[New S2k guideline "Surgical techniques for gender incongruence"]. / Neue S2k-Leitlinie "Chirurgische Maßnahmen bei Geschlechtsinkongruenz".

BACKGROUND: Various techniques for the surgical treatment of gender incongruence (GI) have been available for years. The spectrum is broad and covers various specialties. In recent years, there has been an increase in the number of clinics offering body-modifying procedures. This has led to a considerable variation in methods in some cases. Although the topic has recently found its way more and more into teaching and the relevant specialist literature, there are still no evidence-based recommendations on the various techniques. AIM: A compendium of established surgical techniques was to be compiled, containing recommendations on indication, performance and aftercare as well as complication management and subjecting them to a consensus-based evaluation. MATERIALS AND METHODS: In accordance with "Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften" (AWMF) regulations, the guideline was developed at level S2k, i.e., it is consensus based. The guideline group was founded in February 2019 in a formal constituent meeting. A total of 14 medical societies and 2 interest groups were recruited for the guideline work. In the end, two consensus meetings were held, which was due to the large number of recommendations and background texts to be adopted. RESULTS: The guideline focuses on the choice and applicability of surgical techniques as well as the wishes of those seeking treatment and protection of fertility. There is a wide variety of methods and treatment goals for each individual. Taking into account medical standards, recommendations, and contraindications, an optimal result that minimizes individual suffering can be achieved together with the person seeking treatment. CONCLUSION: The content of the guideline represents a unique compendium of surgical methods, recommendations for the selection of procedures, and common indications in the field of body-modifying surgery for gender incongruence.

Bricker versus Wallace ureteroileal anastomosis: A multi-institutional propensity score-matched analysis.

AIM OF THE STUDY: The aim of our study is to evaluate the difference in stricture rate between matched groups of Bricker and Wallace techniques for ureteroileal anastomosis. PATIENTS AND METHODS: A retrospective analysis of patients undergoing urinary diversion (UD) with Bricker and Wallace ureteroileal anastomosis at two university hospitals. Two groups of Bricker and Wallace patients were matched in a 1:1 ratio based on the age, sex, body mass index (BMI), Charlson comorbidity index (CCI), preoperative hydronephrosis, prior radiation therapy or abdominal surgery, pathologic T and N stages and 30-days-Clavien grade complications≥III. A multivariable Cox regression analysis was conducted to identify predictors of ureteroenteric stricture (UES) in all patients. RESULTS: Overall, 740 patients met the inclusion criteria and 209 patients in each group were propensity matched. At a similar median follow-up of 25 months, UES was detected in 25 (12%) and 30 (14.4%) patients in Bricker and Wallace groups, respectively (p = 0.56). However, only one patient in the Bricker group developed a bilateral stricture compared to 15 patients in the Wallace group, resulting in a significantly higher number of affected renal units in the Wallace group: 45 (10.7%) versus only 26 (6.2%) in the Bricker group (p = 0.00). On multivariable extended Cox analysis, prior radiotherapy, presence of T4 pelvic malignancy and nodal positive disease were independent predictor of UES formation. CONCLUSION: The technique of ureteroileal anastomosis itself does not increase the rate of stricture; however, conversion of two renal units into one is associated with a higher incidence of bilateral upper tract involvement.

Near-infrared fluorescence lymph node template region dissection plus backup lymphadenectomy in open radical cystectomy for bladder cancer using an innovative handheld device: A single center experience.

BACKGROUND: The extent of pelvic lymphadenectomy (PLND) as part of radical cystectomy (RC) for bladder cancer (BC) remains unclear. Sentinel-based and lymphangiographic approaches could lead to reduced morbidity without sacrificing oncologic safety. OBJECTIVE: To evaluate the feasibility and diagnostic value of fluorescence-guided template sentinel region dissection (FTD) using a handheld near-infrared fluorescence (NIRF) camera in open radical cystectomy. DESIGN, SETTING, AND PARTICIPANTS: After peritumoral cystoscopic injection of indocyanine green (ICG) 21 patients underwent open RC with FTD due to BC between June 2019 and June 2021. Intraoperatively, the FIS-00 Hamamatsu Photonics® NIRF camera was used to identify and resect fluorescent template sentinel regions (FTRs) followed by extended pelvic lymphadenectomy (ePLND) as oncological back-up. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: Descriptive analysis of positive and negative results per template region. RESULTS AND LIMITATIONS: FTRs were identified in all 21 cases. Median time (range) from ICG injection to fluorescence detection was 75 (55-125) minutes. On average (SD), 33.4 (9.6) lymph nodes were dissected per patient. Considering template regions as the basis of analysis, 67 (38.3%) of 175 resected regions were NIRF-positive, with 13 (7.4%) regions harboring lymph node metastases. We found no metastatic lymph nodes in NIRF-negative template regions. Outside the standard template, two NIRF-positive benign nodes were identified. CONCLUSION: The concept of NIRF-guided FTD proved for this group all lymph node metastases to be found in NIRF-positive template regions. Pending validation in a larger collective, resection of approximately 40% of standard regions may be sufficient and may result in less morbidity.

Tumor Neurobiology in the Pathogenesis and Therapy of Head and Neck Cancer.

The neurobiology of tumors has attracted considerable interest from clinicians and scientists and has become a multidisciplinary area of research. Neural components not only interact with tumor cells but also influence other elements within the TME, such as immune cells and vascular components, forming a polygonal relationship to synergistically facilitate tumor growth and progression. This review comprehensively summarizes the current state of the knowledge on nerve-tumor crosstalk in head and neck cancer and discusses the potential underlying mechanisms. Several mechanisms facilitating nerve-tumor crosstalk are covered, such as perineural invasion, axonogenesis, neurogenesis, neural reprogramming, and transdifferentiation, and the reciprocal interactions between the nervous and immune systems in the TME are also discussed in this review. Further understanding of the nerve-tumor crosstalk in the TME of head and neck cancer may provide new nerve-targeted treatment options and help improve clinical outcomes for patients.

Risk factors for ureteroenteric stricture after radical cystectomy and urinary diversion: A systematic review.

Introduction: Ureteroenteric stricture (UES) is the leading cause of renal function deterioration after radical cystectomy (RC) and urinary diversion (UD). The aim of the present review is to summarize studies that discussed the risk factors associated with UES development. Identifying the responsible factors is of importance to help surgeons to modify their treatment or follow-up strategies to reduce this serious complication. Materials and Methods: A comprehensive search of the literature using the PubMed database was conducted. The target of the search was only studies that primarily aimed to identify risk factors of UES after RC and UD. References of searched papers were also checked for potential inclusion. Results: The search originally yielded a total of 1357 articles, of which only 15 met our inclusion criteria, comprising 13, 481 patients. All the studies were observational, and retrospective published between 2013 and 2022. The natural history of UES and the reported risk factors varied widely across the studies. In 13 studies, a significant association between some risk factors and UES development was demonstrated. High body mass index (BMI) was the most frequently reported stricture risk factor, followed by perioperative urinary tract infection (UTI), robotic-assisted radical cystectomy (RARC), occurrence of post-operative Clavian grade ≥ 3 complications and urinary leakage. Otherwise, many other risk factors were reported only once. Conclusion: The literature is still lacking well-designed prospective studies investigating predisposing factors of UES. The available data suggest that the high BMI, RARC and complicated postoperative course are the main risk factors for stricture formation.

The Role of SOX2 and SOX9 in Radioresistance and Tumor Recurrence.

Head and neck squamous cell carcinoma (HNSCC) exhibits considerable variability in patient outcome. It has been reported that SOX2 plays a role in proliferation, tumor growth, drug resistance, and metastasis in a variety of cancer types. Additionally, SOX9 has been implicated in immune tolerance and treatment failures. SOX2 and SOX9 induce treatment failure by a molecular mechanism that has not yet been elucidated. This study explores the inverse association of SOX2/SOX9 and their distinct expression in tumors, influencing the tumor microenvironment and radiotherapy responses. Through public RNA sequencing data, human biopsy samples, and knockdown cellular models, we explored the effects of inverted SOX2 and SOX9 expression. We found that patients expressing SOX2LowSOX9High showed decreased survival compared to SOX2HighSOX9Low. A survival analysis of patients stratified by radiotherapy and human papillomavirus brings additional clinical relevance. We identified a gene set signature comprising newly discovered candidate genes resulting from inverted SOX2/SOX9 expression. Moreover, the TGF-ß pathway emerges as a significant predicted contributor to the overexpression of these candidate genes. In vitro findings reveal that silencing SOX2 enhances tumor radioresistance, while SOX9 silencing enhances radiosensitivity. These discoveries lay the groundwork for further studies on the therapeutic potential of transcription factors in optimizing HNSCC treatment.

An ESR1-Related Gene Signature Identifies Head and Neck Squamous Cell Carcinoma with Imputed Susceptibility to Endocrine Therapy.

Head and neck squamous cell carcinoma (HNSCC) is associated with high morbidity and mortality. New personalized treatment strategies represent an unmet medical need to improve the overall survival and the quality of life of patients, which are often limited by the toxicity of established multimodal treatment protocols. Several studies have reported an increased expression of the estrogen receptor 1 (ESR1) in HNSCC, but its potential role in the disease outcome of these tumors remains elusive. Using an integrative analysis of multiomics and clinical data from The Cancer Genome Atlas (TCGA)-HNSC, we established a prognostic risk model based on an ESR1-related 25-gene set. The prognostic value was confirmed in an independent cohort of HNSCC and other solid tumors from TCGA. Finally, we performed in silico drug sensitivity modeling to explore potential vulnerabilities for both risk groups. This approach predicted a higher sensitivity for HNSCC, with prominent ESR1 pathway activity under treatment with specific estrogen receptor modulators. In conclusion, our data confirm the involvement of ESR1-related pathway activity in the progression of a defined subset of HNSCC, provide compelling evidence that these tumors share a specific vulnerability to endocrine therapy, and pave the way for preclinical studies and clinical trials to demonstrate the efficacy of this new therapeutic option.

[Psychiatric, socio-legal and perioperative aspects of vaginoplasty]. / Psychiatrische, sozialrechtliche und perioperative Aspekte bei der Vaginoplastik.

The number of scientific papers on gender-confirming surgeries as well as the surgeries themselves have increased by leaps and bounds in recent years. This leads to sometimes considerable waiting times for people seeking treatment. Social media and the internet do not always provide reliable and high-quality information. Therefore, it is necessary that both surgically and conservatively active urologists are familiar with topics regarding transgender persons. The establishment of structured training, the guarantee of minimum quality standards in the treatment of transgender persons and the further education and training of medical staff pose particular challenges. The German Society for Urology (DGU) and the German Society for Plastic, Reconstructive and Aesthetic Surgery (DGPRÄC) have already founded their own working groups on the surgical side, which coordinate their work. Under the auspices of the professional societies DGU and DGPRÄC, a guideline on surgical procedures for gender incongruence was developed under the umbrella of the AWMF ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften") which is currently being finalised. For a long time, the health care of transgender people has been moving in a field of tension between the right of self-determination of those seeking treatment, on the one hand, and the fear of making the wrong medical decisions, on the other. In contrast to most other conditions in urology, the goal of treatment is largely determined by the person seeking treatment and does not necessarily follow predetermined schedules or content. The treatment should primarily aim at reducing the individual's suffering and promoting quality of life.

Corrigendum: Exploring the dual role of B cells in solid tumors: implications for head and neck squamous cell carcinoma.

[This corrects the article DOI: 10.3389/fimmu.2023.1233085.].

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.

Exploring the dual role of B cells in solid tumors: implications for head and neck squamous cell carcinoma.

In the tumor milieu of head and neck squamous cell carcinoma (HNSCC), distinct B cell subpopulations are present, which exert either pro- or anti-tumor activities. Multiple factors, including hypoxia, cytokines, interactions with tumor cells, and other immune infiltrating lymphocytes (TILs), alter the equilibrium between the dual roles of B cells leading to cancerogenesis. Certain B cell subsets in the tumor microenvironment (TME) exhibit immunosuppressive function. These cells are known as regulatory B (Breg) cells. Breg cells suppress immune responses by secreting a series of immunosuppressive cytokines, including IL-10, IL-35, TGF-ß, granzyme B, and adenosine or dampen effector TILs by intercellular contacts. Multiple Breg phenotypes have been discovered in human and mouse cancer models. However, when compartmentalized within a tertiary lymphoid structure (TLS), B cells predominantly play anti-tumor effects. A mature TLS contains a CD20+ B cell zone with several important types of B cells, including germinal-center like B cells, antibody-secreting plasma cells, and memory B cells. They kill tumor cells via antibody-dependent cytotoxicity and phagocytosis, and local complement activation effects. TLSs are also privileged sites for local T and B cell coordination and activation. Nonetheless, in some cases, TLSs may serve as a niche for hidden tumor cells and indicate a bad prognosis. Thus, TIL-B cells exhibit bidirectional immune-modulatory activity and are responsive to a variety of immunotherapies. In this review, we discuss the functional distinctions between immunosuppressive Breg cells and immunogenic effector B cells that mature within TLSs with the focus on tumors of HNSCC patients. Additionally, we review contemporary immunotherapies that aim to target TIL-B cells. For the development of innovative therapeutic approaches to complement T-cell-based immunotherapy, a full understanding of either effector B cells or Breg cells is necessary.

Predicting HPV association using deep learning and regular H&E stains allows granular stratification of oropharyngeal cancer patients.

Human Papilloma Virus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) represents an OPSCC subgroup with an overall good prognosis with a rising incidence in Western countries. Multiple lines of evidence suggest that HPV-associated tumors are not a homogeneous tumor entity, underlining the need for accurate prognostic biomarkers. In this retrospective, multi-institutional study involving 906 patients from four centers and one database, we developed a deep learning algorithm (OPSCCnet), to analyze standard H&E stains for the calculation of a patient-level score associated with prognosis, comparing it to combined HPV-DNA and p16-status. When comparing OPSCCnet to HPV-status, the algorithm showed a good overall performance with a mean area under the receiver operator curve (AUROC) = 0.83 (95% CI = 0.77-0.9) for the test cohort (n = 639), which could be increased to AUROC = 0.88 by filtering cases using a fixed threshold on the variance of the probability of the HPV-positive class - a potential surrogate marker of HPV-heterogeneity. OPSCCnet could be used as a screening tool, outperforming gold standard HPV testing (OPSCCnet: five-year survival rate: 96% [95% CI = 90-100%]; HPV testing: five-year survival rate: 80% [95% CI = 71-90%]). This could be confirmed using a multivariate analysis of a three-tier threshold (OPSCCnet: high HR = 0.15 [95% CI = 0.05-0.44], intermediate HR = 0.58 [95% CI = 0.34-0.98] p = 0.043, Cox proportional hazards model, n = 211; HPV testing: HR = 0.29 [95% CI = 0.15-0.54] p < 0.001, Cox proportional hazards model, n = 211). Collectively, our findings indicate that by analyzing standard gigapixel hematoxylin and eosin (H&E) histological whole-slide images, OPSCCnet demonstrated superior performance over p16/HPV-DNA testing in various clinical scenarios, particularly in accurately stratifying these patients.

New insights into RAS in head and neck cancer.

RAS genes are known to be dysregulated in cancer for several decades, and substantial effort has been dedicated to develop agents that reduce RAS expression or block RAS activation. The recent introduction of RAS inhibitors for cancer patients highlights the importance of comprehending RAS alterations in head and neck cancer (HNC). In this regard, we examine the published findings on RAS alterations and pathway activations in HNC, and summarize their role in HNC initiation, progression, and metastasis. Specifically, we focus on the intrinsic role of mutated-RAS on tumor cell signaling and its extrinsic role in determining tumor-microenvironment (TME) heterogeneity, including promoting angiogenesis and enhancing immune escape. Lastly, we summarize the intrinsic and extrinsic role of RAS alterations on therapy resistance to outline the potential of targeting RAS using a single agent or in combination with other therapeutic agents for HNC patients with RAS-activated tumors.

Activation of the EGFR/PI3K/AKT pathway limits the efficacy of trametinib treatment in head and neck cancer.

Blocking the mitogen-activated protein kinase (MAPK) pathway with the MEK1/2 inhibitor trametinib has produced promising results in patients with head and neck squamous cell carcinoma (HNSCC). In the current study, we showed that trametinib treatment leads to overexpression and activation of the epidermal growth factor receptor (EGFR) in HNSCC cell lines and patient-derived xenografts. Knockdown of EGFR improved trametinib treatment efficacy both in vitro and in vivo. Mechanistically, we demonstrated that trametinib-induced EGFR overexpression hyperactivates the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In vitro, blocking the PI3K pathway with GDC-0941 (pictilisib), or BYL719 (alpelisib), prevented AKT pathway hyperactivation and enhanced the efficacy of trametinib in a synergistic manner. In vivo, a combination of trametinib and BYL719 showed superior antitumor efficacy vs. the single agents, leading to tumor growth arrest. We confirmed our findings in a syngeneic murine head and neck cancer cell line in vitro and in vivo. Taken together, our findings show that trametinib treatment induces hyperactivation of EGFR/PI3K/AKT; thus, blocking of the EGFR/PI3K pathway is required to improve trametinib efficacy in HNSCC.

Cumulative sum analysis (CUSUM) for evaluating learning curve (LC) of robotic-assisted laparoscopic partial nephrectomy (RALPN).

Robotic-assisted laparoscopic partial nephrectomy (RALPN) is becoming a standard treatment for localized renal tumors worldwide. Data on the learning curve (LC) of RALPN are still insufficient. In the present study, we have attempted to gain further insight in this area by evaluating the LC using cumulative summation analysis (CUSUM). A series of 127 robotic partial nephrectomies were performed by two surgeons at our center between January 2018 and December 2020. CUSUM analysis was used to evaluate LC for operative time (OT). The different phases of surgical experience were compared in terms of perioperative parameters and pathologic outcomes. In addition, multivariate linear regression analysis was used to confirm the results of the CUSUM analysis by adjusting the phases of surgical experience for the other confounding factors that may affect OT. The median age of patients was 62 years, mean BMI was 28, and mean tumor size was 32 mm. Tumor complexity was classified as low, intermediate, and high risk according to the PADUA score in 44%, 38%, and 18%, respectively. The mean OT was 205 min, and trifecta was achieved in 72.4%. According to the CUSUM diagram, the LC of OT was divided into three phases: initial learning phase (18 cases), plateau phase (20 cases), and mastery phase (subsequent cases). The mean OT was 242, 208, and 190 min in the first, second, and third phases, respectively (P < 0.001). Surgeon experience phases were significantly associated with OT in multivariate analysis considering other preoperative and operative parameters. Surgical outcome was comparable between the three phases in terms of complications and achievement of trifecta; hospital stay was shorter in the mastery phase than in the first 2 phases (4 days vs 5 days, P = 0.02). The LC for RALPN is divided into 3 performance phases with CUSUM. Mastery of surgical technique was achieved after performing 38 cases. The initial learning phase of RALPN has no negative impact on surgical and oncologic outcomes .

Establishment of a Machine Learning Model for the Risk Assessment of Perineural Invasion in Head and Neck Squamous Cell Carcinoma.

Perineural invasion is a prevalent pathological finding in head and neck squamous cell carcinoma and a risk factor for unfavorable survival. An adequate diagnosis of perineural invasion by pathologic examination is limited due to the availability of tumor samples from surgical resection, which can arise in cases of definitive nonsurgical treatment. To address this medical need, we established a random forest prediction model for the risk assessment of perineural invasion, including occult perineural invasion, and characterized distinct cellular and molecular features based on our new and extended classification. RNA sequencing data of head and neck squamous cell carcinoma from The Cancer Genome Atlas were used as a training cohort to identify differentially expressed genes that are associated with perineural invasion. A random forest classification model was established based on these differentially expressed genes and was validated by inspection of H&E-stained whole image slides. Differences in epigenetic regulation and the mutational landscape were detected by an integrative analysis of multiomics data and single-cell RNA-sequencing data were analyzed. We identified a 44-gene expression signature related to perineural invasion and enriched for genes mainly expressed in cancer cells according to single-cell RNA-sequencing data. A machine learning model was trained based on the expression pattern of the 44-gene set with the unique feature to predict occult perineural invasion. This extended classification model enabled a more accurate analysis of alterations in the mutational landscape and epigenetic regulation by DNA methylation as well as quantitative and qualitative differences in the cellular composition in the tumor microenvironment between head and neck squamous cell carcinoma with or without perineural invasion. In conclusion, the newly established model could not only complement histopathologic examination as an additional diagnostic tool but also guide the identification of new drug targets for therapeutic intervention in future clinical trials with head and neck squamous cell carcinoma patients at a higher risk for treatment failure due to perineural invasion.

Tumour budding-based grading as independent prognostic biomarker in HPV-positive and HPV-negative head and neck cancer.

BACKGROUND: The prognostic significance of tumour budding (TB) and minimal cell nest size (MCNS) was shown in human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC). However, the optimisation of cutpoints, the prognostic impact in HPV-positive HNSCC, and the comparison with other histopathological grading systems are insufficiently investigated. METHODS: TB and MCNS were analysed digitally in 1 and 10 high-power fields (HPF) of 331 HPV-positive and HPV-negative cases from TCGA. Optimising the cutpoints a new cellular dissociation grading (CDG) system was defined and compared to the WHO grading and the Brandwein-Gensler (BG) risk model. RESULTS: The two-tiered CDG system based solely on TB yielded optimal prognostic stratification with shortened overall survival for CDG-high cases. Optimal cut-offs were two buds (1 HPF) and six buds (10 HPF), respectively. Analysing MCNS did not add prognostic significance to quantifying TB. CDG was a significant prognostic marker in HPV-negative and HPV-positive tumours and prognostically superior to the WHO and BG systems. High CDG was associated with clinically occult lymph-node metastases. CONCLUSIONS: The most comprehensive study of TB in HNSCC so far confirmed its prognostic impact in HPV-negative tumours and for the first time in HPV-positive tumours. Further studies are warranted to evaluate its applicability for therapy guidance in HNSCC.

Tumor treating fields as novel combination partner in the multimodal treatment of head and neck cancer.

BACKGROUND: We aimed to demonstrate the effects of tumor treating fields (TTFields) in head and neck squamous cell carcinoma (HNSCC) cells when combined with radiotherapy (RT) and chemotherapy. METHODS: Two human HNSCC cell lines (Cal27, FaDu) received five different treatments: TTFields, RT +/- TTFields and RT + simultaneous cisplatin +/- TTFields. Effects were quantified using clonogenic assays and flow cytometric analyses of DAPI, caspase-3 activation and γH2AX foci. RESULTS: Treatment with RT + TTFields decreased the clonogenic survival as strong as treatment with RT + simultaneous cisplatin. The triple combination of RT + simultaneous cisplatin + TTFields even further decreased the clonogenic survival. Accordingly, combination of TTFields with RT or RT + simultaneous cisplatin increased cellular apoptosis and DNA double-strand breaks. CONCLUSION: TTFields therapy seems a promising combination partner in the multimodal treatment of locally advanced HNSCC. It could be used to intensify chemoradiotherapy or as alternative to chemotherapy.

A Novel Subgroup of UCHL1-Related Cancers Is Associated with Genomic Instability and Sensitivity to DNA-Damaging Treatment.

PURPOSE: Identification of molecularly-defined cancer subgroups and targeting tumor-specific vulnerabilities have a strong potential to improve treatment response and patient outcomes but remain an unmet challenge of high clinical relevance, especially in head and neck squamous cell carcinoma (HNSC). EXPERIMENTAL DESIGN: We established a UCHL1-related gene set to identify and molecularly characterize a UCHL1-related subgroup within TCGA-HNSC by integrative analysis of multi-omics data. An extreme gradient boosting model was trained on TCGA-HNSC based on GSVA scores for gene sets of the MSigDB to robustly predict UCHL1-related cancers in other solid tumors and cancer cell lines derived thereof. Potential vulnerabilities of UCHL1-related cancer cells were elucidated by an in-silico drug screening approach. RESULTS: We established a 497-gene set, which stratified the TCGA-HNSC cohort into distinct subgroups with a UCHL1-related or other phenotype. UCHL1-related HNSC were characterized by higher frequencies of genomic alterations, which was also evident for UCHL1-related cancers of other solid tumors predicted by the classification model. These data indicated an impaired maintenance of genomic integrity and vulnerability for DNA-damaging treatment, which was supported by a favorable prognosis of UCHL1-related tumors after radiotherapy, and a higher sensitivity of UCHL1-related cancer cells to irradiation or DNA-damaging compounds (e.g., Oxaliplatin). CONCLUSION: Our study established UCHL1-related cancers as a novel subgroup across most solid tumor entities with a unique molecular phenotype and DNA-damaging treatment as a specific vulnerability, which requires further proof-of-concept in pre-clinical models and future clinical trials.