Citations

Melanoma is the deadliest form of skin cancer. The median age at diagnosis is 66. While most patients are treated with immunotherapy, the use of targeted therapy is a valid alternative for patients whose tumors harbor a BRAF or c-KIT driver mutation. These agents, while effective, come with a variety of side effects which limit their use, especially in older patients. We sought to assess the efficacy and toxicity of these agents in older melanoma patients. Melanoma patients over 65 treated with BRAF/MEK or c-KIT inhibitors were retrospectively identified, and their data were analyzed for treatment efficacy and toxicity. All data were compared using the Chi-square test for categorical comparisons and the Kruskal–Wallis method for median comparisons. One hundred and sixteen patients were identified. One hundred and six patients were treated with BRAF/MEK inhibitors. The assessed response rate (RR) was 83% and was comparable across different subgroups, including advanced line patients and those with a more aggressive disease. The median progression free survival (PFS) was 7.9 months, and the median overall survival (OS) was 15.7 months. Twenty-seven percent experienced grade 3–4 toxicity leading to a 24% treatment discontinuation rate. Another 10 patients were treated with the c-KIT inhibitor imatinib, for whom the assessed RR was 55%. The median PFS was 4.3 months, and the median OS was 22.6 months. Forty percent needed dose reductions, yet none had to stop treatment due to adverse effects. The use of targeted therapy in older patients is effective yet challenging due to toxicity. Deploying mitigation strategies can help maximizing their usefulness.

AbstractBackgroundThis study investigates the impact of margin status after colorectal liver metastasis (CLM) resection on outcomes of patients after neoadjuvant treatment versus those who underwent upfront resection.MethodsAn international collaborative database of CLM patients who underwent surgical resection was used. Proportional hazard regression models were created for single and multivariable models to assess the relationship between independent measures and median overall survival (mOS).ResultsR1 was associated with worse OS in the neoadjuvant group (mOS: 51.8 m for R0 vs. 26.0 m for R1; HR: 2.18). In the patients who underwent upfront surgery, R1 was not associated with OS. (mOS: 46.7 m for R0 vs. 42.6 m for R1). When patients with R1 in each group were stratified by adjuvant treatment, there was no significant difference in the neoadjuvant group, while in the upfront surgery group with R1, adjuvant treatment was associated with significant improvement in OS (mOS: 42.6 m for adjuvant vs. 25.0 m for no adjuvant treatment; HR: 0.21).ConclusionR1 is associated with worse outcomes in the patients who receive neoadjuvant treatment with no significant improvement with the addition of adjuvant therapy, likely representing an aggressive tumor biology. R1 did not impact OS in patients with upfront surgery who received postoperative chemotherapy.

Background A combination of intravenous (IVT) or intra-arterial (IAT) thrombolysis with mechanical thrombectomy (MT) for acute ischemic stroke due to large vessel occlusion (AIS-LVO) has been investigated. However, there is limited data on patients who receive both IVT and IAT compared with IVT alone before MT. Methods STAR data from 2013 to 2023 was utilized. We performed propensity score matching between the two groups. The primary outcomes were symptomatic intracranial hemorrhage (sICH) and 90-day modified Rankin Scale (mRS) score 0–2. Secondary outcomes included successful recanalization (modified treatment in cerebral infarction (mTICI) ≥2B, ≥2C), early neurological improvement, any intracranial hemorrhage (ICH), and 90-day mortality. Results A total of 2454 AIS-LVO patients were included. Propensity matching yielded 190 well-matched patients in each group. No significant differences were observed between the groups in either ICH or sICH (odds ratio (OR): 0.80, 95% confidence interval (CI) 0.51–1.24, P=0.37; OR: 0.60, 95% CI 0.29 to 1.24, P=0.21, respectively). Rates of successful recanalization and early neurological improvement (ENI) were significantly lower in MT+IVT + IAT. mRS 0–1 and mortality were not significantly different between the two groups. However, the MT+IVT + IAT group demonstrated superior rates of good functional outcomes (90-day mRS 0–1) compared with patients in the MT+IVT group who had mTICI ≤2B, (OR: 2.18, 95% CI 1.05 to 3.99, P=0.04). Conclusion The combined use of IAT and IVT thrombolysis in AIS-LVO patients undergoing MT is safe. Although the MT+IVT+ IAT group demonstrated lower rates of recanalization and early neurological improvement, long-term functional outcomes were favorable in this group suggesting a potential delayed benefit of IAT.

Background Whereas mechanical thrombectomy (MT) has become standard-of-care treatment for patients with salvageable brain tissue after acute stroke caused by large-vessel occlusions, the results of MT in patients with medium-vessel occlusions (MEVOs), particularly in the posterior cerebral artery (PCA), are not well known. Methods Using data from the international Stroke Thrombectomy and Aneurysm Registry (STAR), we assessed presenting characteristics and clinical outcomes for patients who underwent MT for primary occlusions in the P2 PCA segment. As a subanalysis, we compared the PCA MeVO outcomes with STAR's anterior circulation MeVO outcomes, namely middle cerebral artery (MCA) M2 and M3 segments. Results Of the 9812 patients in STAR, 43 underwent MT for isolated PCA MeVOs. The patients’ median age was 69 years (interquartile range 61–79), and 48.8% were female. The median NIH Stroke Scale score was 9 (range 6–17). After recanalization, 67.4% of patients achieved successful recanalization (modified treatment in cerebral infarction score [mTICI] ≥ 2b), with a first-pass success rate of 44.2%, and 39.6% achieved a modified Rankin score of 0–2 at 90 days. Nine patients (20.9%) had died by the 90-day follow-up. In comparison with M2 and M3 MeVOs, there were no differences in presenting characteristics among the three groups. Patients with PCA MeVOs were less likely to undergo intra-arterial thrombolysis (4.7% PCA vs. 10.1% M2 vs. 16.2% M3, p = 0.046) or to achieve successful recanalization (mTICI ≥ 2b, 67.4%, 86.7%, 82.3%, respectively, p < 0.001); however, there were no differences in the rates of successful first-pass recanalization (44.2%, 49.8%, 52.3%, respectively, p = 0.65). Conclusions We describe the STAR experience performing MT in patients with PCA MeVOs. Our analysis supports that successful first-pass recanalization can be achieved in PCA MEVOs at a rate similar to that in MCA MeVOs, although further study and possible innovation may be necessary to improve successful PCA MeVO recanalization rates.

Background: Arthroscopic access to the hip can be challenging. We present a reproducible, safe, and efficient method for arthroscopic access to the hip. This can be especially beneficial for hips that may be predisposed to more difficult access. Indications: Hip arthroscopy is indicated in patients with symptomatic femoral acetabular impingement (FAI) who have failed conservative treatment options. FAI surgery aims to address both bony impingement and labral pathology in the hip. Technique: In this technique, we describe methodical steps to hip access. These steps include special attention to patient positioning and preoperative radiographs, air arthrogram, bevel control for needle joint entry, careful interpretation of intraoperative fluoroscopy, and adequate capsulotomy for viewing. Results: The majority of patients undergoing hip arthroscopy for FAI have improvements in both hip function and pain. Preoperative findings of increased center edge angle and male sex may predispose patients to more difficult hip arthroscopy access. The use of this technique may aid in reproducible access. Discussion/Conclusion: Hip arthroscopy is a good option for patients who have failed conservative treatment options and have signs and symptoms of FAI. Reproducible, safe, and efficient access to the hip is critical to starting hip arthroscopy cases. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

AbstractBackgroundThermal ablation has recently become a key therapy for the treatment of colorectal liver metastasis (CLM). However, the role of ablation in combination with resection has not yet been firmly established. We hypothesize that in patients with CLM, those who undergo liver resection with ablation (RA) have similar outcomes compared with those who undergo liver resection only.MethodsWe reviewed a multicenter international database of 906 surgical procedures for CLM from 5 high volume hepatobiliary surgical units. Patients undergoing RA (n = 63) were matched based on the number of lesions and tumor size using a 1:1 balanced propensity score analysis with those having resection only (n = 63). Our primary outcomes were overall survival (OS) and disease‐free survival (DFS).ResultsThe mean age of our cohort was 58 ± 11 years, with 43% females. With a median follow‐up of 70.8 months, patients in the resection and RA group had a median OS of 45.1 and 54.8 months (p = 0.71), respectively. The median DFS was 22.7 and 14.2 months (p = 0.045), respectively. Using a multivariate Cox proportional hazards regression model, the treatment approach was not associated with OS (p = 0.94) or DFS (p = 0.059). A higher number of lesions is independently associated with worse DFS (hazard ratio: 1.12, p < 0.01). When there was disease recurrence, the region of recurrence was similar between the RA versus resection only groups (p = 0.27), but there was a shorter time to recurrence in the RA group (p = 0.002).ConclusionFor CLM, the treatment approach was not significantly associated with OS or DFS, while tumor biology likely played an important role. Prospective research on the quality and effectiveness of thermal ablation combined with hepatic resection is warranted.

CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D + R – ) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C + NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4 + T cells, CD3 neg CD56 dim CD57 neg NKG2C pos cells, and CD3 neg CD56 dim CD57 pos NKG2C pos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D + R – LTxR.

Abstract Background Outcomes in alcohol‐associated liver disease (ALD) are influenced by several race and ethnic factors, yet its natural history across the continuum of patients in different stages of the disease is unknown. Methods We conducted a retrospective cohort study of U.S. adults from 2011 to 2018, using three nationally representative databases to examine potential disparities in relevant outcomes among racial and ethnic groups. Our analysis included logistic and linear regressions, along with competing risk analysis. Results Black individuals had the highest daily alcohol consumption (12.6 g/day) while Hispanic participants had the largest prevalence of heavy episodic drinking (33.5%). In a multivariable‐adjusted model, Hispanic and Asian participants were independently associated with a higher ALD prevalence compared to Non‐Hispanic White interviewees (OR: 1.4, 95% CI: 1.1–1.8 and OR: 1.5 95% CI:1.1–2.0, respectively), while Blacks participants had a lower ALD prevalence (OR: .7 95% CI: .6–.9), and a lower risk of mortality during hospitalization due to ALD (OR: .83 95% CI: .73–.94). Finally, a multivariate competing‐risk analysis showed that Hispanic ethnicity had a decreased probability of liver transplantation if waitlisted for ALD (SHR: .7, 95% CI: .6–.8) along with female Asian population (HR: .40, 95% CI: .26–.62). Conclusions After accounting for key social and biological health determinants, the Hispanic population showed an increased risk of ALD prevalence, even with lower alcohol consumption. Additionally, Hispanic and Asian female patients had reduced access to liver transplantation compared to other enlisted patients.

Background Nickel hypersensitivity is the most common metal related allergy. Nickel containing alloys are frequently used in endovascular devices. The use of intracranial stents in patients with nickel hypersensitivity appears to be safe, but these small series only evaluated arterial stent placement. This case series aimed to assess the safety of intracranial venous stent placement in patients with documented nickel allergy. Methods In this retrospective multicenter case series, patients with idiopathic intracranial hypertension and documented nickel allergy underwent treatment with a permanently implanted nickel containing stent in the dural venous sinuses. Results Nine patients with nickel allergy were included. All patients reported clinical improvement in their idiopathic intracranial hypertension symptoms. Of the five patients who had follow-up intracranial venous imaging, all stents remained patent. No patients experienced intraoperative, postoperative, or long term procedure related complications, with follow-up ranging from 1.8 weeks to 49.1 months. Conclusion In this limited case series, the use of nickel containing stents in intracranial venous sinuses in patients with nickel allergy did not result in any allergic reaction or adverse outcome.

TPS2700 Background: Though immunotherapy with anti-PD-1 immune checkpoint inhibitors (ICIs) has led to improvements in clinical outcomes in patients with cancer, when used as monotherapy in the advanced setting, only 18-25% of patients respond to ICI. Notably, ICI frequently lacks anti-tumor activity in immune-cold cancers where T cell priming is missing. Recent breakthroughs in identifying personal neoantigens via a comprehensive analysis of cancer sequencing data have brought increased attention to neoantigen cancer vaccines. Personalized cancer vaccines targeting neoantigens have shown early promise. While neoantigens have recently been investigated in some cancer types, the current neoantigen prediction algorithms have often focused on the MHC class-I subtype, single nucleotide mutations (SNM), small insertions and deletions (INDEL). We recently developed an informatics workflow, REAL-neo, for the identification, quality control (QC), and prioritization of both class-I and class-II human leukocyte antigen (HLA) bound neoantigens that arise from somatic SNM, INDEL, aberrant RNA splicing, and gene fusions, generating much more potent neoantigen candidates. Furthermore, we demonstrated robust T-cell response and prolonged survival by combining ICI and cancer vaccines in preclinical models. This single-arm phase I clinical trial is in progress to assess the safety, feasibility, and immunogenicity of personalized neoantigen vaccines in combination with pembrolizumab in patients with advanced solid cancers. Methods: The vaccine consists of up to 20 peptides (15-30 mer) comprising patient-specific neoantigens identified from tumor DNA and mRNA sequencing data using REAL-neo and delivered with GM-CSF as an adjuvant. The first cohort of three patients will be treated at dose level 1 consisting of 4 or 5 peptides at 300 mcg/peptide and GM-CSF 125 mcg per injection site in each of four limbs. After Cohort 1 is deemed safe, the study will expand to cohort 2, when patients will be enrolled at the same dose level for vaccine plus Pembrolizumab 200 mg i.v. Neoantigen vaccine will be given via subcutaneous injection on days 1, 4, 8, 15, and 21 (cohorts 1 and 2) and weeks 5 and 8 (booster dose for cohort 2 only). Cohort 1 has been completed without dose-limiting toxicity (DLT). Enrollment in Cohort 2 began in January 2024. AEs are assessed according to CTCAE v5. and safety findings are reviewed by data safety medical board (DSMB). Key eligibility criteria include 1) histologically confirmed locally advanced or metastatic solid malignancies and 2) cancer progression after at least one line of the standard-of-care (SOC) systemic treatment. For cohort 2, patients must be eligible to receive pembrolizumab per SOC or the treating physician’s judgment. Clinical trial information: NCT05269381 .