‘Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome’

alexandrossfakianakis shared this article with you from Inoreader Response to 'Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome' via Clinical Infectious Diseases Advance Access to the editor—Gaylis et al offer "an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab" [1]. The disclosure of a public statement [2] and a Warning Letter [3] on leronlimab (PubChem SID 384585377) by the Food and Drug Administration (FDA) is appropriate. Gaylis et al offer no biostatistical methods but cite the clinical trial record. Using the Supplementary Data provided by Gaylis et al [1] with nonparametric Wilcoxon signed ranked test for change (Weeks 8–0), the 2-sided P-values for Figure 1A are .003 (leronlimab) and .0139 (placebo) and for Figure 1B are .0002 (leronlimab, Improving), .7344 (leronlimab, not improving), .0640 (placebo, not improving), and .1272 (placebo, not improving). Paired t-test results were not meaningfully different. Reporting nonsignificance (NS) for the latter 2 P-values with the given sample sizes is not advised, but the NS for placebo (Figure 1A) is significant and affects the conclusion. They do not define "responder" or state if the definition was made a priori. Some of the symptoms may not be independent (eg, cough/sore throat, headache/sleep disturbance) so using them all to generate a "responder" score should be explained. They fail to provide a mechanism of action or gene expression results to explain how a monoclonal antibody to CCR5, a G-protein-coupled receptor (GPCR), might increase the proportion of CD45+/CCR5+ T cells relative to total cell counts or increase expression of CCR5 in T cells. The authors should report the time between positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) test and enrollment, duration of COVID-19 infection, re-exposure to SARS-CoV-2, especially to variants different from the original infecting viruses, other factors that affect immune responses, distribution of severity of COVID-19 among the treatment groups, the results by age and sex, the receptor occupancy, and the potential effects of the half-life of leronlimab. Galanti and Shaman [4] report multiple (re-)infections per year in the same subjects with other coronaviruses. Lee et al [5] reported that "granulocyte macrophage colony-stimulating factor caused a marked decrease of CXCR4 (from ∼5000 ABS to <500) while up-regulating CCR5 expression (from ∼5000 to ∼20 000 ABS)." Jacobson et al [6] reported 'mean terminal half-lives (PRO 140 Serum Concentration) were 3.4 and 3.7 days, but Yang et al [7] suggested an "estimated half-life of about 10 days." With T-cell proliferation and the potential increase in CCR5 expression, the half-life and receptor occupancy need to be appropri ately addressed in different patient populations. Roche and Futura state that "plasma membrane of eukaryotic cells is constantly being internalized" [8]; how long a 146.7 kDa [9] antibody bound to the 62 kDa [10] transmembrane CCR5 (NP_001381712.1) remains at the surface or, when it is internalized, whether it is trafficked back to surface or to the lysosomes is of interest. T-cell exhaustion [11] could help explain the results; with small sample sizes, imbalances can occur so duration, sev erity, and time from PCR test for each patient is important. Finally, genotypes of CCR5, which may affect binding of leronlimab, and of the ligands of CCR5, such as CCL3L1 with copy number variants [12], and any antidrug antibodies (ADA) against leronlimab would help elucidate this finding. View on Web

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Thyroid Surgeries in Asymptomatic Patients

alexandrossfakianakis shared this article with you from Inoreader Thyroid Surgeries in Asymptomatic Patients via JAMA Otolaryngology–Head & Neck Surgery Online First In this issue of JAMA Otolaryngology−Head & Neck Surgery, Dr Sajisevi and colleagues report the findings of a retrospective analysis of 1328 patients in 16 centers in 4 countries who underwent thyroid surgery for thyroid pathology in 2019. Patients were classified by the mode of detection of the thyroid findings that led to surgery: endocrinopathic condition, patient-requested screening, clinician-screening physical examination, radiologic serendipity, diagnostic cascade, symptomatic thyroid disease, and under surveillance. The primary outcomes were the mode of detection and the proportion and size of thyroid cancers discovered in patients who were asymptomatic. The authors found that 41% of patients were asymptomatic at the time of the detection of the thyroid condition, while 34% of patients had structural thyroid symptoms at the time of detection. The remaining 25% of patients were either under surveillance for known thyroid pathology, such as thyroid nodules, or had an endocrinopathic condition, such as hyperthyroidism, hyperparathyroidism, or multiple endocrine neoplasia syndrome. Of the 1328 cases, 613 (46%) revealed thyroid cancer. The authors also found that 51% of these cancers were in asymptomatic patients, while only 30% were in symptomatic patients. Finally, the mean tumor size was significantly larger in symptomatic compared with asymptomatic patients (3.2 cm vs 2.1 cm). View on Web

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Postoperative Gabapentin's Effect on Opioid Consumption and Pain Control Following Sinonasal Surgery

alexandrossfakianakis shared this article with you from Inoreader Postoperative Gabapentin's Effect on Opioid Consumption and Pain Control Following Sinonasal Surgery via The Laryngoscope Objective This study investigates the impact of postoperative gabapentin on opioid consumption and pain control following endoscopic sinus surgery (ESS) and/or septoplasty. Methods Patients who underwent ESS and/or septoplasty at a single institution from 2021 to 2022 were enrolled. All patients received postoperative hydrocodone-acetaminophen for pain control. Half of the patients were also prescribed gabapentin for the first postoperative day in addition to hydrocodone-acetaminophen. Subjects completed the Revised American Pain Society Patient Outcome Questionnaire 24 h and 7 days after surgery. We conducted a multivariable regression analysis to assess opioid consumption and improvement in pain scores in the first week between gabapentin and non-gabapentin groups. Results A total of 102 subjects, 51 in each arm, were enrolled. The mean age was 52 years and 53% of participants were female. Controlling for important baseline demographic, clinical, and surgically related variables, the addition of postoperative gabapentin was associated with a 44% (9.5 mg from 21.6 mg) reduction in opioids consumed in the first postoperative week (B = −9.54, 95% C.I. = [−17.84, −1.24], p = 0.025). In addition, patients in both arms exhibited similar improvement in pain severity and sleep interference in the first 7 days (B = −1.59, 95% C.I. = [−5.03, 1.84], p = 0.36). Conclusion To the best of our knowledge, this is the first study to investigate the impact of postoperative gabapentin on opioid consumption and pain control following ESS and/or septoplasty. Our analysis demonstrated that postoperative gabapentin effectively reduced opioid use during the first postoperative week without compromising pain control. Level of Evidence 3 Laryngoscope, 2022 View on Web

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Acute toxicity in patients treated with concurrent chemoradiotherapy with proton versus intensity‐modulated radiation therapy for nonmetastatic head and neck cancers

alexandrossfakianakis shared this article with you from Inoreader Acute toxicity in patients treated with concurrent chemoradiotherapy with proton versus intensity‐modulated radiation therapy for nonmetastatic head and neck cancers via Head & Neck Abstract Background We evaluated if proton therapy is associated with decreased acute toxicities compared to intensity-modulated radiation therapy (IMRT) in patients receiving concurrent chemoradiotherapy for head and neck cancers. Methods We analyzed 580 patients with nonmetastatic head and neck cancers. Primary endpoint was any 90-day grade ≥3 toxicity, prospectively collected and graded per CTCAEv4. Modified Poisson regression models were used. Results Ninety-five patients received proton and 485 IMRT. The proton group had more HPV-positive tumors (65.6 vs. 58.0%, p = 0.049), postoperative treatment (76.8 vs. 62.1%, p = 0.008), unilateral neck treatment (18.9 vs. 6.6%, p < 0.001) and significantly lower doses to organs-at-risk compared to IMRT group. Adjusted for patient and treatment characteristics, the proton group had decreased grade 2 dysgeusia (RR0.67, 95%CI 0.53–0.84, p = 0.004) and a trend toward lower grade ≥3 toxicities (RR0.60, 95%CI 0.41–0.88, p = 0.06). Conclusions Proton therapy was associated with significantly reduced grade 2 dysgeusia and nonstatistically significant decrease in acute grade ≥3 toxicities compared to IMRT. View on Web

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