33 research outputs found
Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity
Squamous cell carcinoma (SCC) is the most prevalent histological type of human cancer,
including head and neck squamous cell carcinoma (HNSCC). However, reliable prognostic gene
signatures for SCC and underlying genetic and/or epigenetic principles are still unclear. We identified
37 prognostic candidate genes by best cutoff computation based on survival in a pan-SCC cohort
(n = 1334) of The Cancer Genome Atlas (TCGA), whose expression stratified not only the pan-SCC
cohort but also independent HNSCC validation cohorts into three distinct prognostic subgroups.
The most relevant prognostic genes were prioritized by a Least Absolute Shrinkage and Selection
Operator Cox regression model and were used to identify subgroups with high or low risks for
unfavorable survival. An integrative analysis of multi-omics data identified FN1, SEMA3A, CDH2,
FBN1, COL5A1, and ADAM12 as key nodes in a regulatory network related to the prognostic
phenotype. An in-silico drug screen predicted two MEK inhibitors (Trametinib and Selumetinib)
as effective compounds for high-risk SCC based on the Cancer Cell Line Encyclopedia, which is
supported by a higher p-MEK1/2 immunohistochemical staining of high-risk HNSCC. In conclusion,
our data identified a molecular classifier for high-risk HNSCC as well as other SCC patients, who
might benefit from treatment with MEK inhibitors
Free-Flap Reconstruction in Early-Stage Squamous Cell Carcinoma of the Oral Cavity : A Prospective Monocentric Trial to Evaluate Oncological Outcome and Quality of Life
Surgery is generally accepted as standard treatment in oral cancer, but the reconstructive
procedures remain a matter of debate. The aim of this study was to evaluate oncological outcome
and quality of life following surgical resection and free-flap reconstruction in patients with early oral
squamous cell carcinoma. The presented trial was performed as a prospective, single-center observation study. Inclusion criteria were primary surgery in early-stage oral squamous cell carcinoma
with free-flap reconstruction. Endpoints were overall and progression-free survival and quality of
life up to 24 months after surgery. Twenty-six patients were included. Overall survival was 100%
and progression-free survival was 92.3% in a maximum follow-up time of 21 months. Global quality
of life showed no significant alteration after surgery. Patients reported a significant reduction in
pain (p = 0.048) and a decreasing impairment of speech one year after surgery (p = 0.021). Free-flap
reconstruction is a safe procedure that results in excellent oncological outcome and quality of life.
Functional outcome is of high relevance in early-stage tumors of the head and neck and may mostly
be affected by reconstructive procedures. Therefore, a prospective evaluation to explore success and
the effects of surgical therapy is highly warranted
Dynamic Up-Regulation of PD-L1 in the Progression of Oral Squamous Cell Carcinoma
The introduction of immune checkpoint inhibition for recurrent and metastatic head and
neck cancer has brought a new treatment option for patients suffering from advanced oral cancers
without a chance for curation using surgery or radiotherapy. The application of immune checkpoint
inhibitors in most cases is based on the expression levels of PD-L1 in the tumor tissue. To date, there
is a lack of data on the dynamic regulation of PD-L1 during disease progression. Therefore, this study
aimed to evaluate the expression levels of PD-L1 in a large cohort of patients (n = 222) with oral
squamous cell carcinoma including primary and recurrent tumors. Semiautomatic digital pathology
scoring was used for the assessment of PD-L1 expression levels in primary and recurrent oral
squamous cell carcinoma. Survival analysis was performed to evaluate the prognostic significance
of the protein expression at different stages of the disease. We found a significant up-regulation
of PD-L1 expression from primary disease to recurrent tumors (mean PD-L1 H-scores: primary
tumors: 47.1 ± 31.4; recurrent tumors: 103.5 ± 62.8, p < 0.001). In several cases, a shift from low
PD-L1 expression in primary tumors to high PD-L1 expression in recurrent tumors was identified.
Multivariate Cox regression analysis did not reveal a significantly higher risk of death (p = 0.078)
or recurrence (p = 0.926) in patients with higher PD-L1 expression. Our findings indicate that the
exclusive analysis of primary tumor tissue prior to the application of checkpoint blockade may lead
to the misjudgment of PD-L1 expression in recurrent tumors
Impact of Salvage Surgery on Health-Related Quality of Life in Oral Squamous Cell Carcinoma: A Prospective Multi-Center Study
Background: Patients with recurrent oral squamous cell carcinoma (OSCC) have limited
treatment options. Salvage surgery offers potential curative therapy. The need for extensive ablative
surgery together with microvascular reconstruction implies invasive and painful treatment with
questionable functional outcome. To address the impact of salvage surgery on the health-related
quality of life (HRQoL) of patients suffering from recurrent OSCC, a multi-center prospective analysis
was initiated. Material and Methods: Patients with recurrent OSCC from 2015 to 2022 at two German
cancer centers were included. Interdisciplinary tumor board decisions determined surgery as the only
curative treatment modality. HRQoL, was assessed via a EORTC questionnaire (European Organization for Research and Treatment of CancerâEORTC: QLQ-C30 and QLQ-H&N35) in dependence of
the recurrent tumor stage. Patients completed the questionnaires once before surgery (baseline) and
then every 3 months during follow-up or up to the end of treatment. Results: In total, 55 patients were
included. The mean follow-up period was 26.7 ± 19.3 months. Global health status showed superior
mean scores after 12 months (60.83 ± 22.58) compared to baseline (53.33 ± 26.41) in stage 1 and 2
recurrent tumors. In advanced recurrent tumorsâ mean scores for global health showed only minor
positive differences after 12 months (55.13 ± 22.7) compared to baseline (53.2 ± 25.58). In terms of the
mouth pain, mean scores were lower after salvage surgery in small recurrent tumors after 12 months
(20.37 ± 17.73) compared to baseline (41.67 ± 33.07; Wilcoxon two-sample signed-rank test p = 0.028).
In advanced recurrent tumors, a significant reduction in mean scores was detected 3 months after
salvage surgery (29.7 ± 22.94) compared to baseline (47.76 ± 25.77; Wilcoxon two-sample signedrank test p = 0.003). Up to 12 months, swallowing function was evaluated inferior compared to
baseline independent of tumor stage (Mean score recurrent stage I/II: 12-months 48.15 ± 27.57,
baseline 28.7 ± 22.87; stage III/IV: 12-months 49.36.42 ± 27.53; baseline 30.13 ± 26.25). Conclusion:
Improved HRQoL could be obtained in advanced recurrent OSCC after salvage surgery despite
reduced swallowing function. In small recurrent tumors, overall, HRQoL was superior to baseline.
Salvage surgery positively affected pain burden. For advanced recurrent tumors, important pain
relieve could be observed as soon as 3 months after surgery
Full-Thickness Tumor Resection of Oral Cancer Involving the Facial SkinâMicrosurgical Reconstruction of Extensive Defects after Radical Treatment of Advanced Squamous Cell Carcinoma
Advanced tumors of the head and neck are challenging for the treatment specialist due to
the need to synergize oncological and functional requirements. Free flap reconstruction has been
established as the standard of care for defects following tumor resection. However, depending on the
affected anatomic subsite, advanced tumors may impose specific difficulties regarding reconstruction,
especially when full-thickness resection is required. This study aimed to evaluate reconstructive
strategies and oncological outcomes in patients with full-thickness resection of the oral cavity. A
total of 33 patients with extensive defects due to squamous cell carcinoma of the oral cavity were
identified. Indications, reconstructive procedures, and clinical outcome were evaluated. Thirty-two
patients (97%) presented locally advanced tumors (T3/T4). Complete tumor resection was achieved
in 26 patients (78.8%). The anterolateral thigh flap was the most frequently used flap (47.1%), and the
primary flap success rate was 84.8%. The cohort demonstrated a good local control rate and moderate
overall and progression-free survival rates. Most patients regained full competence regarding oral
alimentation and speech. Full-thickness tumor resections of the head and neck area may be necessary
due to advanced tumors in critical anatomic areas. In many cases, radical surgical treatment leads
to good oncological results. Free flap reconstruction has been shown to be a suitable option for
extensive defects in aesthetically challenging regions
HLA-E and Its Soluble Form as Indicators of a Sex-Specific Immune Response in Patients with Oral Squamous Cell Carcinoma
The human leukocyte antigene E (HLA-E) is associated with tumorigenesis in various
cancers. Immunoncology along with sex-specific aspects in cancer therapy are now in scientific
focus. Therefore, immunohistochemical HLA-E expression was retrospectively analysed in a cohort
of oral squamous cell carcinomas (OSCC) after surgical therapy. Then, serum concentration of HLA-E
(sHLA-E) was quantified in a prospective cohort by enzyme-linked immunosorbent assay. High
HLA-E expression was associated with advanced UICC stage (Spearmanâs correlation: p = 0.002)
and worse survival (Cox-regression: progression-free survival: hazard ratio (HR) 3.129, confidence
range (CI) 1.443â6.787, p = 0.004; overall survival: HR 2.328, CI 1.071â5.060, p = 0.033). The sHLA-E
concentration was significantly higher in the control group than in tumor group (MannâWhitney
U-test (MW-U): p = 0.021). Within the tumor group, women showed significantly higher sHLA-E
levels than men (MW-U: p = 0.049). A closer look at the tumor group and the control group showed
that gender-specific differences exist: while no differences in sHLA-E concentration were detectable
between female subjects of tumor group and control group (MW-U: p = 0.916), male subjects of tumor
group had a significantly lower sHLA-E concentration compared to those of control group (MW-U:
p = 0.001). In summary, our results provide evidence for sex-specific differences in immune responses
in OSCC. This fact should be considered regarding future immunotherapy regimens
TREM2 Is Associated with Advanced Stages and Inferior Prognosis in Oral Squamous Cell Carcinoma
Triggering receptor expressed on myeloid cells 2 (TREM2) is suggested to hamper antitumor immune response in multiple cancers. However, the role of TREM2 in oral squamous cell carcinoma (OSCC) and its expression in tumor-associated macrophages (TAMs) are unknown. In this study, TREM2 expression was analyzed in the primary tumors and corresponding lymph-node metastases of OSCC patients via immunohistochemistry on tissue microarrays. Human peripheral blood mononuclear cells (PBMCs) and single-cell suspensions of tumor and healthy adjacent tissues were analyzed for the presence of TREM2+ macrophages and TAMs using flow cytometry. The serum levels of soluble TREM2 (sTREM2) were quantified using an enzyme-linked immunosorbent assay. High TREM2 expression was associated with advanced UICC stages (Spearmanâs rank correlation (SRC), p = 0.04) and significantly reduced survival rates in primary tumors (multivariate Cox regression, progression-free survival: hazard ratio (HR) of 2.548, 95% confidence interval (CI) of 1.089â5.964, p = 0.028; overall survival: HR of 2.17, 95% CI of 1.021â4.613, p = 0.044). TREM2 expression was significantly increased in the PBMCs of OSCC patients in UICC stage IV compared with healthy controls (ANOVA, p < 0.05). The serum levels of sTREM2 were higher in advanced UICC stages, but they narrowly missed significance (SRC, p = 0.059). We demonstrated that TREM2 was multi-factorially associated with advanced stages and inferior prognosis in OSCC patients and that it could serve as a prognostic biomarker in OSCC patients. Targeting TREM2 has the potential to reshape the local and systemic immune landscape for the potential enhancement of patientsâ prognosis
IDO1 is highly expressed in macrophages of patients in advanced tumour stages of oral squamous cell carcinoma
Purpose Strategies for Indolamine-2,3-dioxygenase 1 (IDO1) inhibition in cancer immunotherapy once produced encouraging results, but failed in clinical trials. Recent evidence indicates that immune cells in the tumour microenvironment,
especially macrophages, contribute to immune dysregulation and therefore might play a critical role in drug resistance.
Methods In this study, we investigated the signifcance of IDO1 expressing immune cells in primary tumours and corresponding lymph node metastases (LNMs) in oral squamous cell carcinoma (OSCC) by immunohistochemistry. The link
between IDO1 and macrophages was investigated by fow cytometry in tumour tissue, healthy adjacent tissue and peripheral
blood mononuclear cells (PBMCs). IDO1 activity (measured as Kynurenine/Tryptophan ratio) was assessed by ELISAs.
Results High IDO1 expression in tumour-infltrating immune cells was signifcantly correlated with advanced stages [Spearmanâs rank correlation (SRC), p=0.027] and reduced progression-free survival (multivariate Cox regression, p=0.034).
IDO1 was signifcantly higher expressed in PBMCs of patients in advanced stages than in healthy controls (ANOVA, p<0.05)
and IDO1+ macrophages were more abundant in intratumoural areas than peritumoural (t test, p<0.001). IDO1 expression
in PBMCs was signifcantly correlated with IDO1 activity in serum (SRC, p<0.05). IDO1 activity was signifcantly higher
in patients with LNMs (t test, p<0.01).
Conclusion All in all, IDO1 expressing immune cells, especially macrophages, are more abundant in advanced stages of
OSCC and are associated with reduced progression-free survival. Further investigations are needed to explore their role
in local and systemic immune response. The IDO1 activity might be a suitable biomarker of metastasis in OSCC patients
Organotypic Co-Cultures as a Novel 3D Model for Head and Neck Squamous Cell Carcinoma
Background: Head and neck squamous cell carcinomas (HNSCC) are phenotypically and
molecularly heterogeneous and frequently develop therapy resistance. Reliable patient-derived 3D
tumor models are urgently needed to further study the complex pathogenesis of these tumors and
to overcome treatment failure. Methods: We developed a three-dimensional organotypic co-culture
(3D-OTC) model for HNSCC that maintains the architecture and cell composition of the individual
tumor. A dermal equivalent (DE), composed of healthy human-derived fibroblasts and viscose fibers,
served as a scaffold for the patient sample. DEs were co-cultivated with 13 vital HNSCC explants
(non-human papillomavirus (HPV) driven, n = 7; HPV-driven, n = 6). Fractionated irradiation was
applied to 5 samples (non-HPV-driven, n = 2; HPV-driven n = 3). To evaluate expression of ki-67,
cleaved caspase-3, pan-cytokeratin, p16INK4a, CD45, âsmooth muscle actin and vimentin over time,
immunohistochemistry and immunofluorescence staining were performed Patient checkup data
were collected for up to 32 months after first diagnosis. Results: All non-HPV-driven 3D-OTCs
encompassed proliferative cancer cells during cultivation for up to 21 days. Proliferation indices of
primaries and 3D-OTCs were comparable and consistent over time. Overall, tumor explants displayed heterogeneous growth patterns (i.e., invasive, expansive, silent). Cancer-associated fibroblasts and
leukocytes could be detected for up to 21 days. HPV DNA was detectable in both primary and
3D-OTCs (day 14) of HPV-driven tumors. However, p16INK4a expression levels were varying.
Morphological alterations and radioresistant tumor cells were detected in 3D-OTC after fractionated
irradiation in HPV-driven and non-driven samples. Conclusions: Our 3D-OTC model for HNSCC
supports cancer cell survival and proliferation in their original microenvironment. The model enables
investigation of invasive cancer growth and might, in the future, serve as a platform to perform
sensitivity testing upon treatment to predict therapy response