Assessing the use of the novel tool Claude 3 in comparison to ChatGPT 4.0 as an artificial intelligence tool in the diagnosis and therapy of primary head and neck cancer cases.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is a complex malignancy that requires a multidisciplinary tumor board approach for individual treatment planning. In recent years, artificial intelligence tools have emerged to assist healthcare professionals in making informed treatment decisions. This study investigates the application of the newly published LLM Claude 3 Opus compared to the currently most advanced LLM ChatGPT 4.0 for the diagnosis and therapy planning of primary HNSCC. The results were compared to that of a conventional multidisciplinary tumor board; (2) Materials and Methods: We conducted a study in March 2024 on 50 consecutive primary head and neck cancer cases. The diagnostics and MDT recommendations were compared to the Claude 3 Opus and ChatGPT 4.0 recommendations for each patient and rated by two independent reviewers for the following parameters: clinical recommendation, explanation, and summarization in addition to the Artificial Intelligence Performance Instrument (AIPI); (3) Results: In this study, Claude 3 achieved better scores for the diagnostic workup of patients than ChatGPT 4.0 and provided treatment recommendations involving surgery, chemotherapy, and radiation therapy. In terms of clinical recommendations, explanation and summarization Claude 3 scored similar to ChatGPT 4.0, listing treatment recommendations which were congruent with the MDT, but failed to cite the source of the information; (4) Conclusion: This study is the first analysis of Claude 3 for primary head and neck cancer cases and demonstrates a superior performance in the diagnosis of HNSCC than ChatGPT 4.0 and similar results for therapy recommendations. This marks the advent of a newly launched advanced AI model that may be superior to ChatGPT 4.0 for the assessment of primary head and neck cancer cases and may assist in the clinical diagnostic and MDT setting.

[Results of a survey on the current management of chronic rhinosinusitis with nasal polyps in Germany]. / Ergebnisse einer Umfrage zur aktuellen Behandlung der chronischen Rhinosinusitis mit nasalen Polypen.

INTRODUCTION: With a prevalence of 0.55% to 4%, chronic rhinosinusitis with nasal polyps (CRSwNP) is a relevant part of the daily work of German otolaryngologists. The aim of the questionnaire-based data collection was to assess the current treatment status of CRSwNP in Germany. MATERIAL AND METHODS: For this purpose, 24 questions within an anonymized online questionnaire were sent to all German ENT departments. RESULTS: Of 160 contacted ENT departments, 50 participated in the survey (31.3%). Among these, 76% performed more than 100 sinus surgeries annually and 38% treated more than 50 patients with biologics. Saline irrigations (80%) and intranasal glucocorticoids (GCS, 96%) were the most common conservative therapies. Systemic GCSs (52%) and intranasal GCS irrigation (20%) were less common. 80% of departments used biologics in the therapy of CRSwNP with an overall preference for dupilumab (70%). For therapy of aspirin intolerance, biologics (52%) were preferred to aspirin desensitization (26%). Prior to treatment with biologics clinical workup included the nasal polyp score (90%), the SNOT-22 questionnaire (84%), surrogate markers of type 2 inflammation (60%-72%), and computer tomography (50%). Final treatment success was assessed after 24 weeks (50%). CONCLUSION: Mostly, the responding departments followed German and European recommendations for diagnosis and therapy of CRSwNP. Therapy with biologics is widely used. The value of preoperative systemic GCS and the frequent performance of CT before initiation of therapy with a biologic should be debated in regard to its currently widespread use.

[Nodal metastasis and value of neck dissection in T1/2 oropharyngeal and hypopharyngeal carcinomas]. / Nodale Metastasierung und Stellenwert der Neck Dissection bei T1/2-Oro- und Hypopharynxkarzinomen.

BACKGROUND: Due to heterogeneous data, the indication for elective neck dissection (END) in patients with squamous cell carcinoma of the hypopharynx and oropharynx (HPSCC and OPSCC) in stages T1/2N0 is somewhat unclear. Therefore, in this multicenter study, we performed detailed analysis of the metastatic behavior of HPSCC and OPSCC. MATERIAL AND METHODS: The nodal metastatic patterns of 262 HPSCC and OPSCC patients who had undergone surgery was retrospectively investigated. In addition, recurrence-free and overall survival were recorded. Furthermore, a systematic literature review on the topic was completed. RESULTS: In patients with HPSCC, a discrepancy between clinical and pathologic N status was recorded in 62.1% of patients vs. 52.4% for p16- OPSCC, and 43.6% for p16+ OPSCC. The occult metastasis rate in cT1/2cN0 primary tumors was 38.9% for HPSCC vs. 17.8% (p16- OPSCC) and 11.1% (p16+ OPSCC). Contralateral metastases occurred in 22.2% of cases for HPSCC at stages cT1/2cN0, compared to only 9.1% for p16- OPSCC, and 0% for p16+ OPSCC patients.Patients with p16+ OPSCC had better recurrence-free and overall survival than p16- OPSCC and HPSCC patients. A direct association between patient survival and the extent of neck surgical therapy could not be demonstrated in our patients. CONCLUSION: Patients with HPSCC are at risk for bilateral neck metastases from stage cT1/2cN0, justifying bilateral END. Patients with T1/2 OPSCC present with occult metastases ipsilaterally in >20% of cases; however, the risk for contralateral occult metastasis is <10%. Hence, in strictly lateralized cT1/2CN0 tumors, omission of contralateral END may be considered.

Proposing a surgical algorithm for graduated orbital decompression in patients with Graves' orbitopathy.

PURPOSE: To determine the outcome after orbital decompression using a graduated technique, adapting the surgical technique according to individual patients' disease characteristics. METHODS: We retrospectively examined the postoperative outcome in patients treated with a graduated balanced orbital decompression regarding reduction of proptosis, new onset diplopia and improvement in visual function. 542 patients (1018 orbits) were treated between 2012 and 2020 and included in the study. Clinical examinations including visual acuity, exophthalmometry (Hertel) and orthoptic evaluation were performed preoperatively and at minimum 6 weeks postoperatively. Mean follow-up was 22.9 weeks. RESULTS: Mean proptosis values have significantly decreased after surgery (p < 0.01). In 83.3% of the patients Hertel measurement normalized (≤ 18 mm) after surgery, New onset diplopia within 20° of primary position occurred in 33.0% of patients, of whom 16.0% had preoperative double vision in secondary gaze. Patients suffering from dysthyroid optic neuropathy (DON) had a significant increase in visual acuity (p < 0.01). CONCLUSION: We demonstrated that individually adapted graduated orbital decompression successfully improves key disease parameters of Graves' orbitopathy with low morbidity.

The accuracy of clinical neck staging for p16-positive and negative oropharyngeal cancer and its therapeutic implications.

PURPOSE: Oropharyngeal squamous cell carcinoma (OPSCC) may be treated with primary surgery or primary (chemo)radiation. While surgery with concurrent neck dissection provides definitive pathological staging of the neck, non-surgical treatment relies on clinical staging for treatment planning. To assess the accuracy of clinical neck staging, we compared clinical to surgical staging after primary surgery in patients with p16-negative and p16-positive OPSCC. METHODS: Retrospective analysis of clinical, pathological, and oncologic outcome data of patients with OPSCC treated with primary surgery and bilateral neck dissection. Clinical and pathological nodal status were compared for p16-negative and p16-positive patients. Patients with occult metastatic disease were analyzed in detail. RESULTS: 95 patients were included. 60.5% of p16-negative patients and 66.6% of p16-positive patients had pathologically confirmed metastatic neck disease. p16-positive patients had improved 24-month recurrence-free survival compared to p16-negative patients at 93.3% vs. 69.6%. Pathological N-status differed from clinical N-status in 36.8% of p16-negative patients vs. 31.6% of p16-positive patients. Occult metastatic disease was more common in p16-negative patients at 18.4% vs. 8.8% for p16-positive patients. Clinical detection sensitivity for extranodal extension was low overall; sensitivity was 27.3% and specificity was 91.6% for p16-negative patients vs. 61.5% and 80.0% for p16-positive patients, respectively. CONCLUSION: Our data show a considerable degree of inaccuracy of clinical neck staging results in all OPSCC patients which needs to be taken into consideration during therapy planning. For p16-positive patients, these findings warrant attention in the context of therapy deintensification to avoid undertreatment.

Patient Benefit and Quality of Life after Robot-Assisted Head and Neck Surgery. / Patienten-Benefit und Lebensqualität nach Roboter-assistierten Operationen im Kopf-Hals-Bereich.

Robotic systems for head and neck surgery are at different stages of technical development and clinical application. Currently, robotic systems are predominantly used for transoral surgery of the pharynx and larynx. Robotic surgery of the neck, the thyroid, and the middle and inner ear is much less common; however, some oncological and functional outcomes have been reported. This article provides an overview of the current state of robot-assisted head and neck surgery with a special emphasis on patient benefit and postoperative quality of life (QoL). The focus is placed on the role of transoral robotic surgery (TORS) for the resection of oropharyngeal carcinomas. For this application, reported long-term outcomes show functional post-operative advantages for selected oropharyngeal cancer patients after TORS compared to open surgery and primary radiotherapy. Since TORS also plays a significant role in the context of potential therapy de-escalation for HPV-positive oropharyngeal cancer patients, ongoing trials are presented. Regarding the evaluation of the therapeutic benefit and the QoL of cancer patients, special attention has to be paid to the large degree of variability of individual patients' preferences. Influencing factors and tools for a detailed assessment of QoL parameters are therefore detailed at the beginning of this article. Notably, while some robotic systems for ear and skull base surgery are being developed in Europe, TORS systems are mainly used in North America and Asia. In Europe and Germany in particular, transoral laser microsurgery (TLM) is a well-established technology for transoral tumor resection. Future trials comparing TORS and TLM with detailed investigation of QoL parameters are therefore warranted and might contribute to identifying suitable fields for the application of the different techniques.

Patterns of cervical lymph node metastasis in supraglottic laryngeal cancer and therapeutic implications of surgical staging of the neck.

PURPOSE: Accurate therapeutic management of the neck is a challenge in patients with supraglottic laryngeal cancer. Nodal metastasis is common at all disease stages, and treatment planning relies on clinical staging of the neck, for both surgical and non-surgical treatment. Here, we compared clinical and surgical staging results in supraglottic carcinoma patients treated with primary surgery to assess the accuracy of pre-therapeutic clinical staging and guide future treatment decisions. METHODS: Retrospective analysis of clinical, pathological, and oncologic outcome data of 70 patients treated with primary surgery and bilateral neck dissection for supraglottic laryngeal cancer. Patients where clinical and pathological neck staging results differed, were identified and analyzed in detail. RESULTS: On pathologic assessment, patients with early stage (pT1/2) primaries showed cervical lymph node metastases in 55% (n = 17/31) of cases, compared to 67% (n = 26/39) of patients with pT3/4 tumors. In 24% (n = 17/70) of all patients, cN status differed from pN status, resulting in an upstaging in 16% of cases (n = 11/70) and a downstaging in 9% (n = 6/70) of cases. 14% of patients with cN0 status had occult metastases (n = 5/30). As assessed by a retrospective tumor board, in case of a non-surgical treatment approach, the inaccurate clinical staging of the neck would have led to an over- or undertreatment of the neck in 20% (n = 14/70) of all patients. CONCLUSION: Our data re-emphasize the high cervical metastasis rates of supraglottic laryngeal cancer across all stages. Inaccurate clinical staging of the neck is common and should be taken into consideration when planning treatment.

Risk Factors for New Onset Diplopia After Graduated Orbital Decompression.

PURPOSE: The aim of the study was to identify possible risk factors for new onset diplopia in 20° of primary position (NOD PP) after orbital decompression. A predisposition for NOD has been established for patients with pre-existing diplopia in secondary gaze; therefore, the authors focused on patients without preoperative diplopia. METHODS: Retrospective chart review of patients who underwent balanced orbital decompression between 2012 and 2019 due to Graves orbitopathy at the authors' institution. Exclusion criteria were incomplete clinical data set, revision surgery, and medial or lateral decompression only. The following clinical parameters were evaluated preoperatively and postoperatively: Hertel exophthalmometry, objective measurement of misalignment using the prism-cover-test, assessment of the field of binocular single vision, and measurement of monocular excursions. In addition, the diameter of the extraocular eye muscles was measured in all preoperative CT scans. RESULTS: We included 327 patients (612 orbits), 126 patients (242 orbits) had no preoperative diplopia. In patients with NOD PP (34%, n = 43/126), enlargement of the medial rectus muscle and restriction of abduction and elevation were significantly more frequent than in patients with no NOD PP. The degree of exophthalmos decrease positively correlated with postoperative squint angle. CONCLUSION: We were able to identify the diameter of the medial rectus muscle, restriction of abduction, and elevation as well as an extensive reduction of exophthalmos as risk factors for NOD PP in patients with no preoperative diplopia.

The Flex robotic system compared to transoral laser microsurgery for the resection of supraglottic carcinomas: first results and preliminary oncologic outcomes.

PURPOSE: Transoral robotic surgery (TORS) has the potential to improve some inherent disadvantages of transoral laser microsurgery (TLM). Here, we retrospectively assessed the application of the Medrobotics Flex system for the resection of supraglottic carcinomas compared to TLM. METHODS: 84 patients underwent surgery for supraglottic carcinomas with the Flex robotic system (n = 19, T-stage distribution in %: T1 42, T2 47, T3 11, T4 0) or TLM (n = 65, T-stage distribution in %: T1 40, T2 44, T3 14, T4 2). Clinical and oncologic parameters were compared. RESULTS: All surgeries were successfully completed with the Flex system and tracheostomy rate was 13%. For patients with adequate follow-up, 24-month disease-free survival was 71.4% (n = 5/7) after TORS compared to 64.9% (n = 24/37) after TLM. Local recurrence rates were 0% for TORS and 11% for TLM. CONCLUSIONS: Initial results for supraglottic carcinoma resection using the Medrobotics Flex system are encouraging with excellent local tumor control.

Laminin targeting of a peripheral nerve-highlighting peptide enables degenerated nerve visualization.

Target-blind activity-based screening of molecular libraries is often used to develop first-generation compounds, but subsequent target identification is rate-limiting to developing improved agents with higher specific affinity and lower off-target binding. A fluorescently labeled nerve-binding peptide, NP41, selected by phage display, highlights peripheral nerves in vivo. Nerve highlighting has the potential to improve surgical outcomes by facilitating intraoperative nerve identification, reducing accidental nerve transection, and facilitating repair of damaged nerves. To enable screening of molecular target-specific molecules for higher nerve contrast and to identify potential toxicities, NP41's binding target was sought. Laminin-421 and -211 were identified by proximity-based labeling using singlet oxygen and by an adapted version of TRICEPS-based ligand-receptor capture to identify glycoprotein receptors via ligand cross-linking. In proximity labeling, photooxidation of a ligand-conjugated singlet oxygen generator is coupled to chemical labeling of locally oxidized residues. Photooxidation of methylene blue-NP41-bound nerves, followed by biotin hydrazide labeling and purification, resulted in light-induced enrichment of laminin subunits α4 and α2, nidogen 1, and decorin (FDR-adjusted P value < 10-7) and minor enrichment of laminin-γ1 and collagens I and VI. Glycoprotein receptor capture also identified laminin-α4 and -γ1. Laminins colocalized with NP41 within nerve sheath, particularly perineurium, where laminin-421 is predominant. Binding assays with phage expressing NP41 confirmed binding to purified laminin-421, laminin-211, and laminin-α4. Affinity for these extracellular matrix proteins explains the striking ability of NP41 to highlight degenerated nerve "ghosts" months posttransection that are invisible to the unaided eye but retain hollow laminin-rich tubular structures.

[Immuno-oncology of head and neck tumors]. / Immunonkologie von Kopf-Hals-Tumoren.

Treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) is nowadays multidisciplinary. Therapeutic concepts include modern surgical and radiation techniques as well as systemic therapies. However, the prognosis of these patients is still poor for all stages. In the recurrent or metastatic situation after definitive therapy, there is an indication for palliative systemic treatment, whereby classical platinum-based chemotherapy and the monoclonal epidermal growth factor receptor (EGFR) antibody cetuximab are established, and immunotherapy (IO) has recently been proven a potent treatment option. In this review, the results of trials relevant for approval of checkpoint inhibitors in the palliative setting after platinum failure, as well as ongoing trials evaluating their impact as first-line treatment, in combination with definitive or adjuvant radiation, preoperatively in resectable head and neck cancers, or in combination with other IO therapeutics shall be discussed.

[The role of elective neck dissection during salvage laryngectomy - a retrospective analysis]. / Die Rolle der elektiven Neck dissection bei Salvage Laryngektomie ­ eine retrospektive Analyse.

Elective neck dissection of the N0-neck is routinely performed during salvage laryngectomy (SLE) for recurrent cancer of the larynx or hypopharynx. The therapeutic benefit of additional neck dissection must be weighed against the risk of increased morbidity. In this retrospective analysis, we assessed oncologic parameters of patients who underwent SLE with concurrent bilateral neck dissection for recurrent laryngeal or hypopharyngeal cancer. We compared these data with patients who underwent primary laryngectomy (LE) with bilateral neck dissection for laryngeal and hypopharyngeal cancer.19 patients who had undergone SLE and 83 patients after LE were included in the analysis. The majority of patients had advanced stage tumors prior to LE or primary radiation therapy, as well as advanced stage recurrent tumors prior to SLE. Prior to SLE, 5 % of all patients (n = 1) had clinically pathologic lymph nodes, compared to 47 % (n = 39) prior to LE. 17 % (n = 14) of patients with LE and bilateral neck dissection had occult lymph node metastases, compared to 5 % (n = 1) of patients who underwent SLE with bilateral neck dissection. Overall, 55 % (n = 44) of patients who underwent LE had positive cervical lymph nodes, compared to 10 % (n = 2) of SLE patients. Lymph node yield was higher in patients with LE than in SLE-patients (37.3 vs. 18.7, p < 0.001). 5-year OS was 50 % after LE and 33 % after SLE. Cervical lymph node metastases are rare in patients who undergo SLE for recurrent cancers of the larynx of hypopharynx. However, occult metastases do occur. Therefore, since SLE is the final curative therapy, additional neck dissection should be taken into consideration.

[Extracranial schwannomas of the Head and Neck: Clinical -approach based on 20 cases]. / Extrakranielle Schwannome im Kopf-Hals-Bereich: Klinische Implikationen anhand von 20 Fällen.

Background Schwannomas are rare benign tumors originating from the perineural cells forming the myelin layer in the peripheral nervous system (PNS). While well established therapeutic concepts exist for intracranial schwannomas, there is a lack of consistent clinical standards for extracranial schwannomas. Method This retrospective study describes the clinical pathway of 20 patients with histologically proven extracranial schwannomas of the head and neck. The diagnostic and therapeutic strategies for schwannomas are discussed with special emphasis on localization and functional outcome. Results Extracranial schwannomas of the head and neck region mostly originated from the facial nerve (n = 4), vagal nerve (n = 4) or sympathetic chain (n = 3). Most common symptoms were swelling (n = 12) and pain (n = 3). Preoperative imaging included MRI (n = 13), ultrasound (n = 12) and CT (n = 3). Surgical intervention was performed in 18 cases (n = 14 complete extirpation, n = 3 partial extirpation, n = 1 unknown). Regarding completely extirpated schwannomas of motor nerves (n = 10) severing the nerve of origin was more often required in patients with a preexisting functional deficit (3 out of 4 = 75 %) than in patients without preexisting deficits (2 out of 6 = 33 %). Conclusion Representing rare tumors of the head and neck region mostly originating from the facial nerve, sympathetic chain or caudal cranial nerves extracranial schwannomas require a systematic diagnostic and therapeutic approach. Postoperative functional deficits after complete extirpation must especially be anticipated in patients with a preexisting functional deficit.

Assessing the role of advanced artificial intelligence as a tool in multidisciplinary tumor board decision-making for recurrent/metastatic head and neck cancer cases - the first study on ChatGPT 4o and a comparison to ChatGPT 4.0.

Background: Recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) is characterized by a complex therapeutic management that needs to be discussed in multidisciplinary tumor boards (MDT). While artificial intelligence (AI) improved significantly to assist healthcare professionals in making informed treatment decisions for primary cases, an application in the even more complex recurrent/metastatic setting has not been evaluated yet. This study also represents the first evaluation of the recently published LLM ChatGPT 4o, compared to ChatGPT 4.0 for providing therapy recommendations. Methods: The therapy recommendations for 100 HNSCC cases generated by each LLM, 50 cases of recurrence and 50 cases of distant metastasis were evaluated by two independent reviewers. The primary outcome measured was the quality of the therapy recommendations measured by the following parameters: clinical recommendation, explanation, and summarization. Results: In this study, ChatGPT 4o and 4.0 provided mostly general answers for surgery, palliative care, or systemic therapy. ChatGPT 4o proved to be 48.5% faster than ChatGPT 4.0. For clinical recommendation, explanation, and summarization both LLMs obtained high scores in terms of performance of therapy recommendations, with no significant differences between both LLMs, but demonstrated to be mostly an assisting tool, requiring validation by an experienced clinician due to a lack of transparency and sometimes recommending treatment modalities that are not part of the current treatment guidelines. Conclusion: This research demonstrates that ChatGPT 4o and 4.0 share a similar performance, while ChatGPT 4o is significantly faster. Since the current versions cannot tailor therapy recommendations, and sometimes recommend incorrect treatment options and lack information on the source material, advanced AI models at the moment can merely assist in the MDT setting for recurrent/metastatic HNSCC.

Assessing the role of advanced artificial intelligence as a tool in multidisciplinary tumor board decision-making for primary head and neck cancer cases.

Background: Head and neck squamous cell carcinoma (HNSCC) is a complex malignancy that requires a multidisciplinary approach in clinical practice, especially in tumor board discussions. In recent years, artificial intelligence has emerged as a tool to assist healthcare professionals in making informed decisions. This study investigates the application of ChatGPT 3.5 and ChatGPT 4.0, natural language processing models, in tumor board decision-making. Methods: We conducted a pilot study in October 2023 on 20 consecutive head and neck cancer patients discussed in our multidisciplinary tumor board (MDT). Patients with a primary diagnosis of head and neck cancer were included. The MDT and ChatGPT 3.5 and ChatGPT 4.0 recommendations for each patient were compared by two independent reviewers and the number of therapy options, the clinical recommendation, the explanation and the summarization were graded. Results: In this study, ChatGPT 3.5 provided mostly general answers for surgery, chemotherapy, and radiation therapy. For clinical recommendation, explanation and summarization ChatGPT 3.5 and 4.0 scored well, but demonstrated to be mostly an assisting tool, suggesting significantly more therapy options than our MDT, while some of the recommended treatment modalities like primary immunotherapy are not part of the current treatment guidelines. Conclusions: This research demonstrates that advanced AI models at the moment can merely assist in the MDT setting, since the current versions list common therapy options, but sometimes recommend incorrect treatment options and in the case of ChatGPT 3.5 lack information on the source material.

Standardized Digital Image Analysis of PD-L1 Expression in Head and Neck Squamous Cell Carcinoma Reveals Intra- and Inter-Sample Heterogeneity with Therapeutic Implications.

For practical reasons, in many studies PD-L1 expression is measured by combined positive score (CPS) from a single tumor sample. This does not reflect the heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma (HNSCC). We investigated the extent and relevance of PD-L1 expression heterogeneity in HNSCC analyzing primary tumors and recurrences (LRs), as well as metastases. Tumor tissue from 200 HNSCC patients was immunohistochemically stained for PD-L1 and analyzed using image-analysis software QuPath v3.4 with multiple specimens per patient. CPS was ≥20 in 25.6% of primary tumors. Intra-tumoral heterogeneity led to a therapeutically relevant underestimation of PD-L1 expression in 28.7% of patients, when only one specimen per patient was analyzed. Inter-tumoral differences in PD-L1 expression between primary tumors and lymph node metastasis (LNM) or LR occurred in 44.4% and 61.5% (CPS) and in 40.6% and 50% of cases (TPS). Overall survival was increased in patients with CPS ≥ 1 vs. CPS < 1 in primary tumors and LNM (hazard ratio: 0.46 and 0.35; p < 0.005); CPS in LR was not prognostic. Our analysis shows clinically relevant intra- and inter-sample heterogeneity of PD-L1 expression in HNSCC. To account for heterogeneity and improve patient selection for immunotherapy, multiple sample analyses should be performed, particularly in patients with CPS/TPS < 1.

Surface CD52, CD84, and PTGER2 mark mature PMN-MDSCs from cancer patients and G-CSF-treated donors.

Precise molecular characterization of circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) is hampered by their mixed composition of mature and immature cells and lack of specific markers. Here, we focus on mature CD66b+CD10+CD16+CD11b+ PMN-MDSCs (mPMN-MDSCs) from either cancer patients or healthy donors receiving G-CSF for stem cell mobilization (GDs). By RNA sequencing (RNA-seq) experiments, we report the identification of a distinct gene signature shared by the different mPMN-MDSC populations under investigation, also validated in mPMN-MDSCs from GDs and tumor-associated neutrophils (TANs) by single-cell RNA-seq (scRNA-seq) experiments. Analysis of such a gene signature uncovers a specific transcriptional program associated with mPMN-MDSC differentiation and allows us to identify that, in patients with either solid or hematologic tumors and in GDs, CD52, CD84, and prostaglandin E receptor 2 (PTGER2) represent potential mPMN-MDSC-associated markers. Altogether, our findings indicate that mature PMN-MDSCs distinctively undergo specific reprogramming during differentiation and lay the groundwork for selective immunomonitoring, and eventually targeting, of mature PMN-MDSCs.

SUVmax Above 20 in 18F-FDG PET/CT at Initial Diagnostic Workup Associates with Favorable Survival in Patients with Cancer of Unknown Primary.

Cancer of unknown primary (CUP) is a heterogeneous entity with a limited prognosis. Novel prognostic markers are needed for patient stratification in prospective clinical trials exploring innovative therapies. Methods: In CUP patients treated at the West German Cancer Center Essen, the prognostic value of 18F-FDG PET/CT at the initial diagnostic workup was analyzed by comparing overall survival (OS) in patients who underwent 18F-FDG PET/CT with those who did not. Results: Of 154 patients with a CUP diagnosis, 76 underwent 18F-FDG PET/CT at the initial diagnostic workup. The median overall survival (OS) of the full analysis set was 20.0 mo. Within the PET/CT subgroup, an SUVmax above 20 was associated with significantly superior OS (median OS, not reached vs. 32.0 mo; hazard ratio, 0.261; 95% CI, 0.095-0.713; P = 0.009). Conclusion: Our retrospective work shows that an SUVmax above 20 on 18F-FDG PET/CT at the initial diagnostic workup is a favorable prognostic factor in patients with CUP. This finding deserves further prospective studies for validation.

IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes.

Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. CatchupIVM-red and Ifnar1-/- (type I IFN receptor- deficient) CatchupIVM-red mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1-/- mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.

During early stages of cancer, neutrophils initiate anti-tumor immune responses in tumor-draining lymph nodes.

Tumor-draining lymph nodes (LNs) play a crucial role during cancer spread and in initiation of anti-cancer adaptive immunity. Neutrophils form a substantial population of cells in LNs with poorly understood functions. Here, we demonstrate that, during head and neck cancer (HNC) progression, tumor-associated neutrophils transmigrate to LNs and shape anti-tumor responses in a stage-dependent manner. In metastasis-free stages (N0), neutrophils develop an antigen-presenting phenotype (HLA-DR+CD80+CD86+ICAM1+PD-L1-) and stimulate T cells (CD27+Ki67highPD-1-). LN metastases release GM-CSF and via STAT3 trigger development of PD-L1+ immunosuppressive neutrophils, which repress T cell responses. The accumulation of neutrophils in T cell-rich zones of LNs in N0 constitutes a positive predictor for 5-year survival, while increased numbers of neutrophils in LNs of N1-3 stages predict poor prognosis in HNC. These results suggest a dual role of neutrophils as essential regulators of anti-cancer immunity in LNs and argue for approaches fostering immunostimulatory activity of these cells during cancer therapy.