The COVID-19 pandemic and its consequences for the diagnosis and therapy of head and neck malignancies.

OBJECTIVE: The COVID-19 pandemic and the measures accompanying it have been accused of having a negative influence on the frequency and methods of treatment of various diseases including head and neck cancer (HNSCC). To go further into this assumption, the diagnoses made, and treatments performed at one of Germany's largest head and neck cancer centres were evaluated. PATIENTS AND METHODS: This study consisted of one single centre and involved a retrospective review of all patients with newly diagnosed or recurrent HNSCC. The diagnosis and treatment methods used in the pre-COVID-19 time period between March 1st, 2019, and March 1st, 2020, were analysed and compared with the COVID-19 time period from April 1st, 2020, until April 1st, 2021. The primary objective was defined as the number of malignant diagnoses and the secondary objectives as the disease stage and the time to therapy. RESULTS: A total of 612 patients (160♀; mean 63 yrs.) were included. 319 patients (52%) were treated in the pre-COVID-19 time. The two groups did not differ in terms of age (p=0.304), gender (p=0.941), presence of recurrent disease (p=0.866), tumour subsite (p=0.194) or the duration from presentation to the multidisciplinary tumour board until start of therapy (p=0.202). There were no significant differences in the T stage (p=0.777), N stage (p=0.067) or UICC stage (p=0.922). During the pre-COVID-19 period more patients presented with distant metastases (n= 23 vs. n=8; p=0.011). CONCLUSIONS: This study shows that there was no significant change in either the number and severity of HNSCC diagnoses or the time until start of therapy at this large head and neck cancer centre as a result of the COVID-19 pandemic.

Impact of delayed adjuvant therapy after surgery in p16 positive oropharyngeal cancer: a retrospective analysis.

OBJECTIVE: This study aimed to clarify the impact of delayed adjuvant therapy on the outcome of HPV associated oropharyngeal squamous cell carcinoma (HPV-OPSCC). PATIENTS AND METHODS: A total of 157 patients with HPV-OPSCC treated by surgery and adjuvant radiotherapy or chemoradiation therapy were analyzed retrospectively. We divided participants into two groups implementing adjuvant therapy within or after 50 days. Primary endpoints were the rates of locoregional recurrence and distant metastases, overall survival, and disease-specific survival. RESULTS: Adjuvant treatment began within 50 days (average: 38.8 days) in 79 cases compared to 78 cases after 50 days (average: 71.5 days). Five-year overall survival was 85.7% and 87.4% (p=0.588), the rates of local and regional recurrence were 3.8% and 6.4% (p=0.455) and of distant metastases 5.1% and 9% (p=0.369) implementing adjuvant treatment within or later than 50 days, respectively. CONCLUSIONS: These results suggest that adjuvant therapy initiated later than seven weeks after primary ablative surgery may still be effective HPV-OPSCC.

Viral determinants predicting hepatitis B surface antigen (HBsAg) seroclearance in HIV-/HBV-coinfected patients.

The aim of this retrospective study was the identification of clinically useful viral determinants for the prediction of hepatitis B surface antigen (HBsAg) seroclearance and sustained virological response in hepatitis B virus/human immunodeficiency virus (HBV-/HIV)-coinfected patients receiving HBV-active combined antiretroviral therapy (cART). Quantification of HBsAg, HBeAg and HBV DNA before and after initiation of HBV-active cART in a cohort of 59 HIV-/HBV-coinfected patients was performed. Calculations of receiver operating characteristics (ROC) and Kaplan-Meier analysis were used for the identification of predictors of HBsAg seroclearance for HBeAg-positive [HBeAg(+); n = 36] and HBeAg-negative [HBeAg(-);n = 23] patients. HBeAg(+) patients with an HBsAg on-treatment decline ≥ 1 log IU/mL per year achieved higher HBsAg loss rates (P = 0.0294), whereas the quantification of HBeAg had no predictive value for HBsAg seroclearance. Among HBeAg(-) patients, a pretreatment baseline cut-off level of HBsAg ≤ 100 IU/mL was highly predictive for HBsAg seroclearance. No significant influence of the HBV genotype on HBsAg seroclearance was observed among the entire cohort. Quantitative determination of HBsAg provides a clinically useful viral parameter for the prediction of HBsAg seroclearance both in HBeAg(+) and HBeAg(-) HIV-/HBV-coinfected patients receiving HBV-active cART.

IL10R1 loss-of-function alleles in rheumatoid arthritis and systemic lupus erythematosus.

OBJECTIVE: IL-10 is a pleiotropic cytokine involved in the regulation of innate and cell-mediated immunity and a key mediator within the disturbed SLE immune system. IL-10 binds to IL10R1, which is expressed on a variety of immune cells and activates the JAK-STAT pathway. Two (out of several known) genetic IL10R1 variants may alter IL-10 binding or signal transduction. Here we investigate the differential activity of these IL10R1 variants and their possible association with RA or SLE susceptibility. METHODS: IL10R1-wt, IL10R1-S138G, IL10R1-G330R, or IL10R1- S138G +G330R were cloned into pIRESpuro3 and transfected into HeLa cells. Single cell clones were tested for IL-10-induced SOCS3- and SLAM gene expression by real-time PCR. DNA from 182 RA patients, 222 SLE patients, and 250 healthy controls was genotyped by allele-specific PCR. RESULTS: A biphasic increase of SOCS3 mRNA was observed that peaked at 15 minutes and 4 hours after IL-10 stimulation. The presence of IL10R1 S138G and G330R showed a weaker induction of both SOCS3 and SLAM upon stimulation with IL-10. In RA a homozygous G330R genotype was more commonly present than in controls (15.4% vs. 7.6%; p<0.05). In SLE the G330R allele frequency was also increased (36.3% vs. 30.0%; p<0.05) without showing a gene-dose relationship at the genotype level. CONCLUSIONS: Based on these results, both variants of the IL10R1 gene are loss-of-function alleles. IL10R1 G330R may possibly contribute to RA or SLE disease susceptibility in Caucasian populations.

The IL-10R1 S138G loss-of-function allele and ulcerative colitis.

Genetic predisposition is a risk factor for the development of inflammatory bowel diseases (IBDs). Disruption of the interleukin (IL)-10 pathway in mice causes intestinal inflammation similar to human IBD. Two common non-synonymous IL-10R1 variants, S138G and G330R, were cloned and expressed in HeLa and Ba/F3. A reduction in IL-10-induced STAT1 and STAT3 activation was seen for IL-10R1-S138G (but not IL-10R1-G330R) by phosphospecific western blotting in both cell types. When analyzing 52 world populations for the presence of IL-10R1 variants, a strong dissimilarity was found between major geographical regions. In addition, when 182 IBD-parent trios were genotyped for both variants, a reduced transmission of haplotype -7 (carrying the S138G variant allele) to offspring with ulcerative colitis (UC) was observed. This UC-protective effect of S138G was confirmed in a Hungarian cohort (n=185, allele frequency 11.6 versus 17.5%; P=0.017) but not in an independent Belgian cohort (n=666, allele frequency 15.9 versus 15.5%; P=0.8). In conclusion, the IL-10R1 S138G variant is a loss-of-function allele for IL-10-induced STAT1 and STAT3 activation but does not protect from UC susceptibility.

Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection.

Immune response to viral infection is an important determinant of liver injury in chronic hepatitis C (CHC). Experimental and clinical data suggest a protective role of interleukin-10 (IL-10) in hepatic fibrogenesis. The significance of two SNPs of the interleukin-10 receptor 1 (IL-10R1), S138G (SNP3) and G330R (SNP4) was investigated on (i) susceptibility to CHC, (ii) progression of hepatic fibrosis and (iii) response to interferon/ribavirin therapy. DNA and liver biopsies were obtained from 212 patients with HCV (hepatitis C virus)-genotype-1 infection. The allele frequencies were 0.17 for SNP3 and 0.33 for SNP4, both of which were indifferent from healthy controls (0.17 and 0.32, respectively). Stage 1 liver fibrosis was found in 22 cases (10.4%), stage 2 in 108 (50.9%), stage 3 in 27 (12.8%), and stage 4 (cirrhosis) in 55 (25.9%). An association was found between the SNP4 allele and the presence of cirrhosis (P=0.01). Homozygous SNP4 individual variants segregated within the cirrhosis group (P=0.03). We found neither an association with SNP3 nor with the necroinflammatory disease activity (as measured by ALT levels) nor with the response to antiviral therapy. Our work implies that IL-10R1 SNP4 is a recessively inherited risk factor for hepatic cirrhosis in HCV genotype-1 infection.