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Key Points A large percentage of patients with classic Hodgkin lymphoma (CHL), primary mediastinal B-cell lymphoma (PMBCL), primary testicular lymphoma, and primary central nervous system lymphoma have copy-number alterations and/or translocations involving the 9p24.1 locus The 9p24.1 locus contains the genes encoding programmed cell death 1 ligands 1 and 2 (PD-L1 and PD-L2), and JAK2; lymphoma-associated aberrations in this locus result in increased expression of these proteins PD-L1 and/or PD-L2 induce immunosuppressive signalling via programmed cell-death protein 1 (PD-1); blockade of PD-1 with nivolumab results in response rates as high as 87% in patients with relapsed/refractory CHL Nivolumab is currently approved by the FDA for the treatment of relapsed/refractory CHL, and many trials are underway to evaluate PD-1–PD-L1 blockade in patients with B-cell lymphomas The PD-1–PD-L1 axis is probably important for immune evasion of B-cell lymphomas with a viral aetiology, specifically Epstein–Barr virus (EBV)-associated and human immunodeficiency virus (HIV)-associated lymphomas PD-1 inhibition in diffuse large-B-cell lymphoma might be most effective when directed at specific disease subtypes, including PMBCL, T-cell/histiocyte-rich large-B-cell lymphoma, and EBV-positive disease Immune-checkpoint inhibitors are revolutionizing the treatment of many types of solid cancer. Expression of the inhibitory immune-checkpoint proteins programmed cell-death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are frequently detected in haematological malignancies, and agents targeting these proteins have activity in such diseases, notably Hodgkin lymphoma. Herein, the current evidence supporting the roles of PD-1–PD-L1 blockade in the treatment of various B-cell malignancies is reviewed. Cancer cells can escape T-cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immune checkpoint. Indeed, therapeutic antibodies that block the PD-1–PD-L1 axis induce durable clinical responses against a growing list of solid tumours. B-cell lymphomas also leverage this checkpoint to escape immune recognition, although the outcomes of PD-1–PD-L1 blockade, and the correlations between PD-L1 expression and treatment responses, are less-well elucidated in these diseases than in solid cancers. Nevertheless, in patients with Hodgkin lymphoma, amplification of the gene encoding PD-L1 is commonly associated with increased expression of this protein on Reed–Sternberg cells. Correspondingly, PD-1 blockade with nivolumab has been demonstrated to result in response rates as high as 87% in unselected patients with relapsed and/or refractory Hodgkin lymphoma, leading to the FDA approval of nivolumab for this indication in May 2016. The PD-1/PD-L1 axis is probably also important for immune evasion of B-cell lymphomas with a viral aetiology, including those associated with human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV). This Review is focused on the role of PD-1–PD-L1 blockade in unleashing host antitumour immune responses against various B-cell lymphomas, and summarizes the clinical studies of this approach performed to date.

\"KRAS is probably the most exciting area in clinical trials right now, not only in thoracic oncology but also pancreatic and colorectal cancer, where we've seen a lot of combination therapies. My view is the small molecule inhibitors are the base, not the ceiling.\"

Exosomes and other small extracellular vesicles (sEVs) provide a unique mode of cell-to-cell communication in which microRNAs (miRNAs) produced and released from one cell are taken up by cells at a distance where they can enact changes in gene expression 1 – 3 . However, the mechanism by which miRNAs are sorted into exosomes/sEVs or retained in cells remains largely unknown. Here we demonstrate that miRNAs possess sorting sequences that determine their secretion in sEVs (EXOmotifs) or cellular retention (CELLmotifs) and that different cell types, including white and brown adipocytes, endothelium, liver and muscle, make preferential use of specific sorting sequences, thus defining the sEV miRNA profile of that cell type. Insertion or deletion of these CELLmotifs or EXOmotifs in a miRNA increases or decreases retention in the cell of production or secretion into exosomes/sEVs. Two RNA-binding proteins, Alyref and Fus, are involved in the export of miRNAs carrying one of the strongest EXOmotifs, CGGGAG. Increased miRNA delivery mediated by EXOmotifs leads to enhanced inhibition of target genes in distant cells. Thus, this miRNA code not only provides important insights that link circulating exosomal miRNAs to tissues of origin, but also provides an approach for improved targeting in RNA-mediated therapies. MicroRNAs encode sorting sequences that determine whether they are secreted in exosomal vesicles to regulate gene expression in distant cells or retained in cells that produced them, with different sequences used by individual cell types.

Dysregulation of cell signaling in chondrocytes and in bone cells, such as osteocytes, osteoblasts, osteoclasts, and an elevated burden of senescent cells in cartilage and bone, are implicated in osteoarthritis (OA). Mass spectrometric analyses provides a crucial molecular tool-kit to understand complex signaling relationships in age-related diseases, such as OA. Here we introduce a novel mass spectrometric workflow to promote proteomic studies of bone. This workflow uses highly specialized steps, including extensive overnight demineralization, pulverization, and incubation for 72 h in 6 M guanidine hydrochloride and EDTA, followed by proteolytic digestion. Analysis on a high-resolution Orbitrap Eclipse and Orbitrap Exploris 480 mass spectrometer using Data-Independent Acquisition (DIA) provides deep coverage of the bone proteome, and preserves post-translational modifications, such as hydroxyproline. A spectral library-free quantification strategy, directDIA, identified and quantified over 2,000 protein groups (with ≥ 2 unique peptides) from calcium-rich bone matrices. Key components identified were proteins of the extracellular matrix (ECM), bone-specific proteins (e.g., secreted protein acidic and cysteine rich, SPARC, and bone sialoprotein 2, IBSP), and signaling proteins (e.g., transforming growth factor beta-2, TGFB2), and lysyl oxidase homolog 2 (LOXL2), an important protein in collagen crosslinking. Post-translational modifications (PTMs) were identified without the need for specific enrichment. This includes collagen hydroxyproline modifications, chemical modifications for collagen self-assembly and network formation. Multiple senescence factors were identified, such as complement component 3 (C3) protein of the complement system and many matrix metalloproteinases, that might be monitored during age-related bone disease progression. Our innovative workflow yields in-depth protein coverage and quantification strategies to discover underlying biological mechanisms of bone aging and to provide tools to monitor therapeutic interventions. These novel tools to monitor the bone proteome open novel horizons to investigate bone-specific diseases, many of which are age-related.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined. To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis. A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis. This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis. Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.

Background Oncology rapidly shifted to telemedicine in response to the COVID‐19 pandemic. Telemedicine can increase access to healthcare, but recent research has shown disparities exist with telemedicine use during the pandemic. This study evaluated health disparities associated with telemedicine uptake during the COVID‐19 pandemic among cancer patients in a tertiary care academic medical center. Methods This retrospective cohort study evaluated telemedicine use among adult cancer patients who received outpatient medical oncology care within a tertiary care academic healthcare system between January and September 2020. We used multivariable mixed‐effects logistic regression models to determine how telemedicine use varied by patient race/ethnicity, primary language, insurance status, and income level. We assessed geospatial links between zip‐code level COVID‐19 infection rates and telemedicine use. Results Among 29,421 patient encounters over the study period, 8,541 (29%) were delivered via telemedicine. Several groups of patients were less likely to use telemedicine, including Hispanic (adjusted odds ratio [aOR] 0.86, p = 0.03), Asian (aOR 0.79, p = 0.002), Spanish‐speaking (aOR 0.71, p = 0.0006), low‐income (aOR 0.67, p < 0.0001), and those with Medicaid (aOR 0.66, p < 0.0001). Lower rates of telemedicine use were found in zip codes with higher rates of COVID‐19 infection. Each 10% increase in COVID‐19 infection rates was associated with an 8.3% decrease in telemedicine use (p = 0.002). Conclusions This study demonstrates racial/ethnic, language, and income‐level disparities with telemedicine use, which ultimately led patients with the highest risk of COVID‐19 infection to use telemedicine the least. Additional research to better understand actionable barriers will help improve telemedicine access among our underserved populations. At a tertiary care academic medical center, Hispanic, Asian, Spanish‐speaking, low‐income, and patients with Medicaid insurance were less likely to utilize telemedicine. Additionally, lower rates of telemedicine use were found in zip codes with higher rates of COVID‐19 infection. As such, there were significant racial/ethnic, language, and income‐level disparities with telemedicine use, which ultimately led cancer patients with the highest risk of COVID‐19 infection to use telemedicine the least.

PurposeAngiosarcoma is a rare aggressive endothelial cell cancer with high mortality. Isolated reports suggest immune checkpoint inhibition efficacy in angiosarcoma, but no prospective studies have been published. We report results for angiosarcoma treated with ipilimumab and nivolumab as a cohort of an ongoing rare cancer study.MethodsThis is a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) for metastatic or unresectable angiosarcoma. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free (PFS) and overall survival, and toxicity. A two-stage design was used.ResultsOverall, there were 16 evaluable patients. Median age was 68 years (range, 25–81); median number of prior lines of therapy, 2. Nine patients had cutaneous and seven non-cutaneous primary tumors. ORR was 25% (4/16). Sixty per cent of patients (3/5) with primary cutaneous scalp or face tumors attained a confirmed response. Six-month PFS was 38%. Altogether, 75% of patients experienced an adverse event (AE) (at least possibly related to drug) (25% grade 3–4 AE); 68.8%, an immune-related AE (irAE) (2 (12.5%), grade 3 or 4 irAEs (alanine aminotransferase/aspartate aminotransferase increase and diarrhea)). There were no grade 5 toxicities. One of seven patients in whom tumor mutation burden (TMB) was assessed showed a high TMB (24 mutations/mb); that patient achieved a partial response (PR). Two of three patients with PDL1 immunohistochemistry assessed had high PDL1 expression; one achieved a PR.ConclusionThe combination of ipilimumab and nivolumab demonstrated an ORR of 25% in angiosarcoma, with three of five patients with cutaneous tumors of the scalp or face responding. Ipilimumab and nivolumab warrant further investigation in angiosarcoma.Trial registration numberNCT02834013.

NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug–drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug–radiotherapy combinations.

Quinolines are a prominent heterocyclic motif and crucial building blocks in creating physiologically active compounds. Due to the fast development of novel medicines with a quinoline nucleus, numerous research papers have been published in a short amount of time. Therefore, to comprehend the present state of the quinoline nucleus in medicinal chemistry science, it is necessary to combine new information with older data. So far, several traditional synthesis techniques have been reported in the literature to synthesize this scaffold. Pfitzinger, Gould-Jacob, Friedlander, Skraup, Doebner-von Miller, and Conrad-Limpach are examples of old synthetic methods. However, they need expensive and demanding conditions, such as high temperature, the use of non-biodegradable chemical compounds degrade the ecosystem, create irritation or harm as pollutants, and represent a threat to the environment. However, traditional synthesis processes need a difficult and time-consuming apparatus set-up, resulting in high costs and pollutants. As a result, scientists are presently developing new and innovative techniques to decrease the use of chemicals, solvents, and catalysts, which are detrimental to both humans and the environment. Therefore, we have attempted to shed light in this current review on various reactions to produce quinolines and their derivatives using various green synthetic methods.

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N⁶-methylation of adenosine (m⁶A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m⁶A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m⁶A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m⁶A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.