Citations

Abstract Background: Previous studies demonstrated that activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Further in vivo study showed that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors (ICIs). Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were treated with pembrolizumab 200 mg every 3 weeks plus an oral MEK inhibitor binimetinib. Treatment was started with a 2-week run-in period with single-agent binimetinib. There were 2 dose levels in phase I, including dose level 0 (DL 0) with binimetinib at 45 mg orally twice daily continuously and dose level -1 (DL -1) at 30 mg twice daily. A standard 3+3 design was used in phase I to identify the recommended phase II dose (RP2D) and Simon’s two-stage Optimal design was used in phase II. Results: A total of 22 patients were enrolled. The median age was 58 years old (range 37-77). 14 (63.6%) patients had no prior systemic therapy in the metastatic setting and 8 (36.4%) patients had 1-2 prior lines of therapy. There were 4 patients treated in DL 0. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0 with grade 3 ALT abnormality in one patient and grade 3 flank pain together with grade 3 nausea and vomiting > 48 hours despite anti-emetic therapy in the other patient. Binimetinib dose was reduced to DL -1. In the next 6 patients, there was 1 DLT observed with grade 3 AST/ALT abnormality. Thus, DL -1 was the RP2D, and an additional 12 patients were treated with DL -1 in phase II. Overall, 18 patients were treated in DL -1 and were included in phase II efficacy evaluation. 17 patients were evaluable for response. Objective responses were observed in 5 patients (29.41% 55.96) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR) was 35.29% (95% CI: 14.21 - 61.67) with 6 out of 17 having had CR, PR, or stable disease >= 24 weeks. Since previous studies showed poor responses to ICIs in patients with liver metastases due to macrophage-mediated T cell elimination, we further conduct exploratory analysis to evaluate responses among patients with and without liver metastases. Among all 5 patients with liver metastases, no response was observed. The objective response rate (ORR) in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30) and CBR was 66.67% (95% CI: 29.93-92.51), when excluding 3 patients who discontinued treatment due to adverse events prior to follow-up scans. Median progression-free survival in DL 0 was 2.4 (95%CI: 0.5-NE) and in DL -1 was 8.3 (95% CI: 3.9-NE) months. Median overall survival in DL 0 was 7 (95%CI: 0.5-NE) and in DL -1 was 33.2 (95% CI: 10.3-NE) months. Among patients who responded, 3 out of 5 (60%) had a duration of response greater than 12 months and ongoing even after stopping treatment (range: 5.4 - 32.0 months). Adverse events (AEs) were mostly grade 1-2 including anemia, CPK increase, fatigue, diarrhea, nausea, peripheral neuropathy, acneiform rash, AST increase, cardiac troponin increase, and constipation. Additional correlative studies are ongoing and will be presented at the meeting. Conclusions: Pembrolizumab in combination with binimetinib at 30 mg twice daily appears to be safe with manageable toxicities. Promising activity with durable responses was observed with this combination without chemotherapy, particularly in patients without liver metastases. Future studies are warranted to further evaluate the efficacy of this combination. Citation Format: Saranya Chumsri, Joseph J. Larson, Kathleen S. Tenner, Jun He, Mei-Yin Polley, Morgan T. weidner, Amanda N. Arnold, Dana Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith A. Perez, Keith L. Knutson. Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-17.

It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. We show herein that NAMPT is expressed in CCA cells, and FK866 suppresses the capacity of CCA cells to grow in a dose-dependent manner. Furthermore, by preventing NAMPT activity, FK866 significantly reduced the amount of NAD+ and adenosine 5′-triphosphate (ATP) in HuCCT1, KMCH, and EGI cells. The present study’s findings further show that FK866 causes changes in mitochondrial metabolism in CCA cells. Additionally, FK866 enhances the anticancer effects of cisplatin in vitro. Taken together, the results of the current study suggest that the NAMPT/NAD+ pathway may be a possible therapeutic target for CCA, and FK866 may be a useful medication targeting CCA in combination with cisplatin.

AbstractFocal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD.We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization.FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques.Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.

Although the precise mechanisms for neurodegeneration in Parkinson’s disease (PD) are unknown, evidence suggests that neuroinflammation is a critical factor in the pathogenic process. Here, we sought to determine whether the voltage-gated proton channel, Hv1 (HVCN1), which is expressed in microglia and regulates NADPH oxidase, is associated with dopaminergic neurodegeneration. We utilized data mining to evaluate the mRNA expression of HVCN1 in the brains of PD patients and controls and uncovered increased expression of the gene encoding Hv1, HVCN1, in the brains of PD patients compared to controls, specifically in male PD patients. In an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 × 16 mg/kg) mouse model of PD, Hvcn1 gene expression was increased 2-fold in the striatum. MPTP administration to wild-type (WT) mice resulted in a ~65% loss of tyrosine hydroxylase positive neurons (TH+) in the substantia nigra (SN), while a ~39% loss was observed in Hv1 knockout (KO) mice. Comparable neuroprotective effects of Hv1 deficiency were found in a repeated-dose LPS model. Neuroprotection was associated with decreased pro-inflammatory cytokine levels and pro-oxidant factors in both neurotoxicant animal models. These in vivo results were confirmed in primary microglial cultures, with LPS treatment increasing Hvcn1 mRNA levels and Hv1 KO microglia failing to exhibit the LPS-mediated inflammatory response. Conditioned media from Hv1 KO microglia treated with LPS resulted in an attenuated loss of cultured dopamine neuron cell viability compared to WT microglia. Taken together, these data suggest that Hv1 is upregulated and mediates microglial pro-inflammatory cytokine production in parkinsonian models and therefore represents a novel target for neuroprotection.

Radiation-induced brain injury (RIBI) is a debilitating sequela after radiotherapy to treat head and neck cancer, and 20 to 30% of patients with RIBI fail to respond to or have contraindications to the first-line treatments of bevacizumab and corticosteroids. Here, we reported a Simon’s minmax two-stage, single-arm, phase 2 clinical trial (NCT03208413) to assess the efficacy of thalidomide in patients with RIBI who were unresponsive to or had contraindications to bevacizumab and corticosteroid therapies. The trial met its primary endpoint, with 27 of 58 patients enrolled showing ≥25% reduction in the volume of cerebral edema on fluid-attenuated inversion recovery–magnetic resonance imaging (FLAIR-MRI) after treatment (overall response rate, 46.6%; 95% CI, 33.3 to 60.1%). Twenty-five (43.1%) patients demonstrated a clinical improvement based on the Late Effects Normal Tissues–Subjective, Objective, Management, Analytic (LENT/SOMA) scale, and 36 (62.1%) experienced cognitive improvement based on the Montreal Cognitive Assessment (MoCA) scores. In a mouse model of RIBI, thalidomide restored the blood-brain barrier and cerebral perfusion, which were attributed to the functional rescue of pericytes secondary to elevation of platelet-derived growth factor receptor β (PDGFRβ) expression by thalidomide. Our data thus demonstrate the therapeutic potential of thalidomide for the treatment of radiation-induced cerebral vasculature impairment.

AbstractBackgroundQuantitative methods of Fluorodeoxyglucose Positron Emission Tomography (FDG‐PET) interpretation, including the percent change in FDG uptake from baseline (ΔSUV), are under investigation in lymphoma to overcome challenges associated with visual scoring systems (VSS) such as the Deauville 5‐point scale (5‐PS).MethodsIn CALGB 50303, patients with DLBCL received frontline R‐CHOP or DA‐EPOCH‐R, and although there were no significant associations between interim PET responses assessed centrally after cycle 2 (iPET) using 5‐PS with progression‐free survival (PFS) or overall survival (OS), there were significant associations between central determinations of iPET ∆SUV with PFS/OS. In this patient cohort, we retrospectively compared local vs central iPET readings and evaluated associations between local imaging data and survival outcomes.ResultsAgreement between local and central review was moderate (kappa = 0.53) for VSS and high (kappa = 0.81) for ∆SUV categories (<66% vs. ≥66%). ∆SUV ≥66% at iPET was significantly associated with PFS (p = 0.03) and OS (p = 0.002), but VSS was not. Associations with PFS/OS when applying local review vs central review were comparable.ConclusionsThese data suggest that local PET interpretation for response determination may be acceptable in clinical trials. Our findings also highlight limitations of VSS and call for incorporation of more objective measures of response assessment in clinical trials.

Abstract Immune-mediated blood brain barrier (BBB) disruption is a prominent feature of various neurological conditions for which an emerging role of CD8 T cells is being realized. Our group has developed a unique model of CD8 T cell-mediated BBB disruption which employs Theiler’s murine encephalomyelitis virus (TMEV) infection. Upon intravenous administration of VP2121–130 viral peptide during the peak antiviral adaptive response, Db:VP2121–130 epitope specific CD8 T cells induce BBB disruption in a perforin dependent manner. In this model, we addressed the role of microglia in relation to antigen specific CD8+ T cells and permeable cerebral vessels. Using real time two-photon in vivo imaging, we demonstrate that microglia adopt distinct morphological features, including enlarged cell body and fewer ramified processes as early as 6 hours post administration of VP2 peptide. Notably, microglial population exhibit robust down-regulation of homeostatic markers including CX3CR1 during BBB disruption. This study demonstrates CD8 T cells can promote microglia activation in a perforin-dependent manner during BBB disruption. Importantly, microglial activation occurs concurrently with the onset of vascular permeability and could serve as a critical cell type in this process.

Study Design. Delphi method. Objective. To gain consensus on the following questions: (1) When should anticoagulation/antiplatelet (AC/AP) medication be stopped before elective spine surgery?; (2) When should AC/AP medication be restarted after elective spine surgery?; (3) When, how, and in whom should venous thromboembolism (VTE) chemoprophylaxis be started after elective spinal surgery? Summary of Background Data. VTE can lead to significant morbidity after adult spine surgery, yet postoperative VTE prophylaxis practices vary considerably. The management of preoperative AC/AP medication is similarly heterogeneous. Materials and Methods. Delphi method of consensus development consisting of three rounds (January 26, 2021, to June 21, 2021). Results. Twenty-one spine surgeons were invited, and 20 surgeons completed all rounds of questioning. Consensus (>70% agreement) was achieved in 26/27 items. Group consensus stated that preoperative Direct Oral Anticoagulants should be stopped two days before surgery, warfarin stopped five days before surgery, and all remaining AC/AP medication and aspirin should be stopped seven days before surgery. For restarting AC/AP medication postoperatively, consensus was achieved for low-risk/medium-risk/high-risk patients in 5/5 risk factors (VTE history/cardiac/ambulation status/anterior approach/operation). The low/medium/high thresholds were POD7/POD5/POD2, respectively. For VTE chemoprophylaxis, consensus was achieved for low-risk/medium-risk/high-risk patients in 12/13 risk factors (age/BMI/VTE history/cardiac/cancer/hormone therapy/operation/anterior approach/staged separate days/staged same days/operative time/transfusion). The one area that did not gain consensus was same-day staged surgery. The low-threshold/medium-threshold/high-threshold ranges were postoperative day 5 (POD5) or none/POD3-4/POD1-2, respectively. Additional VTE chemoprophylaxis considerations that gained consensus were POD1 defined as the morning after surgery regardless of operating finishing time, enoxaparin as the medication of choice, and standardized, rather than weight-based, dose given once per day. Conclusions. In the first known Delphi study to address anticoagulation/antiplatelet recommendations for elective spine surgery (preoperatively and postoperatively); our Delphi consensus recommendations from 20 spine surgeons achieved consensus on 26/27 items. These results will potentially help standardize the management of preoperative AC/AP medication and VTE chemoprophylaxis after adult elective spine surgery.

Mixed acinar neuroendocrine carcinoma of the pancreas (MANEC-P) is an extremely rare malignancy with a poor prognosis. However, epidemiological estimates of MANEC-P remain unknown. This study aimed to estimate and compare the incidence, prevalence, and cancer-specific survival (CSS) of MANEC-P in the United States (US). Patients with MANEC-P were identified through the Surveillance, Epidemiology, and End Results (SEER) and National Program of Cancer Registries databases between 2000–2017. The primary outcomes included age-adjusted incidence rate, limited-duration prevalence, and CSS. A total of 630 patients were identified for the incidence analysis and 149 for the prevalence and CSS analyses. The MANEC-P incidence rate was 0.011 per 100,000 individuals, which was the lowest among pancreatic cancer histologic subtypes. The incidence rate was significantly higher in men and Black races and peaked at 75–79 years of age. The incidence rate was the lowest in the midwestern region (0.009) and the highest in the northeastern US (0.013). The 17-year prevalence was 0.00005%, indicating that 189 patients were alive in the United States at the beginning of 2018. The median CSS of MANEC-P was estimated to be 41 (23, 69) months. In conclusion, MANEC-P is very rare, and its incidence rate has been steady in the US over the last two decades. MANEC-P has a poor prognosis and is the 5th leading cause of pancreatic cancer-related death in the US.