Predictive Capacity of Immune-Related Adverse Events and Cytokine Profiling in Neoadjuvant Immune Checkpoint Inhibitor Trials for Head and Neck Squamous Cell Carcinoma\

OBJECTIVES: Certain low-level immune-related adverse events (irAEs) have been associated with survival benefits in patients with various solid tumors on immune checkpoint inhibitors (ICIs). We aimed to investigate the association between irAEs and response to neoadjuvant ICIs in patients with head and neck squamous cell carcinoma (HNSCC) and to identify differences in circulating cytokine levels based on irAE status. METHODS: This was a retrospective cohort study including three neoadjuvant clinical trials from July 2017 to January 2022: NCT03238365 (nivolumab ± tadalafil), NCT03854032 (nivolumab ± BMS986205), NCT03618654 (durvalumab ± metformin). The presence and type of irAEs, pathologic treatment response, and survival were compared. Canonical linear discriminant analysis (LDA) was performed to identify combinations of circulating cytokines predictive of irAEs using plasma sample multiplex assay. RESULTS: Of 113 participants meeting inclusion criteria, 32 (28.3%) developed irAEs during treatment or follow-up. Positive p16 status was associated with irAEs (odds ratio [OR] 2.489; 95% CI 1.069-6.119; p = 0.043). irAEs were associated with pathologic treatment response (OR 3.73; 95% CI 1.34-10.35; p = 0.011) and with higher OS in the combined cohort (HR 0.319; 95% CI 0.113-0.906; p = 0.032). Patients with irAEs within the nivolumab cohort had significant elevations of select cytokines pre-treatment. Canonical LDA identified key drivers of irAEs among all trials, which were highly predictive of future irAE status. CONCLUSIONS: irAEs are associated with response to neoadjuvant ICI therapy in HNSCC and can serve as clinical indicators for improved clinical outcomes. irAEs can be predicted by concentrations of several circulating cytokines prior to treatment

Predictive Capacity of Immune-Related Adverse Events and Cytokine Profiling in Neoadjuvant Immune Checkpoint Inhibitor Trials for Head and Neck Squamous Cell Carcinoma

OBJECTIVES: Certain low-level immune-related adverse events (irAEs) have been associated with survival benefits in patients with various solid tumors on immune checkpoint inhibitors (ICIs). We aimed to investigate the association between irAEs and response to neoadjuvant ICIs in patients with head and neck squamous cell carcinoma (HNSCC) and to identify differences in circulating cytokine levels based on irAE status. METHODS: This was a retrospective cohort study including three neoadjuvant clinical trials from July 2017 to January 2022: NCT03238365 (nivolumab ± tadalafil), NCT03854032 (nivolumab ± BMS986205), NCT03618654 (durvalumab ± metformin). The presence and type of irAEs, pathologic treatment response, and survival were compared. Canonical linear discriminant analysis (LDA) was performed to identify combinations of circulating cytokines predictive of irAEs using plasma sample multiplex assay. RESULTS: Of 113 participants meeting inclusion criteria, 32 (28.3%) developed irAEs during treatment or follow-up. Positive p16 status was associated with irAEs (odds ratio [OR] 2.489; 95% CI 1.069-6.119; p = 0.043). irAEs were associated with pathologic treatment response (OR 3.73; 95% CI 1.34-10.35; p = 0.011) and with higher OS in the combined cohort (HR 0.319; 95% CI 0.113-0.906; p = 0.032). Patients with irAEs within the nivolumab cohort had significant elevations of select cytokines pre-treatment. Canonical LDA identified key drivers of irAEs among all trials, which were highly predictive of future irAE status. CONCLUSIONS: irAEs are associated with response to neoadjuvant ICI therapy in HNSCC and can serve as clinical indicators for improved clinical outcomes. irAEs can be predicted by concentrations of several circulating cytokines prior to treatment

Nivolumab and ipilimumab in combination with radiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: The combination of nivolumab and ipilimumab has been approved for the treatment of multiple solid tumors. This was a phase I study investigating definitive radioimmunotherapy (RIT) with nivolumab and ipilimumab for the treatment of locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients with newly diagnosed, stage IVA-IVB SCCHN eligible for cisplatin-based chemotherapy received nivolumab (3 mg/kg every 2 weeks for a total of 17 doses) and ipilimumab (1 mg/kg every 6 weeks for a total of 6 doses) starting 2 weeks prior to radiotherapy. The primary endpoint was safety of definitive RIT. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the association of baseline programmed death-ligand 1 (PD-L1) expression as well as on-treatment changes in immune bias with treatment outcomes. RESULTS: Twenty-four patients were enrolled. With a median follow-up of 36.1 months, grade 3 or higher treatment-related adverse events were reported in 21 individuals (88%); 5 individuals developed in-field soft tissue ulceration during consolidation immunotherapy, resulting in one fatality. The 3-year PFS and OS rates were 74% (95% CI 58% to 94%) and 96% (95% CI 88% to 100%), respectively. PD-L1 combined positive score (CPS) did not correlate with death or disease progression. Decreases in extracellular vesicle PD-L1 within the concurrent RIT phase were associated with prolonged PFS (p=0.006). Also, interval decreases in circulating interleukin (IL)4, IL9, IL12, and IL17a during concurrent RIT were associated with subsequent ulceration. CONCLUSIONS: Definitive RIT with nivolumab and ipilimumab has sufficient clinical activity to support further development. Early changes in circulating biomarkers appear able to predict treatment outcomes as well as ensuing in-field soft tissue ulceration. TRIAL REGISTRATION NUMBER: NCT03162731

Spatially resolved proteomic profiling identifies tumor cell CD44 as a biomarker associated with sensitivity to PD-1 axis blockade in advanced non-small- cell lung cancer

Most patients with advanced non-small-cell lung cancer (NSCLC) fail to derive significant benefit from programmed cell death protein-1 (PD-1) axis blockade, and new biomarkers of response are needed. In this study, we aimed to discover and validate spatially resolved protein markers associated with sensitivity to PD-1 axis inhibition in NSCLC

Evolving Treatment Landscape of HER2-mutant Non-Small Cell Lung Cancer: Trastuzumab Deruxtecan and Beyond

Successful targeting of HER2-activating mutations in DESTINY-Lung02 phase II study has led to the approval of the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) as second-line treatment in patients with non-small cell lung cancer (NSCLC). Despite the impressive results, several matters need to be addressed, including the clinical activity of T-DXd in patients with disease in the central nervous system as well as the role of T-DXd in the context of HER2 overexpression. Additionally, data regarding novel agents used to target HER2 continue to accumulate. This review highlights the challenges and unanswered questions that have emerged after the approval of T-DXd in patients with HER2-mutant NSCLC

Κλινική σημασία θρομβοεμβολικής νόσου σε ασθενείς με αδενοκαρκίνωμα πνεύμονα

Εισαγωγή: Η φλεβική θρομβοεμβολική νόσος (ΦΘΕΝ) είναι μία πολύ συχνή και συχνά ασυμπτωματική επιπλοκή σε ασθενείς με καρκίνο του πνεύμονα, αγγίζοντας τις 66,7 περιπτώσεις ανά 1000 ανθρωποέτη στους ασθενείς με αδενοκαρκίνωμα. Το Khorana score κατατάσσει τους ασθενείς με καρκίνο υπό χημειοθεραπεία σε τρεις προγνωστικές υποομάδες αναλόγως του κινδύνου ανάπτυξης ΦΘΕΝ. Σκοπός: Η αναδρομική καταγραφή της ΦΘΕΝ και οι συνέπειές της και στη συνέχεια ο έλεγχος της προγνωστικής αξίας του Khorana score σε ασθενείς με αδενοκαρκίνωμα πνεύμονα υπό χημειοθεραπεία πρώτης γραμμής ή επικουρική χημειοθεραπεία. Μέθοδος: Έγινε αναδρομική μελέτη 130 συνεχών, τυχαιοποιημένων ασθενών με αδενοκαρκίνωμα πνεύμονα της Ογκολογικής Μονάδας της Γ’ Πανεπιστημιακής Παθολογικής Κλινικής του ΓΝΝΘΑ «Η Σωτηρία» μεταξύ Ιουνίου 2013 και Φεβρουαρίου 2014. Αποτελέσματα: ΦΘΕΝ παρουσιάστηκε στο 10,0% των ασθενών (7,7% εμφάνισε εν τω βάθει φλεβοθρόμβωση, 76,9% πνευμονική εμβολή και 15,4% ταυτόχρονη εν τω βάθει βλεβοθρόμβωση και πνευμονική εμβολή). Η εμφάνιση ΦΘΕΝ συσχετίστηκε με ελαττωμένη επιβίωση ως το τέλος της γραμμής θεραπείας σε στατιστικά σημαντικό επίπεδο (HR 3,24, 95% CI 1,11-9,49, p=0,032). Χαμηλότερες τιμές αιμοσφαιρίνης και υψηλότερες τιμές λευκών αιμοσφαιρίων και αιμοπεταλίων επίσης σχετίστηκαν με υψηλότερο κίνδυνο θανάτου κατά τη διάρκεια της θεραπείας σε στατιστικά σημαντικό επίπεδο. Τα ποσοστά των θρομβοεμβολικών συμβαμάτων δεν είχαν στατιστική συσχέτιση με τις διαφορετικές προγνωστικές υποομάδες των ασθενών με βάση το Khorana score. Αντιθέτως, μετάβαση από την υποομάδα ενδιάμεσου στην υποομάδα υψηλού κινδύνου καθώς και αύξηση κατά ένα πόντο στο Khorana score βρέθηκε να αυξάνει κατά 3,75 φορές και 2,25 φορές τον κίνδυνο θανάτου κατά τη θεραπεία αντίστοιχα, συσχέτιση η οποία παρέμεινε στατιστικά σημαντική και στο πολυπαραγοντικό μοντέλο ανάλυσης. Συμπεράσματα: Θρομβοεμβολικές επιπλοκές που επισυμβαίνουν στην πρώτη γραμμή χημειοθεραπείας ή στην επικουρική χημειοθεραπεία μειώνουν την επιβίωση ασθενών με αδενοκαρκίνωμα πνεύμονα. Το Khorana score αδυνατεί να προβλέψει την ανάπτυξη ΦΘΕΝ αλλά αποτελεί ανεξάρτητο προγνωστικό παράγοντα επιβίωσης μέχρι το τέλος της γραμμής θεραπείας σε ασθενείς με μη μικροκυτταρικό καρκίνο πνεύμονα αδενικού τύπου.Introduction: Venous thromboembolism (VTE) represents a common yet sometimes asymptomatic complication for patients suffering from lung cancer, with an incidence of 66.7 cases per 1000 persons per year. Khorana score has been created to separate cancer patients undergoing chemotherapy according to their risk of developing thromboembolic events. Purpose: To investigate the incidence and clinical effects of VTE and to further evaluate the predictive value of Khorana score in patients diagnosed with lung adenocarcinoma undergoing first line or adjuvant chemotherapy. Methods: Medical records of 130 lung adenocarcinoma patients receiving first line or adjuvant chemotherapy in the Oncology Unit of the Third University Department of Medicine in Sotiria General Hospital were retrospectively studied during the time period of June 2013-February 2014. Results: 10.0% of patients suffered from VTE. Thromboembolic events were significantly correlated with reduced survival during treatment period (HR 3.24; 95% CI 1.11-9.49; p=0.032). Reduced values of hemoglobin (p<0.001), increased white blood cell (p<0.001) and platelet counts (p=0.03) also raised the risk of death in lung adenocarcinoma patients receiving first line or adjuvant chemotherapy. Khorana score failed to predict VTE. In univariate analysis, the risk of death during treatment period (median 16 weeks) was 3.75 times higher in high versus intermediate risk according to Khorana score patients (95% CI 1,36-10,36; p=0,001) and 2.25 times higher per point increase in Khorana score (95% CI 1,36-3,73; p=0,002); the above results were also reproduced in multivariate analysis. Conclusions: Venous thromboembolic events happening during first line or adjuvant therapy decreased survival of lung adenocarcinoma patients in the same period of time. Khorana score failed to predict VTE but is an independent risk factor for death in lung adenocarcinoma patients receiving first line or adjuvant chemotherapy

The Role of Tinzaparin in Oncology

Current guidelines recommend low-molecular-weight heparin treatment in patients with cancer with established venous thromboembolism (VTE). The aim of this article was to study the pharmacological properties and effectiveness of tinzaparin in patients with cancer as well as its potential anticancer properties. A search of PubMed and ScienceDirect databases up to March 2016 was carried out to identify published studies that detect the properties and use of tinzaparin in oncology. Protamine sulfate partially (60% to 65%) neutralized tinzaparin’s anti-Xa activity. No dose adjustment of tinzaparin is needed even in patients with severe renal impairment and Creatinine Clearance 20 mL/min. Tinzaparin demonstrated a statistically significant decline in VTE recurrence at 1 year post the index thromboembolic event. A statistically significant reduction in minor bleeding rates was also described, whereas major bleeding events did not decrease in patients with cancer treated with tinzaparin versus those who received vitamin K antagonists. Tinzaparin treatment in patients suffering from deep vein thrombosis reduced the incidence of postthrombotic syndrome and venous ulcers. Tinzaparin’s ability to prevent both metastatic dissemination of cancer cells and tumor angiogenesis has been delineated in preclinical research. Current data show that tinzaparin is safe and efficacious either for short-term or for long-term treatment of VTE in patients with cancer. Clinical trials are needed in order to examine the utility of tinzaparin in primary prevention of VTE and validate its potential anticancer advantages exhibited in preclinical research

The Role of Genetics in Sporadic GEP-NETs: A Comprehensive Review of the Literature

Neuroendocrine tumors (NETs) are composed of a heterogeneous group of malignancies from neuroendocrine cell compartments, with roles in both the endocrine and the nervous system. The majority of NETs are gastroenteropancreatic (GEP) in origin, arising in the foregut, midgut, or hindgut. The genomic landscape of GEP-NETs has been scarcely studied in terms of genomic profiling.The following algorithm was followed using the keywords neuroendocrine, genomics, targeted therapy, personalized medicine, gastroenteropancreatic and NET. The search was performed in PubMed and ScienceDirect database. Our current knowledge of sporadic GEP-NETs genetics must be further advanced to elucidate the molecular basis and pathogenesis of the disease, improve the accuracy of diagnosis, and guide tailor-made therapies

The Role of B Cells in Head and Neck Cancer

Host immunity has established its role in deciding the course of cancer evolution. As cellular and molecular components in the tumor microenvironment peripherally appear to be at a constant interplay, favoring either tumor control or progression, it is vital to decrypt the immunity elements, which demonstrate the potential to be harnessed towards cancer elimination. Head and neck cancer has been characterized as densely immune infiltrated but at the same time a highly immunosuppressive malignancy due to a negative equilibrium between active and dysfunctional immune cell populations. B-cells constitute the cornerstone of humoral immunity; however, their role in cancer has been vastly overlooked in comparison to other immune subtypes and reports from multiple studies fail to show agreement on their prognostic impact. This review focuses on the role of B-cells on head and neck cancer with the aim to highlight their effect on anti-cancer immunity, as well as their possible impact on immunotherapy outcomes. Head and neck cancer comprises a heterogenous, highly immune infiltrated malignancy, defined by a predominantly immunosuppressive tumor microenvironment (TME). In recent years, PD-1/PD-L1 immune checkpoint inhibitors have become the standard of care treatment, either as monotherapy or in combination with chemotherapy agents, thus revolutionizing the therapeutic landscape of recurrent/metastatic disease. As a result, preclinical research is increasingly focusing on TME composition and pathophysiology, aiming to comprehensively characterize the specific elements and interactions affecting anti-tumor immunity, as well as to unveil novel predictive biomarkers of immunotherapy outcomes. While T lymphocytic populations have been vastly explored regarding their effect on cancer development, B-cells constitute a far less investigated, yet possibly equally important, aspect of cancer immunity. B-cell presence, either as single cells or as part of tertiary lymphoid structures within the TME, has been associated with several anti-tumor defense mechanisms, such as antigen presentation, antibody production and participation in antibody-dependent cellular cytotoxicity, and has demonstrated prognostic significance for multiple types of malignancies. However, immunoregulatory B-cell phenotypes have also been identified both peripherally and within malignant tissue, bearing inhibitory effects on numerous immune response processes. Consequently, B-cells and their subsets demonstrate the potential to become valuable cancer biomarkers and acquire a leading role in future therapeutic strategies

HER2 Aberrations in Non-Small Cell Lung Cancer: From Pathophysiology to Targeted Therapy

While human epidermal growth factor receptor 2 (HER2) aberrations have long been described in patients with non-small cell lung cancer (NSCLC), they have only recently been effectively targeted. Unlike patients with breast cancer, NSCLC patients can harbor either HER2-activating mutations or HER2 amplification coupled with protein overexpression. The latter has also been the case for patients with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). As preclinical data continue to accumulate, clinical trials evaluating novel agents that target HER2 have produced promising preliminary results. Here, we review existing data on HER2 aberrations in NSCLC. Starting from HER2 biology in normal and disease processes, we summarize discrepancies in HER2 diagnostic assays between breast cancer and NSCLC. Finally, to dissect the therapeutic implications of HER2-activating mutations versus gene amplification and/or protein overexpression, we present data from prospective clinical trials that have employed distinct classes of agents to target HER2 in patients with NSCLC