The Associations of <i>Trans</i>-3′-Hydroxy Cotinine, Cotinine, and the Nicotine Metabolite Ratio in Pediatric Patients with Tobacco Smoke Exposure

(1) Background: Trans-3′-hydroxy cotinine (3HC) and cotinine (COT) are tobacco smoke exposure (TSE) biomarkers and the 3HC/COT ratio is a marker of CYP2A6 activity, an enzyme which metabolizes nicotine. The primary objective was to assess the associations of these TSE biomarkers with sociodemographics and TSE patterns in children who lived with ≥1 smoker. (2) Methods: A convenience sample of 288 children (mean age (SD) = 6.42 (4.8) years) was recruited. Multiple linear regression models were built to assess associations of sociodemographics and TSE patterns with urinary biomarker response variables: (1) 3HC, (2) COT, (3) 3HC+COT sum, and (4) 3HC/COT ratio. (3) Results: All children had detectable 3HC (Geometric Mean [GeoM] = 32.03 ng/mL, 95%CI = 26.97, 38.04) and COT (GeoM = 10.24 ng/mL, 95%CI = 8.82, 11.89). Children with higher cumulative TSE had higher 3HC and COT (β^ = 0.03, 95%CI = 0.01, 0.06, p = 0.015 and β^ = 0.03, 95%CI = 0.01, 0.05, p = 0.013, respectively). Highest 3HC+COT sum levels were in children who were Black (β^ = 0.60, 95%CI = 0.04, 1.17, p = 0.039) and who had higher cumulative TSE (β^ = 0.03, 95%CI = 0.01, 0.06, p = 0.015). Lowest 3HC/COT ratios were in children who were Black (β^ = −0.42, 95%CI = −0.78, −0.07, p = 0.021) and female (β^ = −0.32, 95%CI = −0.62, −0.01, p = 0.044). (4) Conclusion: Results indicate that there are racial and age-related differences in TSE, most likely due to slower nicotine metabolism in non-Hispanic Black children and in younger children

Differential associations of hand nicotine and urinary cotinine with children's exposure to tobacco smoke and clinical outcomes.

BackgroundChildren's overall tobacco smoke exposure (TSE) consists of both inhalation of secondhand smoke (SHS) and ingestion, dermal uptake, and inhalation of thirdhand smoke (THS) residue from dust and surfaces in their environments.ObjectivesOur objective was to compare the different roles of urinary cotinine as a biomarker of recent overall TSE and hand nicotine as a marker of children's contact with nicotine pollution in their environments. We explored the differential associations of these markers with sociodemographics, parental smoking, child TSE, and clinical diagnoses.MethodsData were collected from 276 pediatric emergency department patients (Median age&nbsp;=&nbsp;4.0 years) who lived with a cigarette smoker. Children's hand nicotine and urinary cotinine levels were determined using LC-MS/MS. Parents reported tobacco use and child TSE. Medical records were reviewed to assess discharge diagnoses.ResultsAll children had detectable hand nicotine (GeoM&nbsp;=&nbsp;89.7ng/wipe; 95&nbsp;% CI&nbsp;=&nbsp;[78.9; 102.0]) and detectable urinary cotinine (GeoM&nbsp;=&nbsp;10.4&nbsp;ng/ml; 95%CI&nbsp;=&nbsp;[8.5; 12.6]). Although hand nicotine and urinary cotinine were highly correlated (r&nbsp;=&nbsp;0.62, p&nbsp;&lt;&nbsp;0.001), urinary cotinine geometric means differed between racial groups and were higher for children with lower family income (p&nbsp;&lt;&nbsp;0.05), unlike hand nicotine. Independent of urinary cotinine, age, race, and ethnicity, children with higher hand nicotine levels were at increased risk to have discharge diagnoses of viral/other infectious illness (aOR&nbsp;=&nbsp;7.49; 95%CI&nbsp;=&nbsp;[2.06; 27.24], p&nbsp;=&nbsp;0.002), pulmonary illness (aOR&nbsp;=&nbsp;6.56; 95%CI&nbsp;=&nbsp;[1.76; 24.43], p&nbsp;=&nbsp;0.005), and bacterial infection (aOR&nbsp;=&nbsp;5.45; 95%CI&nbsp;=&nbsp;[1.50; 19.85], p&nbsp;=&nbsp;0.03). In contrast, urinary cotinine levels showed no associations with diagnosis independent of child hand nicotine levels and demographics.DiscussionThe distinct associations of hand nicotine and urinary cotinine suggest the two markers reflect different exposure profiles that contribute differentially to pediatric illness. Because THS in a child's environment directly contributes to hand nicotine, additional studies of children of smokers and nonsmokers are warranted to determine the role of hand nicotine as a marker of THS exposure and its potential role in the development of tobacco-related pediatric illnesses

PD1 blockade enhances K+ channel activity, Ca2+ signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer

Background Immunotherapy has emerged as a promising treatment modality for head and neck squamous cell carcinoma (HNSCC). Pembrolizumab, an anti-programmed death 1 antibody, is an immunotherapy agent currently approved for metastatic HNSCC and curative intent clinical trials. Although clinical responses to pembrolizumab are promising, many patients fail to respond. However, it is well known that T cell cytotoxicity and chemotaxis are critically important in the elimination of HNSCC tumors. These functions depend on ion channel activity and downstream Ca2+ fluxing abilities, which are defective in patients with HNSCC. The purpose of this study was to elucidate the effects of pembrolizumab on potassium (K+) channel (KCa3.1 and Kv1.3) activity, Ca2+ fluxes, and chemotaxis in the cytotoxic T cells of patients with HNSCC and to determine their correlation with treatment response.Methods Functional studies were conducted in CD8+ peripheral blood T cells (PBTs) and tumor infiltrating lymphocytes (TILs) from patients with HNSCC treated with pembrolizumab. Untreated patients with HNSCC were used as controls. The ion channel activity of CD8+ T cells was measured by patch-clamp electrophysiology; single-cell Ca2+ fluxing abilities were measured by live microscopy. Chemotaxis experiments were conducted in a three-dimensional collagen matrix. Pembrolizumab patients were stratified as responders or non-responders based on pathological response (percent of viable tumor remaining at resection; responders: ≤80% viable tumor; non-responders: &gt;80% viable tumor).Results Pembrolizumab increased K+ channel activity and Ca2+ fluxes in TILs independently of treatment response. However, in PBTs from responder patients there was an increased KCa3.1 activity immediately after pembrolizumab treatment that was accompanied by a characteristic increase in Kv1.3 and Ca2+ fluxes as compared with PBTs from non-responder patients. The effects on Kv1.3 and Ca2+ were prolonged and persisted after tumor resection. Chemotaxis was also improved in responder patients’ PBTs. Unlike non-responders’ PBTs, pembrolizumab increased their ability to chemotax in a tumor-like, adenosine-rich microenvironment immediately after treatment, and additionally they maintained an efficient chemotaxis after tumor resection.Conclusions Pembrolizumab enhanced K+ channel activity, Ca2+ fluxes and chemotaxis of CD8+ T cells in patients with HNSCC, with a unique pattern of response in responder patients that is conducive to the heightened functionality of their cytotoxic T cells

Interplay of Immunosuppression and Immunotherapy Among Patients With Cancer and COVID-19

IMPORTANCE: Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. OBJECTIVE: To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. DESIGN, SETTING, AND PARTICIPANTS: This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. EXPOSURES: Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). MAIN OUTCOMES AND MEASURES: The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. RESULTS: The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). CONCLUSIONS AND RELEVANCE: This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04354701

Interplay of Immunosuppression and Immunotherapy Among Patients With Cancer and COVID-19

IMPORTANCE: Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. OBJECTIVE: To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. DESIGN, SETTING, AND PARTICIPANTS: This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. EXPOSURES: Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). MAIN OUTCOMES AND MEASURES: The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. RESULTS: The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). CONCLUSIONS AND RELEVANCE: This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04354701