicholas Turner. Final results from the phase 2, open-label FOENIX-MBC2 study: efficacy and safety of futibatinib in adult patients with locally advanced/metastatic HR+/HER2− breast cancer harboring high-level FGFR1 gene amplification [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF01-04.

Background: Patients with severe aortic stenosis being considered for transcatheter aortic valve replacement (TAVR) undergo aortoiliac computed tomographic angiography (CTA) of the chest/abdomen/pelvis. Despite the increasing number of TAVR procedures worldwide, little is known regarding the clinical significance of non-cardiovascular incidental findings (IFs) on TAVR-CTA scans. Objective: To determine the frequency, clinical significance and impact on survival of non-cardiovascular IFs detected on TAVR-CTA scans. Methods: CTA studies for 424 consecutive patients being evaluated for TAVR were reviewed for non-cardiovascular IFs (62% male, median age 82±8.3 years). The electronic medical record was reviewed to assess for subsequent clinical management and survival. Results: An IF was present in nearly all patients (99%). The mean number of IFs per patient was 5.3 (±2.8; range 0-14). After excluding obviously benign IFs, 67% had at least one potentially pathologic IF (mean 1.1±1.0). Factors associated with higher numbers of IFs were age (p<0.0001) and use of IV contrast (p=0.03). IFs prompted clinical work-up in 39 patients (9.2%) and delayed or cancelled procedures in 7 patients (1.7%). The number needed to image to diagnose a new malignancy or medical condition was 19. The number of IFs was predictive of poor overall survival before (HR 1.09; 95% CI (1.02 to 1.70), p=0.02) and after adjustment for baseline clinical variables (HR 1.07; (1.0 to 1.15); p=0.04). Conclusions: This investigation demonstrates that IFs are present in nearly all TAVR-CTA scans, commonly require further clinical evaluation, and are associated with poorer survival. TAVR institutions should have mechanisms in place to ensure communication and follow-up of IFs.

Background: Patients suffering post operative myocardial infarction (PMI) have higher mortality and morbidity rates than observed with non-PMI subsets. Little is known about the true incidence of PMI and how PMI differs from non-PMI with regard to clinical presentation, management and outcome. Methods: We examined the incidence and outcomes of patients with PMI in 1212 subjects (≥65 years) undergoing hip fracture surgery from 1988 – 2002 using a population-based retrospective cohort study from the Rochester Epidemiology Project in Olmstead County, Minnesota. PMI was defined on the basis of cardiac biomarker and/or electrocardiographic evidence of definitive MI within 7 days post operatively. Results: PMI occurred in 170 (14.0%) patients yet only 36 (21.2 %) patients had one or more clinical symptoms suggesting coronary ischemia. One or more classic symptoms of myocardial infarction were present in 26 (15.3%) including shortness of breath (SOB) in 18 (10.6%), chest/arm pain in 11 (6.5%), nausea/vomiting in 8 (4.7%) and diaphoresis in 1 (0.6%). Delirium was present in 15 (8.8%) patients. Median hospital length of stay was longer (10.0 vs. 8 days, p<0.01) and the in-hospital mortality rate was significantly higher (14.1% vs. 1.6%, p<0.001) among patients who had PMI within 7 days. Conclusion: The clinical presentation of PMI differs from non-PMI in the elderly undergoing hip fracture surgery. Most patients were asymptomatic or had atypical clinical presentations. We observed a significantly higher rate of hospital mortality among those experiencing a PMI. Further studies are necessary to better understand the presentation, optimal management and prevention of PMI. Table 1. Study Population Table 2. Clinical Presentation and Outcomes in Patients with and without Post Operative MI This research has received full or partial funding support from the American Heart Association, National Center.

Abstract One striking clinical hallmark in patients with autoantibodies to leucine-rich glioma inactivated 1 (LGI1) is the very frequent focal seizure semiologies, including faciobrachial dystonic seizures (FBDS), in addition to the amnesia. Polyclonal serum IgGs have successfully modelled the cognitive changes in vivo but not seizures. Hence, it remains unclear whether LGI1-autoantibodies are sufficient to cause seizures. We tested this with the molecularly precise monoclonal antibodies directed against LGI1 [LGI1-monoclonal antibodies (mAbs)], derived from patient circulating B cells. These were directed towards both major domains of LGI1, leucine-rich repeat and epitempin repeat, and infused intracerebroventricularly over 7 days into juvenile male Wistar rats using osmotic pumps. Continuous wireless EEG was recorded from a depth electrode placed in hippocampal CA3 plus behavioural tests for memory and hyperexcitability were performed. Following infusion completion (Day 9), post-mortem brain slices were studied for antibody binding and effects on Kv1.1. The LGI1-mAbs bound most strongly in the hippocampal CA3 region and induced a significant reduction in Kv1.1 cluster number in this subfield. By comparison to control-Ab injected rats video-EEG analysis over 9 days revealed convulsive and non-convulsive seizure activity in rats infused with LGI1-mAbs, with a significant number of ictal events. Memory was not impaired in the novel object recognition test. Peripherally-derived human LGI1-mAbs infused into rodent CSF provide strong evidence of direct in vivo epileptogenesis with molecular correlations. These findings fulfill criteria for LGI1-antibodies in seizure causation.