Aims
Expression profiles and clinical impact of programmed cell death ligand 1 (PD‐L1) and programmed cell death 1 (PD‐1) expressing tumour infiltrating lymphocytes (TILs) in head and neck squamous ...cell carcinoma (HNSCC) are not elucidated fully. This study evaluates expression patterns in primary HNSCC and related lymph node metastasis and the impact on patients’ clinical outcome.
Methods and results
Immunohistochemical staining patterns of PD‐L1 and PD‐1 were evaluated in 129 specimens of primary HNSCC and 77 lymph node metastases. Results were correlated with patients’ clinical data. PD‐L1 expression was observed in 36% of primary carcinoma and 33% of lymph node metastasis, and correlates significantly with decreased overall survival (OS) (P = 0.01) and disease‐free survival (DFS) (P = 0.001) in oral cavity squamous cell carcinoma patients. PD‐L1 expression was associated with presence of lymph node metastasis (P = 0.0223). Infiltration of PD‐1‐expressing lymphocytes correlates significantly with favourable OS (P = 0.001) and DFS (P = 0.001) in oropharyngeal cancer and hypopharyngeal cancer patients OS (P = 0.007) and DFS (P = 0.001). Presence of PD‐1 TILs also correlates significantly with better OS (P = 0.005) and DFS (P = 0) in the human papilloma virus (HPV)‐negative cohort. Cox regression multivariate analysis revealed PD‐1 TIL expression as an independent prognostic marker for OS (P = 0.004) and DFS (P = 0.001) and T stage was validated as negative prognostic marker for OS (P = 0.011). PD‐1‐expressing lymphocytes (P = 0.0412) and PD‐L1 expression (P = 0.0022) patterns correlate significantly in primary cancers and matched lymph node metastases.
Conclusions
Our results characterise the expression profiles of PD‐1 axis proteins in HNSCC which might serve as possible clinical prognostic markers.
Prostate cancer is one of the most prevalent forms of cancer in men worldwide. It remains a clinical challenge to identify lethal metastatic prostate cancers, which escape standard therapeutic ...intervention. Aberrant interleukin-6 (IL-6) / signal transducer and activator of transcription-3 (STAT3) signalling and loss of p53 occur during prostate cancer progression to metastatic disease. The abnormality of the IL-6/STAT3/p53 axis is frequently accompanied by other genetic alterations; however, its potential role as an important mediator of oncogenic reprogramming, invasion and metastatic transformation remains unknown. The failure of anti-IL-6 treatments is still unexplained and may be due to an incomplete understanding of the mechanism of the in vivo role of IL-6/STAT3 in prostate cancer. The identification of the alternative reading frame protein (ARF) / murine double minute protein (MDM2) / p53 tumour suppressor pathway potentially involving the IL-6/STAT3 axis as a restricting factor in prostate cancer deficient in the tumour suppressor phosphatase and tensin homologue (PTEN) opened new avenues to currently available therapies. This review summarises the current knowledge on the role of crucial pathways driving prostate cancer progression as well as metastatic disease and discusses the potential use of novel specific target molecules and how it can be exploited to avoid overtreatment and increase quality of life.
Cancer stem cells (CSCs) are accountable for the progress of head and neck squamous cell carcinoma (HNSCC). This exploratory study evaluated the expression of molecular CSC markers in different ...tissues of HNSCC patients. Tissue specimens of primary tumor, lymph node metastases and macroscopically healthy mucosa of 12 consecutive HNSCC patients, that were treated with surgery and adjuvant radio(chemo)therapy upon indication, were collected. Samples were assessed for the expression of p16 as a surrogate for HPV-related disease and different molecular stem cell markers (ALDH1A1, BCL11B, BMI-1, and CD44). In the cohort, seven patients had HPV-related HNSCC; six thereof were oropharyngeal squamous cell carcinoma. While expression of BMI-1 and BCL11B was significantly lower in healthy mucosa than both tumor and lymph node metastasis, there were no differences between tumor and lymph node metastasis. In the HPV-positive sub-cohort, these differences remained significant for BMI-1. However, no significant differences in these three tissues were found for ALDH1A1 and CD44. In conclusion, this exploratory study shows that CSC markers BMI-1 and BCL11B discriminate between healthy and cancerous tissue, whereas ALDH1A1 and CD44 were expressed to a comparable extent in healthy mucosa and cancerous tissues.
We aimed to identify novel markers for aggressive prostate cancer in a STAT3-low proteomics-derived dataset of mitochondrial proteins by immunohistochemical analysis and correlation with ...transcriptomic data and biochemical recurrence in a STAT3 independent PCa cohort. Formalin-fixed paraffin-embedded tissue (FFPE) sample selection for proteomic analysis and tissue-microarray (TMA) generation was conducted from a cohort of PCa patients. Retrospective data analysis was performed with the same cohort. 153 proteins differentially expressed between STAT3-low and STAT3-high samples were identified. Out of these, 46 proteins were associated with mitochondrial processes including oxidative phosphorylation (OXPHOS), and 45 proteins were upregulated, including NDUFS1/ATP5O. In a STAT3 independent PCa cohort, high expression of NDUFS1/ATP5O was confirmed by immunocytochemistry (IHC) and was significantly associated with earlier biochemical recurrence (BCR). mRNA expression levels for these two genes were significantly higher in intra-epithelial neoplasia and in PCa compared to benign prostate glands. NDUFS1/ATP5O levels are increased both at the mRNA and protein level in aggressive PCa. Our results provide evidence that NDUFS1/ATP5O could be used to identify high-risk PCa patients.
Als Grundlage dient das aktuelle Positionspapier EPOS2020 (European Position Paper on Rhinosinusitis and Nasal Polyps 2020) 1. European Position Paper on Rhinosinusitis and Nasal Polyps 2020 1 ...Symptome und klinisches Bild Eine akute (virale) Rhinosinusitis ist definiert als plötzliches Auftreten von zwei oder mehr der folgenden Symptome, wobei eines der ersten beiden Symptome vorhanden sein muss: nasale Obstruktion/Verstopfung/Blockade oder nasale Sekretion (anterior und/oder posterior). Diagnostik und Warnsignale Die ARS wird anhand der klinischen Symptome (s. o.), deren Schwere und des zeitlichen Verlauf diagnostiziert.
Abstract Purpose Antibody therapy for chronic rhinosinusitis with nasal polyps (CRSwNP) has been established in Germany since 2019. With limited long-term data on biologic treatment for CRSwNP, we ...conducted a comprehensive evaluation of our 4-year data. This monocentric study aims to assess the real-world effects of this treatment on clinical course, quality of life, treatment adherence, biologic switching, dual therapy, and comorbidities. Methods We retrospectively analysed biologic therapy data in patients with severe chronic rhinosinusitis with nasal polyps. 191 patients with CRSwNP treated with Dupilumab, Mepolizumab, or Omalizumab were observed for up to 4 years in a real-life setting. Results We observed clear symptom improvements with few side effects. No loss of efficacy or tolerability was noted during the 4-year period. Patients reported high satisfaction compared to previous therapies, with overall improved quality of life. Revision surgery or oral steroid use during biologic therapy was rare. Some patients prolonged injection intervals or discontinued steroid nasal spray. Biologic switching occurred infrequently due to side effects or inadequate response and was generally well tolerated. Many patients reported additional positive effects such as asthma or allergy symptom improvement and reduced medication intake. Conclusion In summary, this study confirms the potency and tolerability of biologics for CRSwNP treatment, with sustained efficacy over 4 years. Biologic switching is a viable option for inadequate response or intolerable side effects. Therapy positively impacts Th2 comorbidities, corticosteroid requirements, surgery need, and overall compliance remains high. Clinical trial registration Project No.: 22–0802. Registry name: Biologika bei Patient*innen mit chronischer Sinusitis mit Nasenpolypen.
Prostate cancer (PCa) has a broad spectrum of clinical behavior; hence, biomarkers are urgently needed for risk stratification. Here, we aim to find potential biomarkers for risk stratification, by ...utilizing a gene co‐expression network of transcriptomics data in addition to laser‐microdissected proteomics from human and murine prostate FFPE samples. We show up‐regulation of oxidative phosphorylation (OXPHOS) in PCa on the transcriptomic level and up‐regulation of the TCA cycle/OXPHOS on the proteomic level, which is inversely correlated to STAT3 expression. We hereby identify gene expression of pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging, and PSA level. Therefore, low PDK4 is a promising marker for PCa with dismal prognosis.
Synopsis
Transcriptomic and proteomic analyses in prostate cancer (PCa) reveal high TCA/OXPHOS activity and low PDK4 expression in low STAT3 tumors. PDK4 is a promising independent predictor of biochemical recurrence in PCa.
Low STAT3 tumors show enhanced TCA/OXPHOS and ribosome activity in a gene co‐expression network and in transcriptomic and proteomic analyses.
Enhanced ribosome‐ and metabolic activity is found in mice with a deletion of Pten and Stat3 in the prostate epithelium.
Low STAT3 is associated with low PDK4 expression.
PDK4 is an important regulator of TCA/OXPHOS. Analysis of patient data indicates that low PDK4 correlates with earlier biochemical recurrence in PCa.
Transcriptomic and proteomic analyses in prostate cancer (PCa) reveal high TCA/OXPHOS activity and low PDK4 expression in low STAT3 tumors. PDK4 is a promising independent predictor of biochemical recurrence in PCa.
Lymph node metastases are frequently detected in head and neck squamous cell carcinoma (HNSCC) patients. Little is known about biomarkers expressed in lymph node metastases or their influence on ...clinical outcome. Doublecortin-like kinase 1 (DCLK1) is one marker that might be associated with outcome, owing to its correlation with stem cell-like characteristics.
We assessed the expression of DCLK1 in 74 postoperatively irradiated patients in histologically confirmed HNSCC lymph node metastases. Statistical analysis of the association with DCLK1 on clinical outcomes was performed.
DCLK1 was expressed in 63.5% of our patient cohort. DCLK1(+) HNSCC patients, compared with those without DCLK1 expression, showed a significantly poorer time to recurrence. Moreover, we observed a significantly poorer time to recurrence in HPV(-) HNSCC patients, and significantly shorter overall and disease-free survival rates in HPV(-) oropharyngeal cancer patients, compared with HPV(+) patients with these cancers. HPV(+) patients showed no significant differences in survival time according to DCLK1 expression. However, recurrent disease occurred in only DCLK1(+) patients. Mulitivariate analysis showed that DCLK1 expression in lymph node metastases is an independent marker for recurrence.
DCLK1 expression might be associated with poorer clinical outcomes in HNSCC patients, specifically in HPV(-) move patients. However, larger studies are required to verify our results.
Background
Cigarette smoking is a major risk factor for head and neck squamous cell carcinoma. Still, the effect of cigarette smoke on the molecular level is unclear. The aim of the present study was ...to investigate the early effects of cigarette smoke on carcinogenesis of head and neck squamous cell carcinoma.
Methods
Human oral keratinocytes were exposed for 1 week to standardized cigarette smoke extract, and subsequently RT‐quantitative PCR array was performed. Protein expression of dysregulated genes was determined by immunohistochemistry in tissue samples of oral squamous cell carcinoma, oral leukoplakia, and tonsil mucosa.
Results
RT‐PCR revealed upregulation of ITGA‐2 and MMP‐1, whereas TEK receptor tyrosine kinase was downregulated in human oral keratinocytes. ITGA‐2 and MMP‐1 were significantly overexpressed in tissue samples of oral squamous cell carcinoma in comparison to normal mucosa (P <.01 in all experiments).
Conclusion
Upregulation of ITGA‐2 and MMP‐1 induced by cigarette smoke contributes significantly to oral carcinogenesis.
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