Impact of CD151 overexpression on prognosis and therapy in non-small cell lung cancer patients lacking EGFR mutations.

This study investigates CD151, a protein linked to cancer progression, in non-small cell lung cancer (NSCLC) patients without epidermal growth factor receptor (EGFR) mutations. These patients often have limited treatment options. The study used retrospective analysis to examine 157 adenocarcinoma biopsy specimens and 199 patient cases from The Cancer Genome Atlas, correlating CD151 expression with patient survival. Cellular studies revealed that CD151 interacts with EGFR, influencing epidermal growth factor (EGF)-induced cell proliferation and the effectiveness of the EGFR inhibitor, erlotinib. A strong association was found between CD151 expression and EGFR mutation status. High CD151 expression in the absence of EGFR mutations is correlated with poorer survival outcomes. Biological assays showed that CD151 colocalizes and associates with EGFR, playing a crucial role in regulating EGF-induced cell proliferation via the AKT and ERK1/2 pathways. Importantly, CD151 expression was found to influence the anti-proliferative effects of the EGFR tyrosine kinase inhibitor, erlotinib. High CD151 expression, in the absence of EGFR mutations, was associated with poorer survival outcomes. It could serve as a potential prognostic marker and influence cellular responses to EGFR-targeted treatments. This study highlights CD151 as a potential novel target for therapeutic intervention in NSCLC, especially in populations lacking EGFR mutations.

180- Versus 360-Degree Selective Laser Trabeculoplasty in Open Angle Glaucoma and Ocular Hypertension: A Systematic Review and Meta-Analysis.

PRCIS: This systematic review and meta-analysis found that 360-degree selective laser trabeculoplasty (SLT) is significantly more effective than 180-degree SLT at reducing intraocular pressure at 1-month and 1-year follow-ups without increased serious adverse event risk. PURPOSE: To determine the efficacy of 180- versus 360-degree selective laser trabeculoplasty (SLT) in adults with open angle glaucoma (OAG) and ocular hypertension (OHT). METHODS: A systematic review was performed using PubMed, Embase, and Scopus databases, from 1995 to December 30, 2023, for studies comparing 180 and 360-degree SLT in adults with OAG and OHT (PROSPERO ID: CRD42024497832). Meta-analyses were performed to calculate nominal percent and raw reductions in intraocular pressure (IOP) between treatment groups at 1-month, 1-year, and 2-year follow-ups, as well as success rates, defined as a 20% or greater IOP reduction. RESULTS: Nine studies with 1044 eyes were included; 491 received 180-degree SLT, and 553 received 360-degree SLT. At the 1-month follow-up, 360-degree SLT reduced IOP by 3.45% more (WMD=3.45; 95% CI: 2.02-4.88; P <0.00001) and 0.87 mm Hg more (WMD=0.87; 95% CI: 0.35-1.38; P =0.0010). At the 1-year follow-up, 360-degree SLT reduced IOP by 4.33% more (WMD=4.33; 95% CI: 2.35-6.32; P <0.0001) and 1.15 mm Hg more (WMD=1.15; 95% CI: 0.25-2.04; P =0.01). At 2 years of follow-up, 360-degree SLT reduced IOP by 4.86% more (WMD=4.86; 95% CI: -0.32, 10.0; P =0.07) and 1.25 mm Hg more (WMD=1.25; 95% CI: -0.29, 2.79; P =0.11); however, the difference was not statistically significant. Compared with 360-degree SLT, 180-degree SLT had a significantly lower success rate (OR=0.50; 95% CI: 0.35-0.72; P =0.0002). There was no difference in serious complications between interventions. CONCLUSIONS: 360-degree SLT is more effective than 180-degree SLT at lowering IOP at 1-month and 1-year follow-ups as well as achieving successful IOP control without increased risk of serious complications.

Multiregion sampling of de novo metastatic prostate cancer reveals complex polyclonality and augments clinical genotyping.

De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely collected tissue has hindered genomic stratification and precision oncology. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotypes across 607 synchronous primary and metastatic tissue regions plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically relevant genes, resulting in discordant genotypes between select primary restricted regions and synchronous metastases. Additional complexity was driven by polyclonal metastatic seeding from phylogenetically related primary populations. When simulating clinical practice relying on a single tissue region, genomic heterogeneity plus variable tumor fraction across samples caused inaccurate genotyping of dominant disease; however, pooling extracted DNA from multiple biopsy cores before sequencing can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-sensitive primary and metastatic lesions in men with de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.

Growth hormone-releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice.

COVID-19 pneumonia causes acute lung injury and acute respiratory distress syndrome (ALI/ARDS) characterized by early pulmonary endothelial and epithelial injuries with altered pulmonary diffusing capacity and obstructive or restrictive physiology. Growth hormone-releasing hormone receptor (GHRH-R) is expressed in the lung and heart. GHRH-R antagonist, MIA-602, has been reported to modulate immune responses to bleomycin lung injury and inflammation in granulomatous sarcoidosis. We hypothesized that MIA-602 would attenuate rVSV-SARS-CoV-2-induced pulmonary dysfunction and heart injury in a BSL-2 mouse model. Male and female K18-hACE2tg mice were inoculated with SARS-CoV-2/USA-WA1/2020, BSL-2-compliant recombinant VSV-eGFP-SARS-CoV-2-Spike (rVSV-SARS-CoV-2), or PBS, and lung viral load, weight loss, histopathology, and gene expression were compared. K18-hACE2tg mice infected with rVSV-SARS-CoV-2 were treated daily with subcutaneous MIA-602 or vehicle and conscious, unrestrained plethysmography performed on days 0, 3, and 5 (n = 7 to 8). Five days after infection mice were killed, and blood and tissues collected for histopathology and protein/gene expression. Both native SARS-CoV-2 and rVSV-SARS-CoV-2 presented similar patterns of weight loss, infectivity (~60%), and histopathologic changes. Daily treatment with MIA-602 conferred weight recovery, reduced lung perivascular inflammation/pneumonia, and decreased lung/heart ICAM-1 expression compared to vehicle. MIA-602 rescued altered respiratory rate, increased expiratory parameters (Te, PEF, EEP), and normalized airflow parameters (Penh and Rpef) compared to vehicle, consistent with decreased airway inflammation. RNASeq followed by protein analysis revealed heightened levels of inflammation and end-stage necroptosis markers, including ZBP1 and pMLKL induced by rVSV-SARS-CoV-2, that were normalized by MIA-602 treatment, consistent with an anti-inflammatory and pro-survival mechanism of action in this preclinical model of COVID-19 pneumonia.

Amniotic Membrane Patching to Assist Closure of Recalcitrant Macular Holes.

BACKGROUND AND OBJECTIVE: This study reports a case series of patients with persistent macular holes (MHs) who underwent human amniotic membrane subretinal placement to achieve successful anatomic MH closure. PATIENTS AND METHODS: This was a retrospective case series of patients with persistently open full-thickness MHs who underwent human amniotic membrane placement. Patients were observed up to 6 months postoperatively. RESULTS: Ten patients were included. The mean preoperative best-corrected visual acuity was 1.6 logMAR (20/800). Postoperatively, mean best-corrected visual acuity improved to 1.3 logMAR (20/400) at 1 month and 1.1 logMAR (20/250) by the 3- and 6-month visits. In all cases, the MH appeared closed at the 1-week visit and remained closed at their last follow-up. Optical coherence tomography showed closure in all cases. No adverse events were reported. CONCLUSIONS: Human amniotic membrane sub-retinal placement may serve as a useful surgical technique to assist in the closure of recalcitrant macular holes. [Ophthalmic Surg Lasers Imaging Retina 2023;54:218-222.].

Influence of glycan structure on the colonization of Streptococcus pneumoniae on human respiratory epithelial cells.

Virtually all living cells are encased in glycans. They perform key cellular functions such as immunomodulation and cell-cell recognition. Yet, how their composition and configuration affect their functions remains enigmatic. Here, we constructed isogenic capsule-switch mutants harboring 84 types of capsular polysaccharides (CPSs) in Streptococcus pneumoniae. This collection enables us to systematically measure the affinity of structurally related CPSs to primary human nasal and bronchial epithelial cells. Contrary to the paradigm, the surface charge does not appreciably affect epithelial cell binding. Factors that affect adhesion to respiratory cells include the number of rhamnose residues and the presence of human-like glycomotifs in CPS. Besides, pneumococcal colonization stimulated the production of interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractantprotein-1 (MCP-1) in nasal epithelial cells, which also appears to be dependent on the serotype. Together, our results reveal glycomotifs of surface polysaccharides that are likely to be important for colonization and survival in the human airway.

Detection and resection of carcinoma in situ of the bladder: Implications for clinical trial design.

INTRODUCTION: The path to approval of novel therapeutics for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) requires demonstration of efficacy in eradicating carcinoma in situ (CIS), as determined by cytology, white light cystoscopy and only sometimes mandatory re-biopsy. This paradigm is based on the premise that CIS, in contrast to papillary tumors, cannot be completely resected. We aimed to determine the accuracy of CIS by standard means and the rate at which CIS may be eradicated by transurethral bladder tumor resection (TURBT). METHODS: We performed a retrospective analysis of consecutive patients who underwent radical cystectomy (RC) for high risk NMIBC or muscle invasive bladder cancer (MIBC) between 2005 and 2019 in a tertiary academic center. The concordance in the presence of CIS in matched TURBT and RC samples was calculated. RESULTS: Complete pathologic information was available for 816 patients with urothelial carcinoma. CIS was detected at TURBT in 354 (43.4%) patients (64.0% NMIBC, 32.3% MIBC) and at RC in 436 (53.4%) patients (64.7% NMIBC, 47.4% MIBC). CIS was missed by TURBT in 199 (45.6%) of those cases (NMIBC 25.4%, MIBC 60.6%). CIS detected on TURBT was not found in the RC specimen in 33.1% (117/354) of cases. Lack of prospective bladder mapping and central pathology review are limitations. CONCLUSION: Our results suggest that TURBT is inaccurate in detecting CIS. The absence of CIS in the RC specimen after detection in the matched TURBT specimen suggests that CIS may be completely resected by TURBT in a proportion of patients. These factors need to be considered in the design of clinical trials in patients with NMIBC. The use of random biopsies or enhanced cystoscopy could improve the accuracy of CIS detection, but the former is associated with patient morbidity and randomization would alleviate concern about these variables impacting clinical trial outcomes.

Very-Early Onset Chronic Active Colitis with Heterozygous Variants in LRBA1 and CARD11, a Case of "Immune TOR-Opathies".

BACKGROUND: A small subset of cases of inflammatory bowel disease (IBD) occurs as a result of single gene defects, and typically occurs in young or very young pediatric patients, referred to as "monogenic very-early onset IBD (VEO-IBD)". The gene variants leading to monogenic VEO-IBD are often associated with primary immunodeficiency syndromes. CASE REPORT: A six year-old girl presented to our gastroenterology clinic with LRBA deficiency with a heterozygous mutation at c.1399 A > G, p Met467Val, histopathologic chronic active colitis without granulomas and clinical chronic colitis. Her gastrointestinal symptoms began at age 5 with bloody diarrhea, abdominal pain and weight loss. Whole exome sequencing revealed a CARD11 heterozygous de novo mutation (c.220 + 1G > A). She was in clinical remission on only abatacept. DISCUSSION: We present a case of monogenic VEO-IBD associated with two heterozygous variants in LRBA1 and CARD11, both considered as key players in the newly proposed "immune TOR-opathies".

Topical Dexamethasone as an Adjuvant to Mineralocorticoid Receptor Antagonists for the Treatment of Recalcitrant Central Serous Chorioretinopathy.

BACKGROUND AND OBJECTIVE: A previous report demonstrated efficacy of mineralocorticoid antagonist with adjuvant topical dexamethasone (MRA+DEX) in resolving subretinal fluid (SRF) in a chronic central serous chorioretinopathy (CSCR) patient. This pilot study investigates the use of MRA+DEX to treat recalcitrant, chronic CSCR patients. STUDY DESIGN: Retrospective review of chronic, recalcitrant CSCR patients unresponsive to MRA alone who were treated with MRA+DEX and followed for up to 3 months. Apical SRF thickness and visual acuity were measured. RESULTS: Ten eyes of eight chronic, recalcitrant patients were included with an average follow-up of 109 days. Mean percent reduction in apical fluid thickness at one month and at last follow-up after adding dexamethasone (DEX) was 33% and 52%, respectively. Five eyes (50%) achieved complete resolution of SRF. Three eyes (30%) showed partial response and two (20%) eyes had no response. There was no significant change in visual acuity. CONCLUSIONS: MRA+DEX decreased SRF in some recalcitrant, chronic CSCR patients. Large prospective studies are needed to evaluate the utility of MRA+DEX in these chronic CSCR patients. [Ophthalmic Surg Lasers Imaging Retina 2022;53:659-665.].

Clinical utility of thiopurine metabolite monitoring in inflammatory bowel disease and its impact on healthcare utilization in Singapore.

Background and Aim: Thiopurines are recommended for maintenance of steroid-free remission (SFR) in inflammatory bowel disease (IBD). Thiopurine metabolite monitoring (MM) is increasingly used in the West but remains novel in Singapore, with limited information on its therapeutic and economic benefits. Hence, this study aims to investigate MM's clinical utility and its impact on healthcare resource utilization in Singaporean IBD patients. Methods: A retrospective observational study was conducted at Singapore General Hospital outpatient IBD Centre. Patients with IBD, baseline MM during 2014-2017, and weight-based thiopurine doses for ≥4 weeks were followed up for 1 year. Actions were taken to optimize therapy, and metabolite levels before and after the first action were documented. Outcomes assessed included SFR, no therapy escalation or surgery, healthcare resource utilization, and direct healthcare costs. Results: Ninety IBD patients (50 Crohn's disease, 40 ulcerative colitis) were included. Among them, 40% had baseline metabolite levels within therapeutic range, 31.1% sub-therapeutic, 21.1% supra-therapeutic, and 7.8% shunters. Repeated MM with subsequent dose optimization helped 67.2% of patients achieve therapeutic levels after 1 year. Overall, 87.8% of patients achieved SFR and 90% had no therapy escalation or surgery. Despite greater outpatient visits and laboratory investigations with MM, the median total healthcare costs at 1 year only increased marginally (S$6407.66 [shunters] vs S$5215.20 [supra-therapeutic] vs S$4970.80 [sub-therapeutic] vs S$4370.48 [control (within therapeutic range)], P = 0.592). Conclusion: MM guided timely therapy escalation for non-responders, identification of non-adherence, and reversal of shunting. Therefore, it is a useful clinical tool to optimize thiopurines without significantly increasing healthcare costs.

Neuro-ophthalmology malpractice: A review of the Westlaw Database.

BACKGROUND: Neuro-ophthalmologic conditions are at a higher risk of misdiagnosis compared to other ophthalmic conditions. Increased awareness of the most common diagnostic errors in neuro-ophthalmology that lead to malpractice claims can allow ophthalmologists to further improve their diagnostic workup to reduce delays in diagnosis and management, while also mitigating the risk of litigation. METHODS: Malpractice trials in the Westlaw Legal Database that involved cases of neuro-ophthalmologic diagnostic errors or failures by ophthalmologists were included in this study. RESULTS: A total of 43 cases were included, all citing failure to diagnose as the main reason for litigation. The most common diagnoses missed were cerebrovascular pathologies (30.2%), intracranial tumours (27.9%) and giant cell arteritis (25.6%). The majority of verdicts were in favour of the defendants (48.8%). After adjusting for inflation, the average amount awarded was $1,952,154. CONCLUSION: Nearly half of the cases resulted in a defendant verdict. Settlement and plaintiff verdicts were costly, with average awards of approximately two million inflation-adjusted dollars. Failure to diagnose cerebrovascular pathologies was the most common diagnostic error followed by failure to diagnose intracranial tumours and giant cell arteritis. It is crucial for ophthalmologists to be aware of the most common pitfalls that lead to misdiagnosis or delays in diagnosis of neuro-ophthalmologic conditions.

Predictors of Small Bowel Obstruction Post-Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for peritoneal malignancies carries considerable morbidity; however, the significance of postoperative small bowel obstruction (SBO) is not well defined. We aim to identify predictors for post-CRS/HIPEC SBO and their oncologic associations. METHODS: A retrospective review was conducted of all CRS/HIPEC cases performed at a surgical oncology center (2013-2018). Patient demographics, tumor characteristics, perioperative factors, and province-wide hospital readmissions were analyzed. Descriptive statistics were used for baseline characteristics, multivariate logistic regression for predictors of SBO at 1 year, and Kaplan-Meier method with log-rank test for survival analysis. RESULTS: A total of n = 97 CRS/HIPEC procedures were performed for diagnoses of low-grade appendiceal mucinous neoplasm (44%), high-grade appendiceal adenocarcinoma (8%), colorectal adenocarcinoma (34%), and mesothelioma (9%). The median peritoneal carcinomatosis index (PCI) score was 16. Cumulative incidence of post-CRS/HIPEC SBO readmission was 24% at 1 year and 38% at 2 and 3 years. Of 29 patients readmitted with SBO, 14 (48%) had more than one readmission for SBO, and nine surgeries were performed for obstruction. Multivariate regression identified significant independent predictors of SBO within 1-year post-CRS/HIPEC as high-grade appendiceal or colorectal primaries (odds ratio [OR] 4.58, p = 0.02) and PCI ≥ 20 (OR 3.27, p = 0.05). Overall survival (OS) was worse in patients readmitted with SBO within 1 year compared to those without (3-year OS 58% vs. 75%, p = 0.017). CONCLUSION: SBO is the most common readmission diagnosis post-CRS/HIPEC and is associated with worse survival. High-grade appendiceal and colorectal primary tumors and PCI ≥ 20 are predictors for SBO.

Medullary thyroid carcinoma: a narrative historical review.

INTRODUCTION: Sporadic or hereditary medullary thyroid carcinoma (MTC) is an uncommon thyroid malignancy arising from calcitonin secreting parafollicular C cells. Interestingly, MTC and calcitonin were distinct entities that were discovered independently yet concurrently, and their association was unknown. AREAS COVERED: This review aims to present a historical review of the evolution of our understanding of MTC and its tumor marker calcitonin to highlight the prominent individuals that influenced and shaped our knowledge of this uncommon thyroid cancer type up to the dawn of the 21st century. An overview of all published reports of novel research and work summarizing important findings for MTC and calcitonin was carried out. EXPERT OPINION: Surgery remains the cornerstone of treatment for localized MTC. However, several new treatment options are either available or in development for advanced or metastatic MTC, including several novel small molecules targeting oncogenic RET and peptide receptor radionuclide therapy, immunotherapy, radioimmunotherapy, and radiofrequency ablation. In the near future, these novel treatments hold promise for therapy of this very distinct thyroid cancer type.

Clinical Outcomes in Dorsal Preservation Rhinoplasty: A Meta-Analysis.

Background: Dorsal preservation rhinoplasty (PR-D) attempts to preserve as much of the native nasal anatomy as possible when performing a hump reduction, but clinical outcomes are unclear. Objective: In patients undergoing PR-D rhinoplasty, this article investigates the rates of complications and revisions. Methods: This meta-analysis was prospectively registered on the PROSPERO database. The Pubmed, Embase, and Scopus databases were searched. Pooled incidence was calculated in a meta-analysis within a random-effects model. Results: Twenty-two studies representing a cohort of 5660 patients were included in this study. Postoperative hump recurrence rates (4.18%, 95% confidence interval [CI]: 2.41-6.40%), rates of revision rhinoplasty (3.48%, 95% CI: 1.77-5.74%), rates of postoperative nasal deviation (1.13%, 95% CI 0.37-2.28%), and rates of infection (1.89%, 95% CI: 0.35-4.62%) were all found to be low. Conclusion: PR-D has low rates of revision surgery, residual or recurrent hump, postoperative nasal deviation, and postoperative infection.

Second-opinion reads in prostate MRI: added value of subspecialty interpretation and review at multidisciplinary rounds.

PURPOSE: This study evaluates the impact of second-opinion review of multiparametric prostate MRI for cancer detection by a multidisciplinary review board at a tertiary care center when compared with the initial community radiologist interpretation. METHODS: Cases were collected retrospectively from multidisciplinary prostate MRI rounds from 2017 to 2020 at a single tertiary care center. Patients with suspected prostate cancer or on active surveillance were referred for consideration of TRUS/MRI-fusion biopsy based on community-read prostate MRIs. All MRIs were re-read by subspecialized abdominal radiologists and a PI-RADS score assigned. Targeted fusion and 8-12 core systematic biopsy was performed in patients with PIRADS ≥ 3 lesions. Cohen kappa values were used to quantify interobserver agreement. Positive predictive value (PPV) was used to determine accuracy of PI-RADS score for detection of clinically significant prostate cancer (csPCa) (ISUP Grade Group ≥ 2). RESULTS: Three hundred and thirty-two lesions in 303 patients were reviewed and 252 lesions in 198 patients biopsied. The PI-RADS score was concordant in 60.5% of lesions, downgraded in 17.8%, and upgraded in 7.8%. Agreement between community and tertiary center interpretation was fair (κ = 0.354), with greater agreement for PI-RADS ≥ 4 (κ = 0.523) than PI-RADS ≥ 3 (κ = 0.456), and peripheral zone (κ = 0.419) than transition zone lesions (κ = 0.251). Prevalence of csPCa in biopsied lesions was 40.9%. CONCLUSION: There is variability in community and tertiary care center interpretation of prostate MRI in cancer detection, with higher concordance rates for higher grade and peripheral zone lesions. These differences demonstrate the added value of multidisciplinary round review and highlight the need for ongoing education and feedback.

Incidence of Head and Neck Cancers before and after 9/11 in New York City and New York State.

INTRODUCTION: The incidence of cancers in New York State (NYS) before and after 9/11 including lung, colorectal, and renal cancers has been previously described. To date, the incidence of head and neck cancers (HNCs) before and after 9/11 has not been described. METHODS: Cancers involving the oral cavity and oropharynx; the nose, nasal cavity, nasopharynx, and middle ear; larynx; and thyroid were identified using the New York State Cancer Registry (NYSCR). Age-adjusted incidence and rates per 100,000 residents from 1987 to 2015 were analyzed using joinpoint regression. Trends in incidence using annual percent changes are presented. RESULTS: The overall rate of HNC increased slightly by 0.7% (p < 0.001) from 1987 to 2003 in NYS. From 2003 to 2008, the rate increased by 5.73% (p < 0.001), and from 2008 to 2015, the rate increased by 1.68% (p < 0.001). The rate of thyroid cancer increased by 6.79% (p < 0.001) from 1987 to 2003, by 9.99% (p < 0.001) from 2003 to 2009, and by 2.41% (p = 0.001) from 2009 to 2015. The rate of thyroid cancer was higher in women at all time points. In a subset analysis of HNCs excluding thyroid cancer, the rate decreased by 2.02% (p < 0.001) from 1991 to 2001, followed by a nonsignificant increase of 0.1% (p = 0.515) from 2001 to 2015. The rate of oropharyngeal (OP) cancer significantly increased from 1999 to 2015 (2.65%; p < 0.001). The rate of oral cavity cancer significantly decreased from 1987 to 2003 (1.97%; p < 0.001), with no significant change after 2003. The rate of laryngeal cancer decreased significantly by 2.43% (p < 0.001) from 1987 to 2015, as did the rate of nasal cavity/nasopharyngeal cancer (0.33%; p = 0.03). CONCLUSIONS: In NYS, OP cancer and thyroid cancer rates increased significantly during the study period. The rate of thyroid cancer was higher in women. The rate of combined HNC increased significantly after 9/11 compared to before 9/11; however, in a subset analysis of all HNC patients excluding thyroid cancer, the rate decreased significantly prior to 9/11 and then nonsignificantly increased afterward. This suggests that the increase in thyroid cancer accounts for the increase in combined HNC in NYS. The impact of 9/11 on rates of HNC requires further research.

Impact of Treatment Parameters on Racial Survival Differences in Oropharyngeal Cancer: National Cancer Database Study.

OBJECTIVE: To investigate how differences in treatment parameters account for survival differences between races of patients with oropharyngeal squamous cell carcinoma (OPSCC). STUDY DESIGN: Retrospective cohort study. SETTING: National Cancer Database. METHODS: Data of patients with OPSCC undergoing radiation therapy (RT) or concurrent chemoradiation therapy as primary treatment were obtained from the National Cancer Database from 2004 to 2016. We analyzed 4 treatment-related time intervals to determine their impact on survival between races when controlling for human papilloma virus (HPV) status. Cox proportional hazards models, stepwise logistic regressions, covariate adjustments, and propensity score matching were performed. RESULTS: A total of 3152 patients were identified (2877 White, 275 Black). In HPV- cases, Black patients with prolonged radiation duration had a significantly worse overall survival as compared with White patients (hazard ratio, 1.77; 95% CI, 1.03-3.05; P = .039). In a logistic regression model, the only covariate that was significantly associated with prolonged RT was facility type. When further adjusted for facility type, the survival difference between Black and White patients with HPV- status and prolonged RT times was no longer significant (hazard ratio, 1.55; 95% CI, 0.90-2.69; P = .116). CONCLUSIONS: There is a significant disparity in overall survival between Black and White patients with HPV- OPSCC when RT duration is prolonged. Clinicians should be aware of the negative impact of prolonged RT, especially in Black patients, so that they can attempt to decrease treatment-related time intervals. Facility type was also found to affect the outcomes of patients with OPSCC, and efforts should be made to improve patient access to well-equipped, high-volume facilities.

Sentinel Lymph Node Biopsy Versus Elective Node Dissection in Stage cT1-2N0 Oral Cavity Cancer.

OBJECTIVE: To compare overall survival (OS) and disease-free survival (DFS) between sentinel lymph node biopsy (SNB) and elective neck dissection (END) in the surgical management of cT1-2N0 oral cavity squamous cell carcinoma (OCSCC). METHODS: English full-text articles were searched in PubMed and Embase on May 9, 2021. Articles had to compare SNB with END in cT1-T2N0 OCSCC patients; report hazard ratios (HRs), Kaplan-Meier curves, or P-values with total number of events for survival outcomes; be from a clinical trial, cohort, or case-control study. Two reviewers reviewed articles and a third settled disagreements. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Risk of Bias in Non-randomized Studies of Interventions tool and revised Cochrane risk-of-bias tool for randomized trials were used. The generic inverse variance method with a random-effect model was used for meta-analysis. RESULTS: Ten studies, five retrospective, three prospective, and two randomized controlled trials, were included (total number of patients [n] = 10,498, END n = 9102, SNB n = 1396). No significant differences were found in OS (HR = 0.92; 95% confidence interval [CI]: 0.65-1.31) or DFS (HR = 0.70; 95% CI: 0.41-1.20). Heterogeneity was not detected in pooled OS analysis (P = .18; I2  = 30%), but was in pooled DFS analysis (P = .003; I2  = 66%). CONCLUSIONS: No statistically significant differences in OS or DFS were observed between SNB and END in cT1-2N0 OCSCC, suggesting that SNB might be an alternative to END in the management of early-stage, clinically node-negative OCSCC. Laryngoscope, 132:989-998, 2022.

Macrophage inflammatory state influences susceptibility to lysosomal damage.

Macrophages possess mechanisms for reinforcing the integrity of their endolysosomes against damage. This property, termed inducible renitence, was previously observed in murine macrophages stimulated with LPS, peptidoglycan, IFNγ, or TNFα, which suggested roles for renitence in macrophage resistance to infection by membrane-damaging pathogens. This study analyzed additional inducers of macrophage differentiation for their ability to increase resistance to lysosomal damage by membrane-damaging particles. Renitence was evident in macrophages activated with LPS plus IFNγ, PGE2 , or adenosine, and in macrophages stimulated with IFN-ß, but not in macrophages activated with IL-4 or IL-10. These responses indicated roles for macrophage subtypes specialized in host defense and suppression of immune responses, but not those involved in wound healing. Consistent with this pattern, renitence could be induced by stimulation with agonists for TLR, which required the signaling adaptors MyD88 and/or TRIF, and by infection with murine norovirus-1. Renitence induced by LPS was dependent on cytokine secretion by macrophages. However, no single secreted factor could explain all the induced responses. Renitence induced by the TLR3 agonist Poly(I:C) was mediated in part by the type I IFN response, but renitence induced by Pam3CSK4 (TLR2/1), LPS (TLR4), IFNγ, or TNFα was independent of type 1 IFN signaling. Thus, multiple pathways for inducing macrophage resistance to membrane damage exist and depend on the particular microbial stimulus sensed.

Tetraspanins: Host Factors in Viral Infections.

Tetraspanins are transmembrane glycoproteins that have been shown increasing interest as host factors in infectious diseases. In particular, they were implicated in the pathogenesis of both non-enveloped (human papillomavirus (HPV)) and enveloped (human immunodeficiency virus (HIV), Zika, influenza A virus, (IAV), and coronavirus) viruses through multiple stages of infection, from the initial cell membrane attachment to the syncytium formation and viral particle release. However, the mechanisms by which different tetraspanins mediate their effects vary. This review aimed to compare and contrast the role of tetraspanins in the life cycles of HPV, HIV, Zika, IAV, and coronavirus viruses, which cause the most significant health and economic burdens to society. In doing so, a better understanding of the relative contribution of tetraspanins in virus infection will allow for a more targeted approach in the treatment of these diseases.