Citations

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

AbstractEndoscopic eradication therapy (EET) is recommended for the management of dysplastic Barrett’s esophagus (BE) and intramucosal adenocarcinoma. Both radiofrequency (RFA) and cryoballoon ablation (CBA) can induce complete remission of intestinal metaplasia (CRIM). We aimed to compare long-term durability following CRIM in patients treated with RFA vs. CBA.We conducted a retrospective cohort study to analyze patient outcomes following EET with RFA or CBA at two referral centers. We measured and compared the recurrence rate of BE, with or without dysplasia, after CRIM, using Cox proportional hazard models and propensity score-matched analyses. Our secondary aim was to identify predictors of recurrence.681 patients who achieved CRIM were included (RFA 610; CBA 71), with median follow-up of 4.1 years and 4.4 years following RFA and CBA, respectively. A multivariable model revealed a higher risk of any recurrence with RFA (hazard ratio [HR] 2.19, 95%CI 1.18–4.06; P = 0.01), but not dysplastic recurrence (HR 0.88, 95%CI 0.39–1.97; P = 0.75). However, a comparable risk of “any recurrence” was observed after excluding intestinal metaplasia of the gastroesophageal junction (HR 1.18, 95%CI 0.61–2.30; P = 0.62). Propensity score-matched analysis (54 cases in each group) showed that the two groups had comparable recurrence risk. Baseline maximum BE length was associated with a higher risk of any recurrence (HR 1.07; P<0.001) and dysplastic recurrence (HR 1.11; P = 0.001).The rates of any BE recurrence and dysplastic recurrence were comparable with the two modalities in this nonrandomized study.

Abstract Introduction: Heme-binding biguanides inhibit cytochrome P450 monooxygenase-mediated biosynthesis of the epoxy fatty acid (EpFA) (±)14,15-EET, which promotes progression of ER+HER2- breast cancer as well as regulatory T cell (Treg) proliferation. However, there are no known strategies to exploit this vulnerability. Metformin has shown promise but lacks sufficient potency and clinical utility. Through structure-based design, heme binding hexyl cubane derivatives of metformin were identified, which potently inhibited (±)14,15-EET biosynthesis. Fluorination of the hexyl moiety improved pharmacokinetics (PK) and reduced toxicity. Among the fluorinated derivatives, C5F2-HCB potently inhibited (±)14,15-EET biosynthesis (IC50=3.1 uM for C5F2-HCB vs. 5 mM for metformin). C5F2-HCB and metformin are candidate agents for TME activation from “cold” to “hot” due to their inhibition of EETs biosynthesis and EET-driven oxidative phosphorylation (OXPHOS) which promotes tumor hypoxia. We then tested whether C5F2-HCB or metformin could inhibit immune exclusion in the immunologically “cold” ovarian dependent STAT1 KO SSM2ucd mammary carcinoma model, in part, by reducing Tregs and/or increasing CD8 or CD4 tumor infiltrating T cells (TIL). We hypothesized that biguanides, by reducing EETs, would suppress Tregs and promote effector T cells in the TME. We also hypothesized that C5F2-HCB would be more effective than metformin in modulating the TME, based on greater potency for inhibition of (±)14,15-EET biosynthesis. Both biguanides were tested at their maximum tolerated dose (C5F2-HCB; 18 mg/kg daily and metformin; 50 mg/kg every other day). Results: In the SSM2ucd allograft, all combination treatment groups with biguanides reduced tumor growth relative to the IgG control at the endpoint (day 63) : metformin + IgG (51.5±9.8% of control), C5F2-HCB + IgG (53.3±12.8%), metformin + anti-PD-1 (50.4±11.5%), and C5F2-HCB + anti-PD-1 (49.6±12.8%) [(P &lt; 0.05) for all comparisons]. In contrast, anti-PD-1 antibody alone failed to reduce tumor growth at the endpoint. Flow cytometry analysis of the TME revealed that only C5F2-HCB + IgG treatment increased CD8+ tumor-infiltrating lymphocytes (TILs) compared to all other treatment groups (&gt;2-fold; P &lt; 0.05). Additionally, only C5F2-HCB + anti-PD-1 reduced intratumoral Tregs (&gt;3-fold; P &lt; 0.05). C5F2-HCB in combination with IgG or anti-PD-1 reduced intratumoral macrophages by &gt;50% (P &lt; 0.001) and reduced the M2/M1 macrophage ratio by 32-61% (P &lt; 0.05) relative to other groups. No effects on CD4+ T cells were observed. Furthermore, C5F2-HCB and IgG or anti-PD-1 increased intratumoral neutrophils by 75- 120% compared to the anti-PD-1 or IgG (P &lt; 0.05). (Multiple comparisons tested by ANOVA). Conclusion: Relative to IgG alone, C5F2-HCB and metformin inhibited growth of the SSM2ucd allograft in combination with either anti-PD1 or IgG. In contrast to metformin, only C5F2-HCB modulated the TME, including increased CD8+ TILs with IgG, reduced Tregs with anti-PD-1, and decreased M2/M1 macrophage ratio with IgG and anti-PD-1. C5F2-HCB, in contrast tometformin, was effective in modulating an immune excluded TME and may contribute to a strategy for clinical translation. Citation Format: Zhijun Guo, Jianxun Lei, Joshua McCarra, Qing Cao, Michael J. Pryzbilla, Brenda Koniar, Beverly Norris, Robert J. Schumacher, Swaathi Jayaraman, John R. Hawse, Antonino B. D'Assoro, Ilia G. Denisov, Stephen G. Sligar, Kathryn L. Schwertfeger, Michael A. Farrar, Dipak Panigrahy, Hammock D. Bruce, Elizabeth A. Ambrose, Gunda I. Georg, Goetz P. Matthew, David A. Potter. C5F2-hexyl-(cuban-1-yl-methyl)-biguanide (C5F2-HCB) overcomes an immune excluded tumor microenvironment (TME) and suppresses tumor growth in the ovarian dependent ER+HER2- SSM2ucd mammary carcinoma allograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB010.

Abstract Reconstruction of clival defects may be challenging in expanded endonasal skull base surgery. We conducted a systematic review to evaluate the outcomes of vascularized flaps used for clival reconstruction. The following databases were searched using a combination of Medical Subject Headings (MeSH) and keywords related to clival reconstruction in July 2024: Ovid Medline, Ovid Embase, Scopus, and Web of Science. Studies reporting outcomes of clival reconstruction with vascularized free and pedicled flaps in patients were selected for complete review. Twenty-three studies were included for detailed study. Clival reconstruction with free flaps was done in 18 patients; 17 had a successful repair, outcome was not reported for 1. Facial vessels were preferred for microvascular anastomosis. Radial artery forearm flap and anterolateral thigh flap were most utilized. Pedicled flaps were used in 68 patients, with reported success in 85.3%. Nasoseptal flap was the most common intranasal flap, used in 34 patients with successful reconstruction in 85.3%. Temporoparietal fascia flap was the most common extranasal flap, successfully used in 13 patients. Intranasal pedicled flaps, wherever available, were preferably used for primary reconstruction; extranasal flaps were the next choice. Free flaps were reserved for salvage reconstruction due to prior failed or unavailable local pedicled flaps. Satisfactory reconstructive outcomes are reported using pedicled and free flaps. The flap of choice is determined by the previous surgical history, radiotherapy, wound vascularity, defect size, overall health of the surrounding nasal mucosa, simultaneous clival surgery, and the preferred pedicle transposition route (free flaps).

AbstractDue to multiple medical advances over the past several years, angiographic investigation into arterial insufficiency as the cause of erectile dysfunction has decreased. Due to this, there is a general lack of familiarity with penile angiography technique and arterial anatomy, among current practicing interventional radiologists. Some potential indications for penile angiography include evaluation of penile trauma, high-flow priapism, further diagnostic evaluation of an abnormal penile Doppler ultrasound, or in the evaluation or treatment of erectile dysfunction with endovascular or surgical treatments. These indications, although relatively rare, still require practicing IRs to be familiar with angiographic anatomy of the penis. This article will briefly review angiographic technique in penile angiography with an emphasis on arterial anatomy.

Abstract The retrosigmoid approach (RSA) is considered the standard surgical choice to address a neurovascular conflict involving the trigeminal nerve. The subtemporal transtentorial approach (STA) represents the main alternative. We describe here the mini-invasive anterior petrosal intertentorial approach with a view to reduce complications associated with the standard STA. Mini-invasive anterior petrosal intertentorial approach (M-APIA) was described for a case of refractory trigeminal neuralgia. This approach includes a very limited amount of drilling of the petrous ridge to expose the posterior fossa dura and the superior petrosal sinus to facilitate the subsequent tentorial peeling. Tentorial peeling enables to develop an intertentorial plane between the temporal tentorial leaf (TTL) and the posterior fossa tentorial leaf (PFTL). A linear incision over the posterior fossa dura and the PFTL offers a wide exposure of the neurovascular conflict. M-APIA enables to expose the root entry zone (REZ) of the trigeminal nerve without exposing the temporal lobe or the cerebellum. M-APIA can be considered as a safe alternative to the RSA or STA for trigeminal microvascular decompression (MVD), especially for select cases. Additional studies are needed for a better understanding of its advantages and disadvantages.

AbstractThe immune system and sleep are inextricably linked in both health and pathological conditions. Tightly regulated neuroimmune processes are critical for the physiological maintenance of healthy sleep. Reciprocally, sleep disturbances can detrimentally affect immune homeostasis and predispose to increased risk of autoimmune conditions, which themselves are bidirectionally associated with a higher risk of sleep disturbances. Autoimmune diseases of the central nervous system (CNS), particularly conditions that affect neuroanatomical regions involved in sleep homeostasis and nocturnal respiration, are associated with an increased risk sleep disorders that may impact diagnosis, clinical course, and management. This review summarizes the bidirectional relationship between sleep and immunity and highlights several exemplar autoimmune conditions of the CNS that include sleep disorders as a consequence or diagnostic feature of the disorder.

AbstractA thorough understanding of normal biliary anatomy, common variants, and surgically altered anatomy is essential for the success of biliary interventions. Variations in biliary anatomy are seen in up to 40% of patients and frequently influence procedural planning and outcomes. This review highlights classical biliary anatomy, its common variations, and the challenges posed by surgical modifications, such as those encountered after cholecystectomy, liver resection, or biliary reconstructions. Case-based examples are used to explore the implications of these variations and modifications on interventional approaches, including the management of bile leaks, strictures, and complex obstructions. Strategies incorporating advanced imaging and procedural techniques, such as rendezvous interventions, are discussed to address complications and optimize outcomes. This article provides a practical framework for interventional radiologists to navigate challenging biliary cases with confidence and precision.