In comparison with responses in recurrent glioblastoma (rGBM), the intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less well studied. Here, we present an ...integrated single-cell RNA-Seq (scRNA-Seq) study of 19 ICB-naive and 9 ICB-treated BrM samples from our own and published data sets. We compared them with our previously published scRNA-Seq data from rGBM and found that ICB led to more prominent T cell infiltration into BrM than rGBM. These BrM-infiltrating T cells exhibited a tumor-specific phenotype and displayed greater activated/exhausted features. We also used multiplex immunofluorescence and spatial transcriptomics to reveal that ICB reduced a distinct CD206+ macrophage population in the perivascular space, which may modulate T cell entry into BrM. Furthermore, we identified a subset of progenitor exhausted T cells that correlated with longer overall survival in BrM patients. Our study provides a comprehensive immune cellular landscape of ICB's effect on metastatic brain tumors and offers insights into potential strategies for improving ICB efficacy for brain tumor patients.
Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia. However, evidence for clinical efficacy and optimal management of therapy ...is limited.
Patients with COPD, clinicians who care for them, and policy makers.
We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations. Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework.
) We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty);
) we suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty);
) we suggest not initiating long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2-4 weeks after resolution (conditional recommendation, low certainty);
) we suggest not using an in-laboratory overnight polysomnogram to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty); and
) we suggest NIV with targeted normalization of Pa
in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty)
This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure.
In patients with advanced or metastatic non–clear cell renal cell carcinoma, cabozantinib plus nivolumab demonstrated promising efficacy, with an objective response rate of 48%, and potential for ...sustained responses, with a median duration of response of 17 mo. The toxicity profile was as expected for the two agents.
Treatment options are limited for patients with non–clear cell renal cell carcinoma (nccRCC). Patients with nccRCC experienced a favorable objective response rate (ORR) in a phase 2 trial of cabozantinib plus nivolumab. We now report updated efficacy and safety results at median follow-up of 34 mo for patients with papillary, unclassified, or translocation-associated RCC. Cabozantinib and nivolumab were administered at standard doses to patients with metastatic nccRCC that had progressed on zero or one line of systemic therapy. The primary endpoint was the ORR according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Forty patients were treated. At median follow-up of 34 mo for survivors, the ORR was 48% (95% confidence interval CI 31.5–63.9%). Median PFS was 13 mo (95% CI 7–16); the 12-mo and 24-mo PFS rates were 51% (95% CI 34–65%) and 23% (95% CI 11–37%), respectively. Median OS was 28 mo (95% CI 23–43); the 18-mo and 36-mo OS rates were 70% (95% CI 53–82%) and 44% (95% CI 28–60%), respectively. No new safety signals were seen with cabozantinib and nivolumab. This extended follow-up analysis demonstrates promising efficacy, and highlights the potential for sustained responses with cabozantinib plus nivolumab in patients with metastatic nccRCC.
We evaluated outcomes for patients with metastatic kidney cancer of the non–clear cell (NCC) type who were treated with cabozantinib + nivolumab. We found that 48% of the patients responded to the treatment, and there were no unexpected side effects. Among patients who responded to the treatment, the response lasted for a median of 17 months. We conclude that cabozantinib + nivolumab is a safe and effective treatment for NCC kidney cancer.
Type IV pili are polymeric fibers which protrude from the cell surface and play a critical role in adhesion and invasion by pathogenic bacteria. The secretion of pili across the periplasm and outer ...membrane is mediated by a specialized secretin protein, PilQ, but the way in which this large channel is formed is unknown. Using NMR, we derived the structures of the periplasmic domains from N. meningitidis PilQ: the N-terminus is shown to consist of two β-domains, which are unique to the type IV pilus-dependent secretins. The structure of the second β-domain revealed an eight-stranded β-sandwich structure which is a novel variant of the HSP20-like fold. The central part of PilQ consists of two α/β fold domains: the structure of the first of these is similar to domains from other secretins, but with an additional α-helix which links it to the second α/β domain. We also determined the structure of the entire PilQ dodecamer by cryoelectron microscopy: it forms a cage-like structure, enclosing a cavity which is approximately 55 Å in internal diameter at its largest extent. Specific regions were identified in the density map which corresponded to the individual PilQ domains: this allowed us to dock them into the cryoelectron microscopy density map, and hence reconstruct the entire PilQ assembly which spans the periplasm. We also show that the C-terminal domain from the lipoprotein PilP, which is essential for pilus assembly, binds specifically to the first α/β domain in PilQ and use NMR chemical shift mapping to generate a model for the PilP:PilQ complex. We conclude that passage of the pilus fiber requires disassembly of both the membrane-spanning and the β-domain regions in PilQ, and that PilP plays an important role in stabilising the PilQ assembly during secretion, through its anchorage in the inner membrane.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Sleep disordered breathing in decompensated heart failure has physiological consequences (e.g., intermittent hypoxemia) that may predispose to subclinical myocardial injury, yet a temporal ...relationship between sleep apnea and troponin elevation has not been established.
Methods
We assessed the feasibility of performing respiratory polygraphy and measuring overnight high-sensitivity cardiac troponin T change in adults admitted to the hospital with acutely decompensated heart failure. Repeat sleep apnea tests (SATs) were performed to determine response to optimal medical heart failure therapy. Multivariable logistic regression was used to identify associations between absolute overnight troponin change and sleep apnea characteristics.
Results
Among the 19 subjects with acutely decompensated heart failure, 92% of SATs demonstrated sleep disordered breathing (apnea–hypopnea index AHI > 5 events/h). For those with repeat SATs, AHI increased in 67% despite medical management of heart failure. Overnight troponin increase was associated with moderate to severe sleep apnea (vs. no to mild sleep apnea, odds ratio (OR = 18.4 1.51–224.18), central apnea index (OR = 1.11 1.01–1.22), and predominantly central sleep apnea (vs. obstructive, OR = 22.9 1.29–406.32).
Conclusions
Sleep apnea severity and a central apnea pattern may be associated with myocardial injury. Respiratory polygraphy with serial biomarker assessment is feasible in this population, and combining this approach with interventions (e.g., positive airway pressure) may help establish if a link exists between sleep apnea and subclinical myocardial injury.
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Background: Identification of effective systemic therapy for non-clear cell renal cell carcinoma (RCC) remains a unmet need. We reported a two arm, phase 2 trial of cabozantinib plus nivolumab ...(CaboNivo) that showed promising efficacy in the treatment arm comprised primarily of papillary and unclassified histology. (Lee, JCO, 40: 2022). Herein, we report updated results with extended follow up. Methods: Patients had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given for both arms. Arm 1 was comprised of papillary, unclassified, or translocation associated RCC; and Arm 2 had chromophobe RCC (closed early for lack of efficacy). The primary endpoint was objective response rate (ORR) by RECIST; secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Arm 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Correlative analyses by next generation sequencing were performed and will be presented. Results: A total of 40 patients were treated in Arm 1 (data cutoff: Dec 13, 2022). Median follow up time was 34 months (range 20, 51). Twenty-six patients (65%) were previously untreated, and 14 (35%) had 1 prior treatment line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR is 48% (95% CI 31.5–63.9). Median PFS is 13 months (95% CI: 7, 16). Progression-free survival is 51% (95% CI: 34, 65) at 12 months and 23% (95% CI: 11, 37) at 24 months. Median OS is 28 months (95% CI: 23, 43). Overall survival is 70% (95% CI: 53, 82) at 18 months and 44% (95% CI: 28, 60) at 36 months. PFS and OS were similar for previously treated and untreated patients. For responders, median DOR was 17 months (95% CI: 10, 36). Adverse effects of any grade were experienced by 35 patients (88%); grade 3/4 adverse events were experienced by 22 patients (55%). Grade 3/4 AST and ALT elevations were 18% and 23% respectively. Other common grade 3/4 adverse events were hypertension (5, 13%) and pain (4, 10%). Study therapy was discontinued in 9 patients (28%) for toxicity. Conclusions: Updated results with extended follow-up highlight efficacy and safety for CaboNivo in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies. Clinical trial information: NCT03635892 . Table: see text
Abstract
Brain tumors reside in a modified microenvironment where inflammatory processes are heavily regulated. Nevertheless, our recent study showed a significant immune infiltration in recurrent ...glioblastoma (rGBM) treated with neoadjuvant PD-1 checkpoint blockade therapy. In comparison to GBM, the intracranial response of brain metastases (BrM) to immunotherapy has been less well studied. To test this question, we investigated the effect of pre-surgical immune checkpoint blockade (ICB) on the immune compartments of BrM, using multiplex immunofluorescence, single-cell RNA sequencing and spatial transcriptomics on a total of 17 patients. We found that ICB naïve BrM featured an immune exclusion phenotype with accumulation of immune cells in the fibrovascular stroma, necrotic and hemorrhagic peritumoral areas. Following ICB treatment, T cells and monocyte-derived macrophages were then observed within the tumor parenchyma. Computational receptor-ligand analysis suggested that the tumor-infiltrating T cells and macrophages were highly engaged by checkpoint receptor-ligand pairing, which may drive the T cells into an advanced exhausted state. To further explore the organization and interactions between the immune, stroma and tumor cells in BrM, we utilized the sequencing-based spatial transcriptomics technology. Our spatial transcriptomics data further highlighted the distinct spatial architectures between ICB naïve and –treated BrM tumors. It also pinpointed a unique macrophage subset that are preferentially co-localized with the brain vasculature cells and confined the immune infiltrates to the perivascular space. In summary, our study revealed ICB-induced marked changes in the immune composition and spatial organization in BrM and offers insights into new combination therapies that can help improve the clinical efficacy of immunotherapy for BrM patients.
Abstract only
4509
Background: Cabozantinib plus nivolumab (CaboNivo) improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) over sunitinib in a phase 3 ...trial for metastatic clear cell renal cell carcinoma (RCC). (Choueiri, abstract 6960, ESMO 2020) We report the results of a phase 2 trial of CaboNivo in patients (pts) with non-clear cell RCC. Methods: Pts had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given across two cohorts. Cohort 1: papillary, unclassified, or translocation associated RCC; Cohort 2: chromophobe RCC. The primary endpoint was ORR by RECIST; secondary endpoints included PFS, OS, and safety. Cohort 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Cohort 2 was a Simon two-stage design that closed early for lack of efficacy. Correlative analyses by next generation sequencing were performed and to be presented. Results: A total of 40 pts were treated in Cohort 1, and 7 pts were treated in Cohort 2 (data cutoff: Jan 20, 2021). Median follow up time was 13.1 months (range 2.2 – 28.6). In Cohort 1, 26 (65%) pts were previously untreated, and 14 (35%) pts had 1 prior line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR for Cohort 1 was 48% (95% CI 31.5–63.9; Table). Median PFS was 12.5 months (95% CI 6.3–16.4) and median OS was 28 months (95% CI 16.3–NE). No responses were seen among 7 patients in Cohort 2 with chromophobe histology (Table). Grade 3/4 treatment emergent adverse events were consistent with that reported in the phase 3 trial; Grade 3/4 AST and ALT were 9% and 15%, respectively. Cabozantinib and nivolumab were discontinued due to toxicity in 17% and 19% of pts, respectively. Conclusions: CaboNivo had an acceptable safety profile and showed promising efficacy in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies whereas activity in patients with chromophobe RCC was limited. Clinical trial information: NCT03635892. Table: see text
Abstract
BACKGROUND
Current treatment modalities, including surgical resection, radiosurgery and immune checkpoint inhibitors, have improved local control rates of brain metastases, but overall ...prognosis is still poor. AIM: To investigate the immune microenvironment in brain metastases for better understanding of treatment failures.
METHODS
We identified 42 patients with melanoma (M), breast (B) and lung (L) brain metastases and performed multiplex immunofluorescent staining for immune markers (CD4, CD8, CD45, PD1, PD-L1) and quantitative analysis with HALO software. NanoString nCounter mRNA gene expression assay was used for identification of immune pathways. CyTOF and single cell RNA sequencing were done on 12 different brain metastases and their matched peripheral blood samples.
RESULTS
The median CD8, CD4 and PD1 density (as a total number of cells) was 0.24%, 0.13%, and 0.07% for M, 0.24%, 0.51% and 0.08% for B, and 0.87%, 1.36%, 0.67% for L. CD4 and CD8+PD1+ expression was significantly different between all groups (p=0.01), CD4+PD1+ in M vs. L (p=0.03) and PD1 in B vs. L (p=0.03). No significant difference was found in terms of CD45 positive cells (M 2.13%, B, 1.99%, L 4.95%). PD-L1 expression was significantly different between histologies; the highest expression was present in breast metastases (M: 1.51%, B: 49.98%, L: 31.90%, p=0.0002). Spatial distribution revealed a characteristic pattern with a peritumoral border infiltrate in M, and predominant intratumoral distribution in B and L (M 0.2%, B 2.6%, L 3.6%, p=0.02). CyTOF clustering demonstrated that macrophages are the most prevalent immune population overall (83.08%), with an inhibitory phenotype and gene expression pattern present in different histologies (S100A9, CCL20, IFI16, MARCO). T-cells (predominantly CD4+, 3.6%), and B-cells (1.5%) comprise the remaining immune cell populations.
CONCLUSION
Neoadjuvant targeted treatment approaches may be needed to alter predominance of inhibitory macrophages and recruit activated T lymphocytes in brain metastases.
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