Citations

Lung cancer is among the most common and lethal cancers and warrants novel therapeutic approaches to improving patient outcomes. Although immune checkpoint inhibitors (ICIs) have demonstrated substantial clinical benefits, most patients remain unresponsive to currently approved ICIs or develop resistance after initial response. Many ongoing clinical studies are investigating combination therapies to address the limited efficacy of ICIs. Here, we have assessed whether p53 gene therapy via a tumor-targeting nanomedicine (termed SGT-53) can augment anti-programmed cell death-1 (PD-1) immunotherapy to expand its use in non-responding patients. Using syngeneic mouse models of lung cancers that are resistant to anti-PD-1, we demonstrate that restoration of normal p53 function potentiates anti-PD-1 to inhibit tumor growth and prolong survival of tumor-bearing animals. Our data indicate that SGT-53 can restore effective immune responses against lung cancer cells by reducing immuno-suppressive cells (M2 macrophages and regulatory T cells) and by downregulating immunosuppressive molecules (e.g., galectin-1, a negative regulator of T cell activation and survival) while increasing activity of cytotoxic T cells. These results suggest that combining SGT-53 with anti-PD-1 immunotherapy could increase the fraction of lung cancer patients that responds to anti-PD-1 therapy and support evaluation of this combination particularly in patients with ICI-resistant lung cancers.

Abstract Background Recommendations regarding signs and symptoms that should prompt referral of patients with inflammatory bowel disease (IBD) to an IBD specialist for a consultation could serve to improve the quality of care for these patients. Our aim was to develop a consult care pathway consisting of clinical features related to IBD that should prompt appropriate consultation. Methods A scoping literature review was performed to identify clinical features that should prompt consultation with an IBD specialist. A panel of 11 experts was convened over 4 meetings to develop a consult care pathway using the RAND/UCLA Appropriateness Method. Items identified via scoping review were ranked and were divided into major and minor criteria. Additionally, a literature and panel review was conducted assessing potential barriers and facilitators to implementing the consult care pathway. Results Of 43 features assessed, 13 were included in the care pathway as major criteria and 15 were included as minor criteria. Experts agreed that stratification into major criteria and minor criteria was appropriate and that 1 major or 2 or more minor criteria should be required to consider consultation. The greatest barrier to implementation was considered to be organizational resource allocation, while endorsements by national gastroenterology and general medicine societies were considered to be the strongest facilitator. Conclusions This novel referral care pathway identifies key criteria that could be used to triage patients with IBD who would benefit from IBD specialist consultation. Future research will be required to validate these findings and assess the impact of implementing this pathway in routine IBD-related care.

Because lung cancer remains the most common and lethal of cancers, novel therapeutic approaches are urgently needed. RB94 is a truncated form of retinoblastoma tumor suppressor protein with elevated anti-tumor efficacy. Our investigational nanomedicine (termed scL-RB94) is a tumor-targeted liposomal formulation of a plasmid containing the gene encoding RB94. In this research, we studied anti-tumor and immune modulation activities of scL-RB94 nanocomplex in preclinical models of human non-small cell lung cancer (NSCLC). Systemic treatment with scL-RB94 of mice bearing human NSCLC tumors significantly inhibited tumor growth by lowering proliferation and increasing apoptosis of tumor cells in vivo. scL-RB94 treatment also boosted anti-tumor immune responses by upregulating immune recognition molecules and recruiting innate immune cells such as natural killer (NK) cells. Antibody-mediated depletion of NK cells blunted the anti-tumor activity of scL-RB94, suggesting that NK cells were crucial for the observed anti-tumor activity in these xenograft models. Treatment with scL-RB94 also altered the polarization of tumor-associated macrophages by reducing immune-suppressive M2 macrophages to lower immune suppression in the tumor microenvironment. Collectively, our data suggest that the efficacy of scL-RB94 against NSCLC is due to an induction of tumor cell death as well as enhancement of innate anti-tumor immunity.

Abstract Background The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown. Purpose To ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV. Methods In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV(+)), 25 with AM and negative gene testing (DGV(−)), and 36 AM patients without genetics (w/o genetics). All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance imaging (CMRI). In 86 patients CMRI changes in function and structure were re-assessed at follow-up. Results In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular (LV) ejection fraction was 56% on CMRI (p=NS vs. the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared to DGV(−) and w/o genetics patients (62.3% vs. 17.5% vs. 5.3% at 5 years respectively; p<0.0001), driven by myocarditis recurrence and ventricular arrhythmias (Figure 1A, B). At follow-up CMRI, a higher number of late-gadolinium enhanced segments was found in DGV(+) AM. Conclusions Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with AM patients without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health

Abstract Background Treatment for breast cancer (BC) frequently involves radiotherapy. Guidelines recommend screening for cardiac adverse events starting 10 years after radiotherapy. The rationale for recommending this interval is unclear and informed the objective of this study. Objectives Study cardiovascular event rates in the first decade following curative radiotherapy for breast cancer, the time frame before guidelines recommend screening. Methods We performed a monocentric, retrospective study enrolling all women with unilateral BC in 2007–2008, who received radiotherapy as part of their curative treatment. We compared event rates during 10 years follow-up with an age and risk factor-matched control population (FLEMENGHO population). Results We included 1095 BC patients (median age 55y, IQR: 47–66y). Two hundred and eighteen (19.9%) women died. Cancer and cardiovascular mortality accounted for 107 (49.1%) and 22 (10.1%) deaths, respectively. The incidence of coronary artery disease was similar compared to age and risk-matched women [risk ratio 0.75 (95% CI 0.48–1.18)], yet heart failure (HF) [risk ratio 1.97 (95% CI 1.19–3.25)] and atrial fibrillation or flutter (AF) (risk ratio 1.82 (95% CI 1.07–3.08) occurred more often. Age [HR 1.040 (95% CI 1.012–1.069)], tumor grade [HR 1.646 (95% CI 1.103–2.458)], and neo-adjuvant treatment setting [HR 3.079 (95% CI 1.432–6.620)] were risk factors for mortality; hormonal therapy [HR 0.007 (95% CI 0.001–0.042)] proved protective. Risk factors for MACE were mean heart dose [HR 1.079 (95% CI 1.012–1.151], hormonal therapy, history of cardiovascular disease [HR 2.771 (95% CI 1.253–6.126)], and Mayo Clinic Cardiotoxicity Risk Score [HR 2.547 (95% CI 1.538–4.217)]. While mean heart dose [HR 1.141 (95% CI 1.017–1.282)] and cardiovascular history [HR 3.374 (95% CI 1.259–9.043] clearly associated with new onset HF, only a trend towards higher AF burden with increasing mean heart dose could be observed. Conclusions Ten-year mortality following curative treatment for unilateral BC was mainly cancer-related. HF and AF constituted significantly increased risks in the first decade following irradiation. Mean heart dose, pre-existing cardiovascular diseases, and Mayo Clinic Cardiotoxicity Risk Score were risk factors for early cardiac mortality and adverse events and should guide early dedicated cardio-oncological follow-up. Funding Acknowledgement Type of funding sources: None.

Abstract Cytoglobin is a highly conserved redox sensor heme protein with unknown physiological function. Unexpectedly, genetic deletion of zebrafish cytoglobin (cygb2) causes cardiac and gastro-intestinal tract laterality defects, modeling Kartagener’s syndrome, which in humans is associated with low airway epithelial nitric oxide (NO) production. Cygb2 co-localized with cilia and the NO synthase Nos2b in the Kupffer’s vesicle (KV) laterality organ and the structure and function of cilia were disrupted in cygb2 mutants, abolishing fluid flow within the KV. Abnormal ciliary function and organ laterality was phenocopied by depletion of nos2band gucy1a, the canonical NO receptor soluble guanylate cyclase (sGC) homolog in fish, and rescued by exposing cygb2 mutant embryos to an NO donor or an sGC stimulator and with over-expression of nos2b. Consistent with a conserved role in the modulation of ciliary function, cytoglobin knock out in the mouse also impaired airway epithelial ciliary structure and beat frequency. This is the first evidence that cytoglobin is essential for normal development stage-specific NO signaling, ciliogenesis and cilia motility, required for the establishment of left-right patterning.

ImportanceRosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent studies showing alterations in the MAPK pathway, most commonly in the KRAS and MEK genes in about 40% of patients. Reports on the use of MEK-inhibitor therapy in RDD have been limited to small case studies. There are no approved treatments for this neoplasm, and therefore patients with RDD need efficacious treatments.ObjectiveTo study the outcomes after treatment with cobimetinib based on MAPK pathway alterations in patients with RDD.Design, Setting, and ParticipantsThis retrospective cohort study conducted at 2 tertiary care centers included patients with RDD who underwent treatment with cobimetinib between January 1, 2013, and December 1, 2021. Cobimetinib was administered at a dosage of 20 to 60 mg orally once daily as a single agent for 21 days in a 28-day cycle. Pathology was centrally reviewed. Response assessment was centrally conducted and was based on the established positron emission radiography response criteria used for clinical trials of targeted therapies in histiocytosis.Main Outcomes and MeasuresMain outcomes were overall response rate (ORR), progression-free survival (PFS), adverse events (AEs) of cobimetinib in the entire cohort, and ORRs and PFS based on MAPK pathway alterations in patients with RDD.ResultsA total of 16 patients (median [range] age at cobimetinib initiation, 57 [31-74] years; 11 [69%] women) were included in the study. The median follow-up duration was 19.0 months (95% CI, 8.4-27.8 months). The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses. Somatic alterations in the KRAS or MEK genes were detected in 8 (50%) patients. Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03), deeper responses (complete responses among responders: 71% vs 0%; P = .002), and better PFS (at 1 year, 100% vs 29% were free from progression or death, respectively; P < .001) compared with those without such alterations. Grade 2 or higher AEs occurred in 12 (75%) patients, and 9 (56%) required dose reduction or temporary/permanent treatment discontinuation due to AEs.Conclusions and RelevanceIn this cohort study, treatment with cobimetinib was associated with positive outcomes in KRAS- or MEK-variant RDD. However, AEs requiring dose modifications were common.

Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 ( TBK1 ) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg 228 →His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72 , TBK1 , and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.

A dementia friendly community allows people with dementia and their care partners to remain engaged in their community well into the disease. This study presents the results of primary research aimed at exploring perceptions regarding building a dementia friendly community in an African American neighborhood in northeast Florida. Twelve focus groups and five interviews were conducted with people living with dementia, informal and formal care partners, community stakeholders and neighborhood residents, and analyzed using a grounded theory approach. Three main themes emerged from the analyses, including (1) perceived needs, (2) facilitators and barriers to being dementia friendly, and (3) opportunities for the community to become more dementia friendly. Study findings highlight the unique needs of a single African American neighborhood and the importance of culturally tailoring the dementia friendly model to diverse communities.