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Cough is a defense mechanism that prevents the entry of noxious materials into the respiratory system and clears foreign materials and excess secretions from the lungs and respiratory tract. In advanced cancer, it is a common symptom that interferes with the patient's daily activity and quality of life. Empiric treatment with antitussive agents is often needed. Two classes of antitussive drugs are available: (1) centrally acting: (a) opioids and (b) non-opioids; (2) peripherally acting: (a) directly and (b) indirectly. Antitussive availability varies widely around the world. Many antitussives, such as benzonatate, codeine, hydrocodone, and dextromethorphan, were extensively studied in the acute and chronic cough settings and showed relatively high efficacy and safety profiles. Benzonatate, clobutinol, dihydrocodeine, hydrocodone, and levodropropizine were the only antitussives specifically studied in cancer and advanced cancer cough. They all have shown to be effective and safe in recommended daily dose for cough. In advanced cancer the patient's current medications, previous antitussive use, the availability of routes of administration, any history of drug abuse, the presence of other symptoms and other factors, all have a role in the selection of antitussives for prescription. A good knowledge of the pharmacokinetics, dosage, efficacy, and side effects of the available antitussives provides for better management. [ABSTRACT FROM AUTHOR]

We present a retrospective study of the frequency, pattern, and management of infections in advanced cancer. Three hundred ninety-three patients were admitted to an acute care palliative medicine unit in an 8-month period for evaluation and palliation of cancer-related symptoms and complications. One hundred fifteen had at least one positive bacteriological culture, and 100 of these patients were evaluable. One hundred fifty-two infections and 192 isolates were identified. Sixty-eight patients had polymicrobial infections. Sixty-six patients had urinary tract infections. Forty-one were found to have multisystemic infections. Eighty-one had invasive devices; 32 had more than one invasive device. Fifty-three were taking corticosteroids at the time of infection. Only 3 were neutropenic. Urinary tract infections were significantly more common in those taking corticosteroids. The median duration of antibiotic treatment was 11 days and the median hospital stay, 14 days. Twenty-eight patients died in the hospital; 10 of those who died had lung cancer, which was a statistically significant observation. In conclusion, infections are an underrecognized but common complication in nonneutropenic hospitalized patients with advanced solid tumors. Urinary tract infections appear to be associated with the use of corticosteroids. Lung cancer patients are at greater risk for fatal infections. Infections increase morbidity in debilitated patients with solid tumors, are a frequent cause of hospital admission, and are associated with significant mortality. [ABSTRACT FROM AUTHOR]

BACKGROUND In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings. METHODS We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (MO) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute <10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events. RESULTS A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%). CONCLUSIONS Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.). [ABSTRACT FROM AUTHOR]

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.

Background: A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI., Methods: Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women)., Results: Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P =1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 ( P =0.05) and multi-organ ( P =0.02) irAE., Conclusions: In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 von Itzstein, Yang, Wang, Hsiehchen, Sheffield, Fattah, Popat, Ahmed, Homsi, Dowell, Rashdan, Lohrey, Hammers, Hughes, Wang, Xie and Gerber.)

The existing T cell-centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSC), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily B3 (LILRB3), an immune inhibitory receptor containing tyrosine-based inhibitory motifs (ITIM), is expressed solely on myeloid cells. However, it is unknown whether LILRB3 is a critical checkpoint receptor in regulating the activity of immunosuppressive myeloid cells, and whether LILRB3 signaling can be blocked to activate the immune system to treat solid tumors. Here, we report that galectin-4 and galectin-7 induce activation of LILRB3 and that LILRB3 is functionally expressed on immunosuppressive myeloid cells. In some samples from patients with solid cancers, blockade of LILRB3 signaling by an antagonistic antibody inhibited the activity of immunosuppressive myeloid cells. Anti-LILRB3 also impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent manner. LILRB3 blockade may prove to be a novel approach for immunotherapy of solid cancers., (©2023 American Association for Cancer Research.)

Background: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival., Methods: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing., Findings: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths., Interpretation: For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need., Funding: Regeneron Pharmaceuticals and Sanofi., Competing Interests: Declaration of interests NDG reports institutional research funding from Regeneron Pharmaceuticals; speaker honoraria from AiCME; and advisory board and consulting fees from PDS Biotechnology, Replimmune, Regeneron Pharmaceuticals, and Merck. DMM reports honoraria for advisory or consultant roles from Castle Biosciences, EMD Serono, Merck KGaA, Merck Sharpe & Dome, Pfizer, Regeneron Pharmaceuticals, Incyte, Sanofi Genzyme, and Bristol Myers Squibb; equity options from Checkpoint Therapeutics and Avstera Therapeutics Corp; and research funding from Kartos Therapeutics, NeoImmune Tech, and Regeneron Pharmaceuticals. NIK reports grants and advisory board fees from Regeneron Pharmaceuticals, Bristol Myers Squibb, Merck, Replimmune, and Novartis; advisory board fees from Iovance, Instil Bio, Castle Biosciences, Nektar, Incyte (data safety monitoring committee), AstraZeneca (data safety monitoring committee), and Jounce Therapeutics; grants from GlaxoSmithKline, HUYA, and Celgene; honoraria from Genzyme, National Comprehensive Cancer Network (paid by Pfizer), Nektar (study steering committee), Regeneron Pharmaceuticals (study steering committee), Bristol Myers Squibb (study steering committee). and Replimmune (study steering committee); grant from Modulation Therapeutics; travel support from Regeneron Pharmaceuticals; and common stock ownership of Bellicum Pharmaceuticals, Amarin, and Asensus Surgical (formerly Transenetrix). VD reports institutional research funding from Genentech, and advisory board fees from Regeneron Pharmaceuticals. ESR reports advisory board and consulting fees from Genentech, Feldan Therapeutics, Regeneron Pharmaceuticals, and Sanofi, and serves on the board of directors for Checkpoint Therapeutics. EJL reports institutional research funding from Regeneron Pharmaceuticals and Sanofi; institutional grants from Bristol Myers Squibb and Merck; advisory board fees from Bristol Myers Squibb, Eisai, Genentech, Instil Bio, Merck, Natera, Nektar Therapeutics, Odonate Therapeutics, Pfizer, Rain Therapeutics, Regeneron Pharmaceuticals, Replimmune, and Sanofi; payment for speaker's fee from Bristol Myers Squibb; and consulting fees from Bristol Myers Squibb, Macrogenics, OncoSec, Merck, Novartis, CareDX, and Pfizer. FM reports travel support, speaker's fees or advisor's honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; and research funding from Novartis and Roche. PLS reports institutional research grants from Ascentage Pharma and Pfizer, and advisory board roles for Elevar Therapeutics, Prelude Therapeutics, and Regeneron Pharmaceuticals. JA reports payment or honoraria for speakers bureaus and presentations from Bristol Myers Squibb and Regeneron Pharmaceuticals; advisory board and consulting fees from Bristol Myers Squibb, Castle Biosciences, Pfizer, Regeneron Pharmaceuticals, and Sanofi. JLG reports institutional research funding from Alkermes, EMD Serono, Merck, Regeneron Pharmaceuticals, and Roche/Genentech; and advisory board or consultant fees from Astellas, Exelixis, EMD Serono, Merck, and Regeneron Pharmaceuticals. AH reports grants and personal fees from Amgen, Bristol Myers Squibb, Merck-Pfizer, MSD/Merck, Philogen, Pierre Fabre, Regeneron Pharmaceuticals, Roche, Sanofi-Genzyme, Novartis Pharma, Eisai, Replimmune, NeraCare; consulting fees from Seagen, IO Biotech, Dermagnostix, Incyte, Highlight Therapeutics, and Iovance; speaker's honoraria from Kyowa Kirin; advisory board fees from Immunocore; and institutional grants from Huya Biosciences outside the submitted work. JHC reports consulting or advisory roles for Exelixis, Coherus Biosciences, Merck Sharp & Dohme, Eisai, and Regeneron Pharmaceuticals, and institutional research funding from Arcus Biosciences and Genmab. BGMH reports consulting or advisory roles at AstraZeneca, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer, and Roche, and institutional research funding from Amgen. DS reports honoraria from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron Pharmaceuticals, 4SC, Sanofi, Regeneron Pharmaceuticals, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, and Sandoz; consulting fees from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Nektar; speaker fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Merck; advisory board fees from AstraZeneca, Daiichi-Sankyo, Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Nektar; institutional research funding from Bristol Myers Squibb, Novartis, Roche, MSD Oncology, and Array BioPharma/Pfizer; unpaid leadership or fiduciary roles with Dermatologic Cooperative Oncology Group, European Organisation for Research and Treatment of Cancer-Melanoma Group, Hiege-Stiftung, and Nationale Versorgungskonferenz Hautkrebs; and travel and accommodation expenses from Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi, and Regeneron Pharmaceuticals. VAP reports honoraria for advisory or consulting roles from Sun Pharma, Almirall, Biofrontera, PhD Biosciences, Regeneron Pharmaceuticals, and Sanofi Genzyme; speakers bureau fees from Regeneron Pharmaceuticals, and Sanofi Genzyme, equity in Avstera Therapeutics and Science 37; and research funding from Regeneron Pharmaceuticals. JMT reports honoraria for advisory or consultant roles for Bristol Myers Squibb, Merck & Co, AstraZeneca, Genentech/Roche, Regeneron Pharmaceuticals, Compugen, Lunaphore, and Akoya Biosciences; stock options in Akoya Biosciences; equipment loan and reagent provision from Akoya Biosciences; and research funding from Bristol Myers Squibb and Akoya Biosciences. AML reports uncompensated consultancy for Eisai, research funding support from Sanofi/Regeneron Pharmaceuticals, and support from a Peter MacCallum Cancer Centre Discovery Partner Fellowship. RF reports grants or investigator-initiated trial support from Merck, Pfizer, Gilead, and Ayala; royalties from UpToDate for a chapter on olfactory neuroblastoma; payment for expert testimony from Guidepoint; and advisory board participation with Regeneron Pharmaceuticals, Prelude Therapeutics, Elevar Therapeutics, Eisai, Remix Therapeutics, and Coherus BioSciences. S-YY, HH, FS, and IL are employees and shareholders of Regeneron Pharmaceuticals. MM and MGF report receipt of support for attending meetings or travel, and are also employees, patent holders, and shareholders of Regeneron Pharmaceuticals. DR reports institutional research grant and funding from Regeneron Pharmaceuticals, Genentech, Sanofi, Kura Oncology, Roche, Merck Sharp & Dohme, Decibel Therapeutics, Bristol Myers Squibb, GlaxoSmithKline, and ALX Oncology; and uncompensated scientific committee and advisory board roles for Merck Sharp & Dohme, Regeneron Pharmaceuticals, Sanofi, and Eisai. YBS and JH declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Preclinical studies have demonstrated the ability of radiation therapy (RT) to augment immune response and tumor control by immune checkpoint inhibitors (ICI). However, numerous clinical trials combining RT and ICI have yielded relatively disappointing results. To improve understanding of optimal use of these therapies, we assessed systemic immune effects of prior RT in patients receiving ICI., Methods and Materials: Pre- and post-ICI blood samples were collected from patients enrolled in a prospective immunotherapy biospecimen protocol. Mutiplex panels of 40 cytokines and 120 autoantibodies (Ab) were analyzed. We identified differences in these parameters according to receipt, timing, and type of prior RT. We calculated P values using the Pearson product-moment correlation coefficient and false discovery rate (FDR) using the Benjamini-Hochberg Procedure., Results: Among 277 total patients, 69 (25%) received RT in the 6 months prior to ICI initiation. Among RT-treated patients, 23 (33%) received stereotactic RT, and 33 (48%) received curative intent RT. There was no significant difference in demographics or type of immunotherapy between patients according to prior RT exposure. Baseline complement C8 Ab and MIP-1d/CCL15 were significantly higher among patients with prior RT. For MIP-1d/CCL15, only prior stereotactic RT was associated with significant differences., Conclusions: Prior RT is associated with few changes in systemic immune parameters in patients receiving ICI. The underlying mechanisms and optimal approach to harnessing the potential synergy of RT and ICI require further prospective clinical investigation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: US Patent Applications 16/487335 and 17/045482 PREDICTION AND TREATMENT OF IMMUNOTHERAPEUTIC TOXICITY (to Farjana Fattah., Yang Xie., Jason Park., Quan-Zhen Li., Edward K. Wakeland., and David E. Gerber)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.

Soft tissue sarcomas (STS) are rare malignancies of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as retroperitoneal/intra-abdominal STS, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis and treatment of retroperitoneal/intra-abdominal STS, outlines treatment recommendations, and reviews the evidence to support the guidelines recommendations.

Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II restricted presentation of multiple melanoma antigens. There is variable GILT protein expression in malignant melanocytes in melanoma specimens. High GILT mRNA expression in melanoma specimens is associated with improved overall survival, before the advent of immune checkpoint inhibitors (ICI). However, the association of GILT in metastatic melanoma with survival in patients treated with ICI and the cell type expressing GILT associated with survival have not been determined. Using RNA sequencing datasets, high GILT mRNA expression in metastatic melanoma specimens was associated with improved progression-free and overall survival in patients treated with ICI. A clinical dataset of metastatic melanoma specimens was generated and annotated with clinical information. Positive GILT immunohistochemical staining in antigen presenting cells and melanoma cells was observed in 100% and 65% of metastatic melanoma specimens, respectively. In the subset of patients treated with ICI in the clinical dataset, high GILT protein expression within melanoma cells was associated with improved overall survival. The association of GILT mRNA and protein expression with survival was independent of cancer stage. These studies support that high GILT mRNA expression in bulk tumor samples and high GILT protein expression in melanoma cells is associated with improved survival in ICI-treated patients. These findings support further investigation of GILT as a biomarker to predict the response to ICI.

Antibiotic administration is associated with worse clinical outcomes and changes to the gut microbiome in cancer patients receiving immune checkpoint inhibitors (ICI). However, the effects of antibiotics on systemic immune function are unknown. We, therefore, evaluated antibiotic exposure, therapeutic responses, and multiplex panels of 40 serum cytokines and 124 antibodies at baseline and six weeks after ICI initiation, with p < 0.05 and false discovery rate (FDR) < 0.2 considered significant. A total of 251 patients were included, of whom the 135 (54%) who received antibiotics had lower response rates and shorter survival. Patients who received antibiotics prior to ICI initiation had modestly but significantly lower baseline levels of nucleolin, MDA5, c-reactive protein, and liver cytosol antigen type 1 (LC1) antibodies, as well as higher levels of heparin sulfate and Matrigel antibodies. After ICI initiation, antibiotic-treated patients had significantly lower levels of MDA5, CENP.B, and nucleolin antibodies. Although there were no clear differences in cytokines in the overall cohort, in the lung cancer subset (53% of the study population), we observed differences in IFN-γ, IL-8, and macrophage inflammatory proteins. In ICI-treated patients, antibiotic exposure is associated with changes in certain antibodies and cytokines. Understanding the relationship between these factors may improve the clinical management of patients receiving ICI.

Background: Given the rapidly evolving nature of the field, the current state of "high-risk" head and neck cutaneous squamous cell carcinoma (HNcSCC) is poorly characterized., Methods: Narrative review of the epidemiology, diagnosis, workup, risk stratification, staging and treatment of high-risk HNcSCC., Results: Clinical and pathologic risk factors for adverse HNcSCC outcomes are nuanced (e.g., immunosuppression and perineural invasion). Frequent changes in adverse prognosticators have outpaced population-based registries and the variables they track, restricting our understanding of the epidemiology of HNcSCC and inhibiting control of the disease. Current heterogeneous staging and risk stratification systems are largely derived from institutional data, compromising their external validity. In the absence of staging system consensus, tumor designations such as "high risk" and "advanced" are variably used and insufficiently precise to guide management. Evidence guiding treatment of high-risk HNcSCC with curative intent is also suboptimal. For patients with incurable disease, an array of trials are evaluating the impact of immunotherapy, targeted biologic therapy, and other novel agents., Conclusion: Population-based registries that broadly track updated, nuanced, adverse clinicopathologic risk factors, and outcomes are needed to guide development of improved staging systems. Design and development of randomized controlled trials (RCTs) in advanced-stage HNcSCC populations are needed to evaluate (1) observation, sentinel lymph node biopsy, or elective neck dissection for management of the cN0 neck, (2) indications for surgery plus adjuvant radiation versus adjuvant chemoradiation, and (3) the role of immunotherapy in treatment with curative intent. Considering these knowledge gaps, the authors explore a potential high-risk HNcSCC treatment framework., (© 2021. Society of Surgical Oncology.)

Purpose: To validate healthcare claim-based algorithms for neurodevelopmental disorders (NDD) in children using medical records as the reference., Methods: Using a clinical data warehouse of patients receiving outpatient or inpatient care at two hospitals in Boston, we identified children (≤14 years between 2010 and 2014) with at least one of the following NDDs according to claims-based algorithms: autism spectrum disorder/pervasive developmental disorder (ASD), attention deficit disorder/other hyperkinetic syndromes of childhood (ADHD), learning disability, speech/language disorder, developmental coordination disorder (DCD), intellectual disability, and behavioral disorder. Fifty cases per outcome were randomly sampled and their medical records were independently reviewed by two physicians to adjudicate the outcome presence. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated., Results: PPVs were 94% (95% CI, 83%-99%) for ASD, 88% (76%-95%) for ADHD, 98% (89%-100%) for learning disability, 98% (89%-100%) for speech/language disorder, 82% (69%-91%) for intellectual disability, and 92% (81%-98%) for behavioral disorder. A total of 19 of the 50 algorithm-based cases of DCD were confirmed as severe coordination disorders with functional impairment, with a PPV of 38% (25%-53%). Among the 31 false-positive cases of DCD were 7 children with coordination deficits that did not persist throughout childhood, 7 with visual-motor integration deficits, 12 with coordination issues due to an underlying medical condition and 5 with ADHD and at least one other severe NDD., Conclusions: PPVs were generally high (range: 82%-98%), suggesting that claims-based algorithms can be used to study NDDs. For DCD, additional criteria are needed to improve the classification of true cases., (© 2021 John Wiley & Sons Ltd.)

Background: Hemodialysis patients with COVID-19 have been reported to be at higher risk for death than the general population. Several prognostic factors have been identified in the studies from Asian, European or American countries. This is the first national Lebanese study assessing the factors associated with SARS-CoV-2 mortality in hemodialysis patients., Methods: This is an observational study that included all chronic hemodialysis patients in Lebanon who were tested positive for SARS-CoV-2 from 31st March to 1st November 2020. Data on demographics, comorbidities, admission to hospital and outcome were collected retrospectively from the patients' medical records. A binary logistic regression analysis was performed to assess risk factors for mortality., Results: A total of 231 patients were included. Mean age was 61.46 ± 13.99 years with a sex ratio of 128 males to 103 females. Around half of the patients were diabetics, 79.2% presented with fever. A total of 115 patients were admitted to the hospital, 59% of them within the first day of diagnosis. Hypoxia was the major reason for hospitalization. Death rate was 23.8% after a median duration of 6 (IQR, 2 to 10) days. Adjusted regression analysis showed a higher risk for death among older patients (odds ratio = 1.038; 95% confidence interval: 1.013, 1.065), patients with heart failure (odds ratio = 4.42; 95% confidence interval: 2.06, 9.49), coronary artery disease (odds ratio = 3.27; 95% confidence interval: 1.69, 6.30), multimorbidities (odds ratio = 1.593; 95% confidence interval: 1.247, 2.036), fever (odds ratio = 6.66; 95% confidence interval: 1.94, 27.81), CRP above 100 mg/L (odds ratio = 4.76; 95% confidence interval: 1.48, 15.30), and pneumonia (odds ratio = 19.18; 95% confidence interval: 6.47, 56.83)., Conclusions: This national study identified older age, coronary artery disease, heart failure, multimorbidities, fever and pneumonia as risk factors for death in patients with COVID-19 on chronic hemodialysis. The death rate was comparable to other countries and estimated at 23.8%.

The NCCN Guidelines for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with soft tissue sarcomas. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including the development of a separate and distinct guideline for gastrointestinal stromal tumors (GISTs); reconception of the management of desmoid tumors; inclusion of further recommendations for the diagnosis and management of extremity/body wall, head/neck sarcomas, and retroperitoneal sarcomas; modification and addition of systemic therapy regimens for sarcoma subtypes; and revision of the principles of radiation therapy for soft tissue sarcomas.

Multiple human polyomaviruses (HPyV) can infect the skin, but only Merkel cell polyomavirus (MCPyV) has been implicated in the development of a cancer, Merkel cell carcinoma (MCC). While expression of HPyV6, HPyV7, and MCPyV small T antigens (sT), all induced a senescence-associated secretory phenotype (SASP), MCPyV sT uniquely activated noncanonical NF-κB (ncNF-κB), instead of canonical NF-κB signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-κB signaling both by inducing H3K4 trimethylation-mediated increases of NFKB2 and RELB transcription and also by promoting NFKB2 stabilization and activation through FBXW7 inhibition. Noncanonical NF-κB signaling was required for SASP cytokine secretion, which promoted the proliferation of MCPyV sT-expressing cells through autocrine signaling. Virus-positive MCC cell lines and tumors showed ncNF-κB pathway activation and SASP gene expression, and the inhibition of ncNF-κB signaling prevented VP-MCC cell growth in vitro and in xenografts. We identify MCPyV sT-induced ncNF-κB signaling as an essential tumorigenic pathway in MCC. IMPLICATIONS: This work is the first to identify the activation of ncNF-κB signaling by any polyomavirus and its critical role in MCC tumorigenesis., (©2020 American Association for Cancer Research.)

Introduction: Major colorectal surgery procedures are complex operations that can result in significant postoperative pain and complications. More evidence is needed to demonstrate how opioid-related adverse drug events (ORADEs) after colorectal surgery can affect hospital length of stay (LOS), hospital revenue, and what their association is with clinical conditions. By understanding the clinical and economic impact of potential ORADEs within colorectal surgery, we hope to further guide approaches to perioperative pain management in an effort to improve patient care and reduce hospital costs. Materials and Methods: We conducted a retrospective study utilizing the Centers for Medicare and Medicaid Services (CMS) Administrative Database to analyze Medicare discharges involving three colorectal surgery diagnosis-related groups (DRGs) to identify potential ORADEs. The impact of potential ORADEs on mean hospital LOS and hospital revenue was analyzed. Results: The potential ORADE rate in patients undergoing colorectal surgery was 23.92%. The mean LOS for discharges with a potential ORADE was 5.35 days longer than without an ORADE. The mean hospital revenue per day with a potential ORADE was $418 less than without an ORADE. Any type of open surgery had a statistically significant higher potential ORADE rate than the matched laparoscopic case ( P  < .001). Clinical conditions most strongly associated with ORADEs in colorectal surgery included septicemia, pneumonia, shock, and fluid and electrolyte disorders. Conclusion: The incidence of ORADEs in colorectal surgery is high and is associated with longer hospital stays and reduced hospital revenue. Reducing the use of opioids in the perioperative setting, such as using multimodal analgesia strategies, may lead to positive outcomes with shorter hospital stays, increased hospital revenue, and improved patient care.

Acute management of a severely burned patient is an infrequent and stressful situation that requires medical knowledge as well as immediate coordinated action. Many adverse events in health care result from issues related to the application of 'non-technical' skills such as communication, teamwork, leadership and decision making rather than lack of medical knowledge. Training in these skills is known as Crisis Resource Management (CRM) training. In order to create well-prepared burn teams, it is critical to teach CRM principles through high-fidelity simulation (HFS). While CRM teaches foundational non-technical skills, HFS incorporates lifelike, whole-body, fully-responsive mannequins in order to provide a realistic emergency situation. The aim of the study is to describe the development of a novel high-fidelity simulation course called "SIMBurns: High Fidelity Simulation Program for Emergency Burn Management" that uses CRM as its foundation and is focused on management of burn injuries. The course was designed by a panel of simulation and burns experts from Meyer Children's Hospital in Italy and Birmingham Children's Hospital in the U.K. Simulation Program experts were certified by Boston Children's Hospital's Simulation Program. In this paper, we describe the course's design, development, structure, and participant's assessment of the course. Since the creation of the SIMBurns course in 2013, 9 courses have been conducted and 101 participants have attended the course. The course was well-received and its "Overall Satisfaction" was rated at 4.8/5. The primary objective in the SIMBurns course - to teach teamwork and CRM skills to medical staff involved in emergency burn care - was also met at 4.8/5. Participants felt that the course developed their ability to interact with other team members, further improved their understanding of how to appropriately use resources, emphasized the importance of role clarity and developed their communication skills. Additional quantitative and qualitative analyses obtained from participants were also reviewed after each course. The SIMBurns course aims to contribute to the education of those in healthcare in order to improve patient safety and to continue advancing the education of our emergency burn care teams., (Copyright © 2018 Elsevier Ltd and ISBI. All rights reserved.)

Background: HDIL-2 is approved for advanced melanoma based on its durable antitumor activity. MAGE-A3 cancer immunotherapeutic (MAGE-A3 CI) is a recombinant MAGE-A3 protein combined with an immunostimulant adjuvant system and has shown antitumor activity in melanoma. We assessed the safety and anti-tumor activity of HDIL-2 combined with MAGE-A3 CI in advanced melanoma., Methods: Patients with unresectable Stage III or Stage IV MAGE-A3-positive melanoma were enrolled in this phase II study. Treatment included an induction phase of MAGE-A3 CI plus HDIL-2 for 8 cycles followed by a maintenance phase of MAGE-A3 CI monotherapy. The primary endpoints were safety and objective response assessed per RECIST v1.1. Immune biomarker and correlative studies on tumor and peripheral blood were performed., Results: Eighteen patients were enrolled. Seventeen patients were evaluable for safety and sixteen for response. Responses occurred in 4/16 (25%) patients with 3 complete responses, and stable disease in 6/16 (38%) patients with a disease control rate of 63%. The median duration of response was not reached at median follow-up of 36.8 months. Induction therapy of HDIL-2 + MAGE-A3 CI had similar toxicities to those reported with HDIL-2 alone. Maintenance MAGE-A3 monotherapy was well-tolerated. Increased immune checkpoint receptor expression by circulating T regulatory cells was associated with poor clinical outcomes; and responders tended to have increased tumor infiltrating T cells in the baseline tumor samples., Conclusions: The safety profile of HDIL-2 + MAGE-A3 CI was similar to HDIL-2 monotherapy. Maintenance MAGE-A3 CI provides robust anti-tumor activity in patients who achieved disease control with induction therapy. Immune monitoring data suggest that MAGE-A3 CI plus checkpoint inhibitors could be a promising treatment for MAGE-A3-positive melanoma., Trial Registration: ClinicalTrials.gov, NCT01266603 . Registered 12/24/2010, https://clinicaltrials.gov/ct2/show/NCT01266603.

Objectives: Hepatic arterial infusion (HAI) of cytotoxic chemotherapy is a strategy to deliver high dose of anticancer therapy to liver metastases that derive their blood supply from the hepatic artery. Metastatic melanoma (MM) has a high incidence of liver metastases, with uveal subtype in particular exhibiting a predilection for liver dissemination. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has demonstrated efficacy in MM and first-pass hepatic metabolism. Therefore, we hypothesized that HAI of nab-paclitaxel would deliver an effective dose of drug to the end organ of interest, with minimal systemic exposure., Patient and Methods: We performed a single-institution open-label phase I/II study of HAI of nab-paclitaxel in MM patients with liver metastasis. Patients received treatment every 21 days at 4 different dose levels. The primary objective of the phase I portion of the study was safety and determination of the maximum-tolerated dose. The primary objective of the phase II portion of the study was overall response rate per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0., Results: A total of 30 patients were treated between 2009 and 2013, 16 of whom had uveal melanoma. The maximum-tolerated dose was 220 mg/m and 19 patients were treated at this dose. There was 1 patient (5%) with a partial response at this dose, and 8 patients (42%) with stable disease at this dose., Conclusions: HAI nab-paclitaxel demonstrates rare objective responses in melanoma patients with liver metastases. This treatment should be studied in combination with checkpoint blockade or other novel treatments to enhance meaningful responses but should not be considered effective monotherapy.

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia 1 . This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.

Background: No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma., Methods: We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review., Results: In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event., Conclusions: Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).