TNM 8 staging system beyond p16: Double HPV/p16 status is superior to p16 alone in predicting outcome in oropharyngeal squamous cell carcinoma.

PURPOSE: The assessment of p16INK4a (p16) in oropharyngeal squamous cell carcinoma (OPSCC) has been incorporated into tumor classification, as p16 has been shown to impact survival probability. However, a recent study demonstrated that human papillomavirus (HPV) status in addition to p16 may have a better discriminatory effect on survival probability. This study aims to determine the impact of combined evaluation of p16 and HPV on prognosis. METHODS: This was a multicenter, multinational analysis including retrospective and prospective cohorts of patients treated for primary OPSCC with curative intent, based on the data of the HNCIG-EPIC study. The primary outcome was to determine how the combined assessment of HPV and p16 status predicts prognosis of patients with OPSCC compared to p16 assessment alone. We employed multivariable analyses models to compute hazard ratios regarding survival. Analyses were stratified by stage, smoking status, and sub-anatomical region. RESULTS: The study included 7654 patients, with approximately half of the tumors being p16-negative (50.3 %, n = 3849). A total of 9.2 % of patients had discordant p16 and HPV status (n = 704). HPV status significantly impacted overall survival and disease-free survival regardless of p16 status and across both UICC 8th stage I-II and III-IVb cancers. p16-positive/HPV-positive OPSCC patients exhibited the best survival probability. CONCLUSION: The detection of HPV had a significant impact on survival probability for OPSCC patients with both p16-positive and p16-negative tumors. HPV testing should be integrated in cancer staging, especially in regions of low attributable fraction, alongside p16 evaluation to ensure a comprehensive assessment of prognosis.

Analysis of Expression and Regulation of AKR1C2 in HPV-Positive and -Negative Oropharyngeal Squamous Cell Carcinoma.

Head and Neck Squamous Cell Carcinoma (HNSCC), particularly Oropharyngeal Squamous Cell Carcinoma (OPSCC), is a major global health challenge due to its increasing incidence and high mortality rate. This study investigates the role of aldo-keto reductase 1C2 (AKR1C2) in OPSCC, focusing on its expression, correlation with Human Papillomavirus (HPV) status, oxidative stress status, and clinical outcomes, with an emphasis on sex-specific differences. We analyzed AKR1C2 expression using immunohistochemistry in formalin-fixed, paraffin-embedded tissue samples from 51 OPSCC patients. Additionally, we performed RT-qPCR in cultured HPV16-E6*I and HPV16-E6 overexpressing HEK293 cell lines (p53WT). Statistical analyses were performed to assess the correlation between AKR1C2 expression and patient data. Our results indicate a significant association between increased AKR1C2 expression and higher AJCC classification (p = 0.009) as well as positive HPV status (p = 0.008). Prognostic implications of AKR1C2 varied by sex, whereby female patients with high AKR1C2 expression had better overall survival, whereas male patients exhibited poorer outcomes. Additionally, AKR1C2 expression was linked to HPV status, suggesting a potential HPV-specific regulatory mechanism. These findings underscore the complex interplay among AKR1C2, HPV, and patient sex, highlighting the need for personalized treatment strategies for OPSCC. Targeted inhibition of AKR1C2, considering sex-specific differences, may enhance therapeutic outcomes. Future research should investigate these mechanisms to enhance treatment efficacy.

The European Larynx Organ Preservation Study [MK-3475-C44].

The European Larynx Organ Preservation Study (ELOS; NCT06137378) is a prospective, randomized, open-label, two-armed parallel group controlled, phase II multicenter larynx organ preservation (LOP) trial in locoregionally advanced (LA) stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHSCC) amenable for total laryngectomy (TL) with PD-L1 expression within tumor tissue biopsy, calculated as CPS ≥ 1. Induction chemotherapy (IC) with docetaxel and cisplatin (TP) followed by radiation will be compared to TP plus PD-1 inhibition by pembrolizumab (MK-3475; 200 mg i.v. starting day 1 q3w for 17 cycles). After a short induction early response evaluation (ERE) 21 ± 3 days after the first cycle of IC (IC-1), responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥30% will get an additional two cycles of IC followed by intensity-modulated radiotherapy 70-72 Gy (EQD2/α/ß = 10) aiming at LOP. Nonresponders (ETSS < 30% or progressing disease) will receive TL and bilateral neck dissection followed by postoperative radiation or chemoradiation as recommended by the clinic's multidisciplinary tumor board. Pembrolizumab treatment will be continued in the intervention arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent of subsequent decisions on adjuvant therapy after TL. Clinical Trial Registration: clinicaltrials.gov, identifier NCT06137378.

Criteria for Re-Irradiation.

BACKGROUND: The treatment options for patients with progressive malignant tumors despite primary radiotherapy are often limited. In selected cases, re-irradiation can be offered. This article concerns the selection criteria and results of re-irradiation for certain types of cancer. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, with particular attention to glioblastoma, head and neck tumors, and prostatic carcinoma. RESULTS: The published studies of re-irradiation are few in number and often of limited methodological quality. For glioblastoma, a randomized controlled trial (RCT) found that adding re-irradiation to treatment with bevacizumab yielded no significant improvement in either median progression-free survival or median overall survival (hazard ratio [HR] 0.73; p = 0.05 and HR 0.98; p = 0.46, respectively). Re-irradiation is a treatment option for locoregional recurrences of head and neck tumors after primary radiotherapy, but it carries a risk of serious side effects. For unresectable recurrences of nasopharyngeal carcinoma, an RCT has shown that hyperfractionated re-irradiation is more effective than normofractionated re-irradiation (overall survival: HR 0.54, p = 0.014). For locally recurrent prostatic carcinoma after radiotherapy, re-irradiation can yield good oncologic outcomes with an acceptable level of urogenital and gastrointestinal side effects (5-year recurrence-free survival: stereotactic body radiation therapy (SBRT), 58%; high dose rate (HDR) brachytherapy, 77%; versus salvage prostatectomy, 72%). RCTs on this topic are lacking. CONCLUSION: Re-irradiation is a treatment option for selected cancer patients. As the available scientific evidence is limited, multidisciplinary collaboration and participatory decision-making are particularly important.

Bi-institutional analysis of microbiological spectrum and therapeutic management of parotid abscesses.

BACKGROUND: A parotid abscess (PA) is a complication of an acute bacterial parotitis with a potentially life-threatening course. To date, data on the diagnosis and therapy of PA is sparse and mostly consists of case reports or case series. Therefore, this study aimed at comprehensively analyzing the microbiological spectrum and the therapeutic management in a bi-institutional setting. METHODS: A retrospective clinical chart review was performed to identify all patients surgically treated for PA at two tertiary care centers in Germany. Data on demographics, clinical management and microbiological data including species identification, pathogenicity, type of antibiotic therapy, adjustment of antibiotics, antibiotic sensitivity testing, and smear test results were extracted. Intervention-related variables and etiology were analyzed for their statistical association with outcome variables. RESULTS: Overall, 85 patients were included. Most patients (92.9%) underwent surgical incision. Around half of the patients (45.9%) were treated under local anesthesia. No facial nerve palsy was observed. The most frequently detected pathogens were Streptococci (n = 23), followed by Staphylococcus aureus (n = 6) including one case of methicillin-resistant Staphylococcus aureus. Most patients (68.2%) received an aminopenicillin ± beta-lactamase inhibitor as empiric antibiotic therapy. In 6 cases the antibiotic therapy was modified after receiving the antibiogram. Four patients (5.2%) presented with recurrent PA. Etiology was idiopathic (42.4%), followed by tumorous (12.9%), obstructive, and immunosuppressive (each 11.8%). Patients with a dental focus (p = 0.007) had a longer duration of hospitalization. CONCLUSION: The results show that the surgical therapy of PA under local anesthesia is safe. A dental examination should routinely be performed to rule out a dental focus. Obtaining a microbiological specimen in order to modify antibiotic therapy if necessary and a histopathological specimen to rule out a tumorous etiology is obligate.

Quantification of human papillomavirus cell-free DNA from low-volume blood plasma samples by digital PCR.

The incidence rate of human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is increasing in countries with high human development index. HPV cell-free DNA (cfDNA) isolated from 3 to 4 mL blood plasma has been successfully used for therapy surveillance. A highly discussed application of HPV-cfDNA is early detection of HPV-OPC. This requires sensitive and specific cfDNA detection as cfDNA levels can be very low. To study the predictive power of pre-diagnostic HPV-cfDNA, archived samples from epidemiological cohorts with limited plasma volume are an important source. To establish a cfDNA detection workflow for low plasma volumes, we compared cfDNA purification methods [MagNA Pure 96 (MP96) and QIAamp ccfDNA/RNA] and digital PCR systems (Biorad QX200 and QIAGEN QIAcuity One). Final assay validation included 65 low-volume plasma samples from oropharyngeal cancer (OPC) patients with defined HPV status stored for 2-9 years. MP96 yielded a 28% higher cfDNA isolation efficiency in comparison to QIAamp. Both digital PCR systems showed comparable analytical sensitivity (6-17 copies for HPV16 and HPV33), but QIAcuity detected both types in the same assay. In the validation set, the assay had 80% sensitivity (n = 28/35) for HPV16 and HPV33 and a specificity of 97% (n = 29/30). In samples with ≥750 µL plasma, the sensitivity was 85% (n = 17/20), while in samples with <750 µL plasma, it was 73% (n = 11/15). Despite the expected drop in sensitivity with decreased plasma volume, the assay is sensitive and highly specific even in low-volume samples and thus suited for studies exploring HPV-cfDNA as an early HPV-OPC detection marker in low-volume archival material.IMPORTANCEHPV-OPC has a favorable prognosis compared to HPV-negative OPC. However, the majority of tumors is diagnosed after regional spread, thus making intensive treatment necessary. This can cause lasting morbidity with a large impact on quality of life. One potential method to decrease treatment-related morbidity is early detection of the cancer. HPV cfDNA has been successfully used for therapy surveillance and has also been detected in pre-diagnostic samples of HPV-OPC patients. These pre-diagnostic samples are only commonly available from biobanks, which usually only have small volumes of blood plasma available. Hence, we have developed a workflow optimized for small-volume archival samples. With this method, a high sensitivity can be achieved despite sample limitations, making it suitable to conduct further large-scale biobank studies of HPV-cfDNA as a prognostic biomarker for HPV-OPC.

[Update: Epidemiology and Prevention of Oropharyngeal Cancer]. / Update: Epidemiologie und Prävention des Oropharynxkarzinoms.

Due to the association with the causal HPV-16 infection, the oropharyngeal carcinoma spreads into two separate entities depending on HPV-16 positivity. More recent data show a diversified picture of the importance and prevalence of the surrogate parameter p16 (discordance) for a definitive HPV-16 association, which varies worldwide. In the context of prevention options, vaccination is of major and HPV screening of healthy people only of little importance.

The extent of androgen receptor and HER2 expression allows for targeted therapy in most cases of salivary duct carcinoma: analysis of clinical and histopathological data in a tertiary care center.

PURPOSE: The incidence of salivary duct carcinoma (SDC) seems to be underestimated due to inaccurate classification. Further, the frequency of SDC patients with targeted therapy options according to current guidelines is unclear. Therefore, this study aimed at (a) describing the proportion of SDC among salivary gland carcinoma (SGC) before and after reclassification of cases initially classified as adenocarcinoma, not otherwise specified (ANOS); and (b) quantifying the frequency of SDC patients with targeted therapy options. METHODS: All patients with SDC or ANOS treated in a tertiary care center between 1996 and 2023 were identified. Histopathological diagnosis was verified for patients primarily diagnosed with SDC and reviewed for patients initially diagnosed with ANOS. Clinical data for SDC patients were retrieved from clinical charts. Immunohistochemical (IHC) androgen receptor (AR) and HER2 staining was performed. RESULTS: Among 46 SDC, 34 were primarily diagnosed as SDC and 12 had initially been classified as ANOS. The proportion of SDC among SGC was 12.1% and was rising when comparing the time periods 2000-2015 (7.1-11.5%) versus 2016-2023 (15.4-18.1%). Nuclear AR staining in > 70% of tumor cells was found in 56.8% and HER2 positivity (IHC 3 +) in 36.4% of cases. 70.5% of patients showed AR staining in > 70% of tumor cells and/or HER2 positivity and therefore at least one molecular target. 5-year overall and disease-free survival (DFS) were 62.8% and 41.0%. Multivariate Cox regression revealed positive resection margins (HR = 4.0, p = 0.03) as independent negative predictor for DFS. CONCLUSIONS: The results suggest a rising SDC incidence and show that the extent of the AR and HER2 expression allows for targeted therapy in most SDC cases.

Concordance Analysis of the Pressure Chamber and Tubomanometer According to Estève for the Determination of Eustachian Tube Opening Pressure.

INTRODUCTION: For the diagnosis of Eustachian tube dysfunction (ETD), clinical procedures such as tympanometry, micro-otoscopy, and maneuvers according to Toynbee and Valsalva only allow an indirect assessment for the moment. With a prevalence of up to 5%, the selection of patients with ETD and its subtypes is clinically relevant. Dynamic methods of Eustachian tube function assessment include a hypo/hyperbaric pressure chamber and Estève's tubomanometer (TMM). One method of assessing ETD is the evaluation of Eustachian tube opening pressure (ETOP). MATERIAL AND METHODS: We performed a concordance analysis between pressure chamber and TMM to determine ETOP. For this purpose, we analyzed the measurements of both methods from 28 healthy subjects using Bland-Altman plots, regression according to Passing-Bablok and Lin's concordance correlations coefficient. The maximum tolerated clinical deviation of measured values was set at 10%. RESULTS: A maximum of 53 measurements of ETOP between pressure chamber and TMM were compared. Mean ETOP for TMM was 28.7 hPa, passive opening was 32 hPa, Toynbee maneuver was 28.4 hPa, and Valsalva maneuver was 54.6 hPa. Concordance analysis revealed following results: passive opening versus TMM: Bland-Altman mean difference 3.3 hPa, limits of agreement ±31.8 hPa; Passing-Bablok regression y = 0.67 x + 9.36; Lin's rccc = 0.18. Toynbee versus TMM: Bland-Altman mean difference 0.7 hPa, limits of agreement ±35.8 hPa; Passing-Bablok regression y = 0.47x + 14.03; Lin's rccc = 0.14. Valsalva versus TMM: Bland-Altman mean difference 24.2 hPa, limits of agreement ±117.5 hPa; Passing-Bablok regression y = 0.17x + 25.12; Lin's rccc = 0.18. CONCLUSION: Estève's tubomanometer and pressure chamber measurements of ETOP are not concordant. The two methods cannot be interchanged without reservation.

Cochlear measurement in computed tomography and magnetic resonance imaging data sets by the Otoplan measurement tool: a retrospective comparative study.

BACKGROUND: Using Otoplan software, it is possible to measure the cochlea before cochlear implant surgery. Until now, computed tomography (CT) of the cochlea has been necessary for this purpose. The aim of this study was to find out whether measuring the cochlea with magnetic resonance imaging (MRI) using Otoplan is possible with the same accuracy. METHODS: The cochlea of 44 patients of the local cochlear implant centre was measured by Otoplan using high-resolution CT-bone and MRI images, and the determined lengths were compared. RESULTS: No significant difference was found between the cochlear lengths measured, regardless of whether the length measurement was based on a CT or an MRI data set. CONCLUSION: For the determination of cochlear length prior to cochlear implant surgery, MRI images are just as suitable as CT images, therefore CT is not mandatory for length measurement by Otoplan, which could reduce the patient's radiation exposure.

The TORP-PORP: A Tympanoplasty Technique for Isolated Defects of the Stapes Suprastructure.

OBJECTIVE: Investigating the outcomes of a surgical approach to treat isolated defects of the stapes suprastructure, using a modified total ossicular replacement prosthesis (TORP) prosthesis as a PORP between the footplate and the incus, effectively creating a TORP-PORP configuration. PATIENTS: Eleven patients (mean age, 37.2 years; 36% male and 64% female) between the years 2007 and 2022. INTERVENTIONS: Therapeutic (ossiculoplasty). MAIN OUTCOME MEASURES: Hearing gain (in dB) in air conduction thresholds at 0.5, 1, 2, 3, and 4 kHz, stability of bone conduction, revision rate. RESULTS: Significant improvement in air conduction between the preoperative and the postoperative cohorts (p = 0.002) with a mean postoperative hearing level of 30.00 ± 5.25 dB. The bone conduction remained stable. We encountered no perioperative complications, and there were no revisions surgery. CONCLUSIONS: The described ossiculoplasty procedure is a safe and effective approach to treat isolated defects of the stapes suprastructure.

Co-expression patterns of cancer associated fibroblast markers reveal distinct subgroups related to patient survival in oropharyngeal squamous cell carcinoma.

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing in high income countries due to its association with persistent high-risk human papilloma virus (HPV) infection. Recent scientific advances have highlighted the importance of the tumor microenvironment in OPSCC. In this study, including 216 OPSCC patients, we analyze the composition of four established markers of cancer associated fibroblasts (CAFs) in the context of intratumoral CD8 T-cell infiltration. Methods: Immunohistochemical staining for fibroblast activation protein (FAP), platelet-derived growth factor receptor beta (PDGFRb), periostin, alpha smooth muscle actin (α-SMA) and CD8 were analyzed digitally and their association with survival, tumor- and patient characteristics was assessed. Results: Co-expression of CAF markers was frequent but not associated with HPV status. FAPhigh and PDGFRbhigh expression were associated with increased CD8 T-cell infiltration. Low expression of PDGFRb improved patient survival in female patients but not in male patients. We identified PDGFRblow periostinlow α-SMAlow status as an independent predictor of improved survival (hazard ratio 0.377, p = 0.006). Conclusion: These findings elucidate the co-expression of four established CAF markers in OPSCC and underscore their association with T-cell infiltration and patient survival. Future analyses of CAF subgroups in OPSCC may enable the development of individualized therapies.

Combination of nivolumab with standard induction chemotherapy in children and adults with EBV-positive nasopharyngeal carcinoma : Protocol of a prospective multicenter phase 2 trial.

BACKGROUND: Treatment of Epstein-Barr virus(EBV)-positive nasopharyngeal carcinoma (NPC) with cisplatin/5-fluorouracil (5-FU) induction chemotherapy, followed by radiochemotherapy and subsequent interferon­ß, has yielded high survival rates in children, adolescents, and young adults. A previous study has shown that reduction of radiation dose from 59.4 to 54.0 Gy appears to be safe in patients with complete response (CR) to induction chemotherapy. As immune checkpoint-inhibitors have shown activity in NPC, we hypothesize that the addition of nivolumab to standard induction chemotherapy would increase the rate of complete tumor responses, thus allowing for a reduced radiation dose in a greater proportion of patients. METHODS: This is a prospective multicenter phase 2 clinical trial including pediatric and adult patients with their first diagnosis of EBV-positive NPC, scheduled to receive nivolumab in addition to standard induction chemotherapy. In cases of non-response to induction therapy (stable or progressive disease), and in patients with initial distant metastasis, treatment with nivolumab will be continued during radiochemotherapy. Primary endpoint is tumor response on magnetic resonance imaging (MRI) and positron emission tomography (PET) after three cycles of induction chemotherapy. Secondary endpoints are event-free (EFS) and overall survival (OS), safety, and correlation of tumor response with programmed cell death ligand 1 (PD-L1) expression. DISCUSSION: As cure rates in localized EBV-positive NPC today are high with standard multimodal treatment, the focus increasingly shifts toward prevention of late effects, the burden of which is exceptionally high, mainly due to intense radiotherapy. Furthermore, survival in patients with metastatic disease and resistant to conventional chemotherapy remains poor. Primary objective of this study is to investigate whether the addition of nivolumab to standard induction chemotherapy in children and adults with EBV-positive NPC is able to increase the rate of complete responses, thus enabling a reduction in radiation dose in more patients, but also offer patients with high risk of treatment failure the chance to benefit from the addition of nivolumab. TRIAL REGISTRATION: EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) No. 2021-006477-32.

[ENT in zero g: the cosmic challenges of otolaryngology]. / Hals, Nase und Ohren in der Schwerelosigkeit: die kosmischen Herausforderungen der HNO-Heilkunde.

Manned spaceflight places special demands on the human body, including the organs in the ENT region. These organs play a critical role in maintaining the health and safety of astronauts in space. In this paper, we review common ENT problems of spaceflight, including upper airway edema, middle ear and mastoid effusions, hearing loss, and dizziness with nausea. We discuss the underlying mechanisms contributing to these complaints, their clinical manifestations, and potential treatment strategies. In addition, we examine the potential impact of these conditions on astronaut health and mission outcomes. Finally, we emphasize the importance of preventive measures and future research in this area to optimize astronaut health and safety on future missions.

[Vestibular Schwannoma: Factors in Therapy Decision-Making]. / Vestibularisschwannom: Faktoren bei der Therapieentscheidung.

The treatment of vestibular schwannomas (VS) has always posed a challenge for physicians. Three essential treatment principles are available: wait-and-scan, surgery, and stereotactic radiotherapy. In addition to the type of treatment, decisions must be made regarding the optimal timing of therapy, the combination of different treatment modalities, the potential surgical approach, and the type and intensity of radiation. Factors influencing the therapy decision include tumor location and size or stage, patient age, comorbidities, symptoms, postoperative hearing rehabilitation options, patient preferences, and, not least, the experience of the surgeons and the personnel and technical capabilities of the clinical site. This article begins with a brief overview of vestibular schwannomas, then outlines the fundamental interdisciplinary treatment options, and finally discusses the ENT (ear, nose, and throat)-relevant factors in the therapy decision.

Sex-specific aspects in patients with oropharyngeal squamous cell carcinoma: a bicentric cohort study.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is the only subgroup of head neck cancer that presents with an increased incidence. Gender-specific studies in other cancer entities have revealed differences in treatment response and prognosis. However, only limited data in OPSCC according to gender and human papillomavirus (HPV) status exist. Therefore, we aimed to investigate sex-specific differences in OPSCC and how these may be distributed in relation to HPV and other risk factors. METHODS: This retrospective, bicentric study included 1629 patients with OPSCC diagnosed between 1992 and 2020. We formed subgroups based on TNM status, American Joint Cancer Committee 8th edition (AJCC8), HPV status, treatment modality (surgery (± radio(chemo)therapy (RCT) vs. definitive RCT) and patient-related risk factors and investigated gender differences and their impact on patients survival via descriptive-,uni- and multivariate analysis. RESULTS: With the exception of alcohol abuse, no significant differences were found in risk factors between men and women. Females presented with better OS than males in the subgroup T1-2, N + , independent of risk factors (p = 0.008). Males demonstrated significant stratification through all AJCC8 stages (all p < 0.050). In contrast, women were lacking significance between stage II and III (p = 0.992). With regard to therapy (surgery (± R(C)T) - vs. definitive RCT) women treated with surgery had better OS than men in the whole cohort (p = 0.008). Similar results were detected in the HPV-negative OPSCC sub-cohort (p = 0.042) and in high-risk groups (AJCC8 stage III and IV with M0, p = 0.003). CONCLUSION: Sex-specific differences in OPSCC represent a health disparity, particularly according to staging and treatment, which need to be addressed in future studies.

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.

Nectin-4 is frequently expressed in primary salivary gland cancer and corresponding lymph node metastases and represents an important treatment-related biomarker.

Many locally advanced and metastatic salivary gland carcinomas (SGC) lack therapeutic targets. Enfortumab vedotin, an antibody-drug conjugate binding to Nectin-4, recently gained FDA approval for third-line urothelial carcinoma. Therefore, the aim of this study was to assess the expression of Nectin-4 in primary SGC and corresponding lymph node metastases and to correlate it with clinicopathological data. Immunohistochemical staining for Nectin-4 was performed for patients who had undergone surgery with curative intent for primary SGC of the parotid or submandibular gland in a tertiary referral center between 1990 and 2019. One hundred twenty-two primary SGC and twenty corresponding lymph node metastases were included. Nectin-4 was expressed in 80.3% of primary SGC with a mean Histo(H-)score of 61.2 and in 90.0% of lymph node metastases with a mean H-score of 75.6. A moderate or high Nectin-4 expression was found in 25.9% of salivary duct carcinomas (SaDu) and in 30.7% of adenoid cystic carcinomas (ACC). SaDu patients with a lower T-stage (p = 0.04), no loco-regional lymph node metastases (p = 0.049), no vascular invasion (p = 0.04), and no perineural spread (p = 0.03) showed a significantly higher mean Nectin-4 H-score. There was a statistical tendency towards a more favorable disease-free survival among SaDu patients with a higher Nectin-4 expression (p = 0.09). Nectin-4 is expressed in SGC and therefore represents a potential therapeutic target, especially in entities with a high rate of local recurrence and metastatic spread such as SaDu and ACC.

[ctHPV-DNA based precision oncology for patients with oropharyngeal cancer - Where are we?] / ctHPV-DNA-basierte Präzisionsonkologie für Patienten mit Oropharynxkarzinom ­ wo stehen wir?

Human papillomavirus (HPV) is an established etiologic factor for cancers in the head and neck region, specifically for Oropharyngeal Squamous Cell Carcinoma (OPSCC). The comparatively good overall survival justifies the current discussion regarding therapy de-escalation for patients with a low-risk profile. In addition to the immunohistochemistry-based biomarker p16INK4a, there is still a need for diagnostic and prognostic biomarkers that allow risk stratification and monitoring during therapy and follow-up of these patients. In recent years, liquid biopsy, especially in the form of plasma samples, has gained importance and is already used to monitor viral DNA in patients with Epstein-Barr virus-associated nasopharyngeal carcinoma. Circulating DNA (ctDNA) released by the tumor into the bloodstream is particularly suitable for a high specificity in detecting virus-associated tumors. Detection of viral E6 and E7 oncogenes in HPV-positive OPSCC is predominantly performed by droplet digital/quantitative PCR as well as next generation sequencing. Detection of circulating HPV-DNA derived from tumor cells (ctHPV-DNA) at diagnosis is associated with advanced tumor stage, locoregional and distant metastases. Longitudinal studies have further demonstrated that detectable and/or increasing ctHPV-DNA levels are associated with treatment failure and disease relapse. However, a standardization of the diagnostic procedure is necessary before introducing liquid biopsy into the clinical routine. In the future, this might allow a valid reflection of disease progression in HPV-positive OPSCC.