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Introduction Currently the same threshold value is used to identify a positive D-dimer result for all patients presenting to our ambulatory clinic with suspected pulmonary emboli (PE). It has been suggested that adjusting the threshold value according to the pre-test probability would exclude PE in more patients than using the same cutoff point regardless of clinical probability. Methods Data from 362 consecutive patients presenting to the ambulatory PE clinic was collected. A pre-test probability of PE was recorded for all patients and those with a high pre-test probability had radiological investigations. Patients with a low or intermediate pre-test probability had a latex agglutination D-dimer test. If this result was =0.5 µg/ml they had further investigations, otherwise they were discharged. The diagnosis of PE was made if a VQ scan showed ventilation/perfusion mismatch or CTPA report demonstrated PE. Receiver operating characteristic curve analysis was performed separately for patients with low and intermediate probability and the optimum cut-off value to exclude PE determined. Sensitivity, specificity, negative predictive value and positive predictive value for different cut-off points were determined. Results 362 patients were included in the analysis, 207 (57%) had low, 129 (36%) intermediate and 26 (7%) high pre-test probability. Prevalence of PE was 2% in the low probability group, 14% in the intermediate probability group and 42% in the high probability group. No patients with a D-dimer of <0.5 µg/ml who were discharged without further tests have re-presented with similar symptoms. In the low pre-test probability group, a cut-off point of 1.07 improved the specificity from 64% to 89% while maintaining a sensitivity of 100% and negative predictive value of 100%. Analysis in patients in the intermediate risk group suggested that a cut-off of 0.5 µg/ml was appropriate. By adjusting the D-dimer threshold to >1.0 µg/ml in the low probability group, a further 53 patients could have been discharged home without need for radiological investigation. Conclusion The diagnostic accuracy of D-dimer testing may be improved in patients with a low pre-test probability by adjusting the cut-off threshold. [ABSTRACT FROM AUTHOR]

Introduction Suspected Pulmonary Embolism (PE) is a significant cause of admission to hospital. The objective of this study was to establish the feasibility and safety of managing suspected and proven PE in an out-patient setting. Methods Criteria for low risk patients with suspected PE suitable for treatment in an ambulatory setting were established based on modified Pulmonary Embolism Severity Score (PESI) criteria. Patients deemed low risk were referred to a nurse-led clinic. Clinical pre-test probability of PE was recorded for all patients and those with a low/intermediate probability had D-dimer testing. Patients with a high pre-test probability or D-dimer=0.5 µg/ml had radiological investigations. Data were collected prospectively. Missing information was completed from pathology, imaging systems and case-note review. Results 362 patients (Median age 46, Female 70%) with suspected PE were referred to the ambulatory clinic in 12 months from June 2010. 269 (74%) patients presented with chest pain. 145 patients (40%) had a negative D-dimer and were discharged. 210 patients (58%) had subsequent imaging in the form of 65 (31%) VQ scan, 138 (66%) CT scan, 7 (3%) both. Median time to imaging was 1 day (range 0-5 days). 34 patients were diagnosed with PE (9%). 11 patients (3%) were admitted, of which 5 (45%) were due to right heart strain. Likelihood of PE correlated strongly to clinical probability (low 2%, intermediate 14%, high 42%). One patient with a negative D-Dimer and intermediate clinical probability was diagnosed with PE. 294 (81%) patients were discharged with no follow-up, 28 (8%) patients were followed-up by consultant care. One patient admitted as they did not meet criteria for ambulatory care (tachycardia) had a cardiorespiratory arrest as an inpatient due to massive PE but was successfully resuscitated. To date three patients have (0.8%) died since attending the clinic, no death was related to PE. Savings to PCTs were estimated at £120 000 over 12 months. Conclusion Selected patients with suspected and proven PE may be managed safely in an ambulatory PE clinic setting resulting in significant savings to the healthcare community. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) is the seventh most common cancer globally, resulting in 440 000 deaths per year. While there have been advancements in chemoradiotherapy and surgery, relapse occurs in more than half of HNCs, and these patients have a median survival of 10 months and a 2-year survival of < 20%. Only a subset of patients displays durable benefits from immunotherapies in metastatic and recurrent HNC, making it critical to understand the tumor microenvironment (TME) underpinning therapy responses in HNC. To recognize biological differences within the TME that may be predictive of immunotherapy response, we applied cutting-edge geospatial whole-transcriptome profiling (NanoString GeoMx Digital Spatial Profiler) and spatial proteomics profiling (Akoya PhenoCycler-Fusion) on a tumor microarray consisting of 25 cores from 12 patients that included 4 immunotherapy-unresponsive (8 cores) and 2 immunotherapy-responsive patients (5 cores), as well as 6 immunotherapy naïve patients (12 cores). Through high-plex, regional-based transcriptomic mapping of the tumor and TME, pathways involved with the complement system and hypoxia were identified to be differentially expressed in patients who went on to experience a poor immunotherapy response. Single-cell, targeted proteomic analysis found that immune cell infiltration of the cancer cell mass and interactions of CD8 T cells with tumor and other immune cells were associated with positive immunotherapy response. The relative abundance of specific tumor phenotypes and their interactions with various immune cells was identified to be different between response groups. This study demonstrates how spatial transcriptomics and proteomics can resolve novel alterations in the TME of HNC that may contribute to therapy sensitivity and resistance., (© 2024 The Author(s). Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.)

Background: In the phase 2 EMPOWER-CSCC-1 study (NCT02760498), cemiplimab demonstrated antitumor activity against metastatic cutaneous squamous cell carcinoma (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC)., Objectives: To report final analysis of weight-based cemiplimab in mCSCC and laCSCC (groups 1 and 2), fixed-dose cemiplimab in mCSCC (group 3), and primary analysis of fixed-dose cemiplimab in mCSCC/laCSCC (group 6)., Methods: Patients received cemiplimab (3 mg/kg intravenously every 2 weeks [groups 1 and 2]) or cemiplimab (350 mg intravenously [groups 3 and 6]) every 3 weeks. The primary end point was objective response rate (ORR). Duration of response (DOR) and progression-free survival (PFS) are presented per protocol, according to post-hoc sensitivity analyses that only include the period of protocol-mandated imaging assessments., Results: At 42.5 months, ORR for groups 1-3 (n = 193) was 47.2%, estimated 12-month DOR was 88.3%, and median PFS was 26.0 months. At 8.7 months, ORR for group 6 (n = 165 patients) was 44.8%; median DOR and median PFS were not reached. Serious treatment-emergent adverse event rates (grade ≥3) were groups 1-3: 31.1% and group 6: 34.5%., Limitations: Nonrandomized study, nonsurvival primary end point., Conclusion: EMPOWER-CSCC-1 provides the largest prospective data on long-term efficacy and safety for anti-programmed cell death-1 therapy in advanced CSCC., Competing Interests: Conflicts of interest Dr Hughes reports consulting/advisory roles at AstraZeneca, Bristol-Myers Squibb, Eisai, Merck, Merck Sharp & Dohme, Pfizer, and Roche; and institutional research funding from Amgen. Dr Guminski reports personal fees and advisory board and travel support from Bristol-Myers Squibb and Sun Pharma; advisory board fees from Eisai, Merck KGaA, and Pfizer; travel support from Astellas; and clinical trial unit support from PPD Australia. Dr Bowyer reports advisory board roles for Eli Lilly Australia, Ipsen, Merck Sharp & Dohme, and Sanofi; virtual meeting sponsorship from Bristol-Myers Squibb and Merck Sharp & Dohme Australia; and travel support from Merck Sharp & Dohme and AstraZeneca. Michael Migden reports honoraria and travel expenses from Regeneron Pharmaceuticals, Inc, and Sanofi; consulting fees from Feldan Therapeutics, Replimune, Stamford Pharma, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Inc, and Replimune. Dr Schmults reports steering committee membership for Castle Biosciences; steering committee membership and consultancy for Regeneron Pharmaceuticals, Inc; consultancy for Sanofi; research funding from Castle Biosciences, Genentech, Merck, Novartis, and Regeneron Pharmaceuticals, Inc; and serving as a chair for the National Comprehensive Cancer Network. Dr Khushalani reports grants and advisory board fees from Bristol-Myers Squibb, Merck, Novartis, and Regeneron Pharmaceuticals, Inc; advisory board fees from AstraZeneca (data safety monitoring committee), Castle Biosciences, Incyte (data safety monitoring committee), Instil Bio, Iovance, Jounce Therapeutics, Nektar, and Replimune; grants from Celgene, GlaxoSmithKline, HUYA, Modulation Therapeutics, and Replimune; honoraria from Genzyme, National Comprehensive Cancer Network (grant funding from general research support through Pfizer), and Nektar (study steering committee); common stock ownership of Amarin, Bellicum Pharmaceuticals, and Transenetrix; study steering committee membership for Bristol-Myers Squibb, Regeneron Pharmaceuticals, Inc, and Replimune; and travel support from Regeneron Pharmaceuticals, Inc. Dr Chang reports consulting and advisory roles with Merck, and Regeneron Pharmaceuticals, Inc; research funding from Galderma, Merck, Novartis, and Regeneron Pharmaceuticals, Inc, and consultancy for Castle Biosciences and Feldan. Dr Grob reports serving on an advisory board for Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Pfizer, Philogen, Roche, and Sanofi; and an advisory role for Bristol-Myers Squibb. Dr Lewis reports employment, stock, and other ownership interests at Regeneron Pharmaceuticals, Inc. At the time of this study, Dr Lewis was affiliated with the University of Colorado Denver Cancer Center and is now an employee of Regeneron Pharmaceuticals, Inc. Dr Day reports serving on an advisory board for Amgen, travel support from Merck; and clinical trial support (investigational medical product provision, no financial support) from AstraZeneca and Bristol-Myers Squibb. Dr Ladwa reports honoraria from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme; consulting or advisory roles for AstraZeneca, and Roche; and travel, accommodation, and expenses from Merck Sharp & Dohme. Dr Stein reports ownership of stocks/shares in Icon Group. Dr Muñoz Couselo reports serving on an advisory board for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Roche; and clinical trial participation (principal investigator) for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi. Dr Meier reports travel support, speaker’s fees, or advisor’s honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; and research funding from Novartis and Roche. Dr Hauschild reports institutional grants, speaker’s honoraria, and consultancy fees from Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Pierre Fabre, Provectus, Roche, and Novartis; institutional grants and consultancy fees from Merck Serono, Philogen, and Regeneron Pharmaceuticals, Inc; and consultancy fees from OncoSec. Dr Schadendorf reports honoraria from 4SC AG, Array BioPharma, Bristol-Myers Squibb, Immunocore, InflarxGmbH, Merck, Merck Sharp & Dohme, NeraCare GmbH, Novartis, Pierre Fabre, Pfizer, Philogen, Regeneron Pharmaceuticals, Inc, Sandoz, Sanofi, Serono, Sun Pharma, Roche/Genentech, and Ultimovacs; advisory board and consulting fees from 4SC AG, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc, Roche/Genentech, Sanofi, and Nektar; speaker fees from Bristol-Myers Squibb, Merck KgaA, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc, and Sanofi; institutional research funding from Array BioPharma/Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche; and travel/accommodation expenses from Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc, Roche/Genentech, and Sanofi. Dr Basset-Seguin reports serving as an invited speaker, advisory board member, and consultant for Galderma, Regeneron Pharmaceuticals, Inc, Sanofi, and Sun Pharma. Dr Modi reports consulting/advisory board participation for Merck, Regeneron Pharmaceuticals, Inc, and Sanofi Genzyme; and speaker bureau participation for Regeneron Pharmaceuticals, Inc, and Sanofi Genzyme. Dr Dalac-Rat reports honoraria from Bristol Myers Squibb, Merck Sharpe & Dohme, Novartis, and Sun Pharma. Dr Dunn reports advisory board participation for Merck and Regeneron Pharmaceuticals, Inc; and research support from CUE-101, Regeneron Pharmaceuticals, Inc, Replimune Pharmaceuticals, and Seagen. Dr Flatz reports research funding from Hookipa Pharma; and advisory board fees from Bristol-Myers Squibb, Novartis, Philogen, and Sanofi. Dr Mortier reports personal fees and nonfinancial support from Bristol-Myers Squibb, and Merck Sharp & Dohme, Novartis, and Roche. Dr Guégan reports consulting fees from Bristol-Myers Squibb, Janssen, and Pierre Fabre; and technical support for congress attendance from Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, and Sanofi. Dr Heinzerling reports consulting fees from Bristol-Myers Squibb, Highlight Therapeutics, Novartis, Pierre Fabre, Roche, and Sanofi; lecture fees from Astellas, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche, and Sanofi; and travel grants from Bristol-Myers Squibb, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Roche. Dr Mehnert reports advisory board fees from Bristol-Myers Squibb, Eisai, Novartis, Pliant Therapeutics, Regeneron Pharmaceuticals, Inc, and Seagen; and consultancy fees from Merck. Dr Soria-Rivas reports speaker’s honoraria from Bristol-Myers Squibb, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche Pharma, and Sanofi Aventis; and advisory board fees from Bristol-Myers Squibb, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals Inc, and Sanofi Aventis. Dr Stratigos reports advisory board or steering committee roles for Janssen, Regeneron Pharmaceuticals Inc, Roche, and Sanofi; and research support from AbbVie, Bristol Myers Squibb, Genesis Pharma, LEO Pharma, Novartis, and Pfizer. Dr Ulrich reports advisory board and speaker roles for Regeneron Pharmaceuticals Inc, Roche, Sanofi, and Sun Pharma. Dr Wong reports grant funding to institution from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, F-Star Therapeutics, Genentech, Gilead, Kura Oncology, Merck Sharp & Dohme, Pfizer, Regeneron Pharmaceuticals Inc, and TopAlliance Biosciences, and consulting fees from Blueprint Medicines, Genzyme/Sanofi, and Regeneron Pharmaceuticals Inc. Dr Beylot-Barry reports institutional research funding from Roche and speaker honoraria from Sun Pharma. Dr Bossi reports advisory board or conference honoraria for Merck, Merck Sharp & Dohme, Sanofi-Regeneron, and Sun Pharma. Dr Bugés Sánchez reports personal fees from Amgen, Merck, Novartis, and Sanofi. Dr Chandra reports honoraria from Array BioPharma, Bristol Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, and Sanofi; consulting/advisory roles for Array BioPharma, Bristol Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, and Sanofi; and institutional research funding from Bristol Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, and Sanofi. Dr Robert reports grants, personal fees, and advisory board roles for Amgen, Biothera, Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Ultimovacs. Dr Silk reports institutional research grant and funding from Biohaven Pharmaceuticals, Merck, Morphogenesis, Regeneron Pharmaceuticals, Inc, Replimune, and Shattuck Laboratories; advisory board fees from Natera, Merck and Regeneron Pharmaceuticals, Inc; consulting fees from Leerink, and royalties from UpToDate, Inc. Ms Booth and Drs, Yoo, Seebach, Lowy, and Fury report employment, stock, and other ownership interests at Regeneron Pharmaceuticals, Inc. Dr Rischin reports institutional research grant and funding from ALX Oncology, Bristol-Myers Squibb, GlaxoSmithKline, Kura Oncology, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc, Roche, and Sanofi; and uncompensated scientific committee and advisory board roles for Eisai, Bicara, GlaxoSmithKline, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc, and Sanofi. Drs Ansstas, Trabelsi, and Russell have no conflicts of interest to declare., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) generally has a poor prognosis for patients with limited treatment options. While incorporating immune checkpoint inhibitors (ICIs) has now become the standard of care, the efficacy is variable, with only a subset of patients responding. The complexity of the tumor microenvironment (TME) and the role of tertiary lymphoid structures (TLS) have emerged as critical determinants for immunotherapeutic response., Methods: In this study, we analyzed two independently collected R/M HNSCC patient tissue cohorts to better understand the role of TLS in response to ICIs. Utilizing a multi-omics approach, we first performed targeted proteomic profiling using the Nanostring GeoMx Digital Spatial Profiler to quantify immune-related protein expression with spatial resolution. This was further characterized by spatially resolved whole transcriptome profiling of TLSs and germinal centers (GCs). Deeper single-cell resolved proteomic profiling of the TLSs was performed using the Akoya Biosciences Phenocycler Fusion platform., Results: Our proteomic analysis revealed the presence of T lymphocyte markers, including CD3, CD45, and CD8, expressing cells and upregulation of immune checkpoint marker PD-L1 within tumor compartments of patients responsive to ICIs, indicative of 'hot tumor' phenotypes. We also observed the presence of antigen-presenting cells marked by expression of CD40, CD68, CD11c, and CD163 with upregulation of antigen-presentation marker HLA-DR, in patients responding to ICIs. Transcriptome analysis of TLS and GCs uncovered a marked elevation in the expression of genes related to immune modulation, diverse immune cell recruitment, and a potent interferon response within the TLS structure. Notably, the distribution of TLS-tumor distance was found to be significantly different across response groups (H = 9.28, p = 0.026). The proximity of TLSs to tumor cells was found to be a critical indicator of ICI response, implying that patients with TLSs located further from tumor cells have worse outcomes., Conclusion: The study underscores the multifaceted role of TLSs in modulating the immunogenic landscape of the TME in R/M HNSCC, likely influencing the efficacy of ICIs. Spatially resolved multi-omics approaches offer valuable insights into potential biomarkers for ICI response and highlight the importance of profiling the TME complexity when developing therapeutic strategies and patient stratification., (© 2024. The Author(s).)

Cancer systemic therapeutics and radiotherapy are often associated with dermatological toxicities that may reduce patients' quality of life and impact their course of cancer treatment. These toxicities cover a wide range of conditions that can be complex to manage with increasing severity. This review provides details on twelve common dermatological toxicities encountered during cancer treatment and offers measures for their prevention and management, particularly in the Australian/New Zealand context where skincare requirements may differ to other regions due to higher cumulative sun damage caused by high ambient ultraviolet (UV) light exposure. Given the frequency of these dermatological toxicities, a proactive phase is envisaged where patients can actively try to prevent skin toxicities.

Background: Programmed cell death ligand 1 (PD-L1) inhibitors have limited efficacy as monotherapy in patients with recurrent/metastatic (R/M) Human Papilloma Virus (HPV) oropharyngeal squamous cell carcinoma (OPSCC). A phase I study of the therapeutic HPV-16 DNA vaccine AMV002 in curatively treated patients with OPSCC demonstrated a measurable immune response against HPV while being associated with high safety and tolerability. This prospective phase Ib single centre pilot study aims to test the safety and tolerability of combined PD-L1 inhibitor, Durvalumab, with AMV002 in 12 patients with recurrent OPSCC., Methods: Participants had evidence of R/M HPV-associated OPSCC. They received three intradermal administrations of AMV002 with Durvalumab followed by Durvalumab maintenance. Safety and tolerability data was the primary endpoint. The study was conducted with ethical approval (HREC/2018/QMS/47293) in Brisbane, Australia., Findings: The most common adverse event (AE) related to vaccine administration was erythema at the injection site. There were no grade 3 or 4 vaccine related AEs. There was one presumed immune-related grade 3 elevation in lipase secondary to Durvalumab with no intervention required. No patient ceased study due to treatment-related AEs. At week 16, objective response rate was 8% (N=1) and disease control rate was 17% (N=2). At a median follow up of 25.6 (20.0-26.6) months there was one long term complete response while all other participants developed progressive disease. Of the 11 evaluated patients, 9, (82%) had E6 and/or E7-specific T cell responses to the vaccine., Conclusion: The combination of AMV002 therapeutic HPV-16 vaccine and Durvalumab was found to be safe and well tolerated with no increased safety signals generated. T cell responses to vaccine were observed but further work will be required to improve efficacy., Competing Interests: Author NF was employed by the company Jingang Medicine (Australia) Pty Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ladwa, Chandra, Woo, Finlayson, Liu, McGrath, See, Hughes, Cooper, Jackson, Dzienis, Xu, Panizza, Frazer and Porceddu.)

Background: Advanced skull base malignancies are a heterogenous subset of head and neck cancers, and management is often complex. In recent times, there has been a paradigm shift in surgical technique and the advent of novel systemic options. Our goal was to analyse the long-term outcomes of a single quaternary head and neck and skull base service., Methods: A retrospective review of 127 patients with advanced anterior skull base malignancies that were treated at our institution between 1999 and 2015 was performed. Multiple variables were investigated to assess their significance on 5 and 10-year outcomes., Results: The mean age was 60.9 (± 12.6 SD). Sixty-four percent were males and 36% were females. Ninety percent of patients had T4 disease. Median survival time was 133 months. The 5-year overall survival (OS) was 66.2%, disease-specific survival (DSS) was 74.7%, and recurrence-free survival (RFS) was 65.0%. The 10-year OS was 55.1%, DSS was 72.1%, and RFS was 53.4%. Histological type and margin status significantly affected OS & DSS., Conclusion: Surgical management of advanced skull base tumours has evolved over the last few decades at our institution with acceptable survival outcomes and complication rates. Histological diagnosis and margin status are the main predictors of survival. The addition of neoadjuvant systemic agents in current trials may improve outcomes., (© 2024 Royal Australasian College of Surgeons.)

Objectives: Globally, non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and the leading cause of cancer-related deaths. Tumor-associated circulating cells in NSCLC can have a wide variety of morphological and phenotypic characteristics, including epithelial, immunological or hybrid subtypes. The distinctive characteristics and potential clinical significance of these cells in patients with NSCLC are explored in this study., Methods: We utilised a spiral microfluidic device to enrich large cells and cell aggregates from the peripheral blood samples of NSCLC patients. These cells were characterised through high-resolution immunofluorescent imaging and statistical analysis, correlating findings with clinical information from our patient cohort., Results: We have identified varied populations of heterotypic circulating tumor cell clusters with differing immune cell composition that included a distinct class of atypical tumor-associated macrophages that exhibits unique morphology and cell size. This subtype's prevalence is positively correlated with the tumor stage, progression and metastasis., Conclusions: Our study reveals a heterogeneous landscape of circulating tumor cells and their clusters, underscoring the complexity of NSCLC pathobiology. The identification of a unique subtype of atypical tumor-associatedmacrophages that simultaneously express both tumor and immune markers and whose presence correlates with late disease stages, poor clinical outcomes and metastatic risk infers  the potential of these cells as biomarkers for NSCLC staging and prognosis. Future studies should focus on the role of these cells in the tumor microenvironment and their potential as therapeutic targets. Additionally, longitudinal studies tracking these cell types through disease progression could provide further insights into their roles in NSCLC evolution and response to treatment., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Introduction: The profile and outcomes of head and neck cancer throughout Australia has changed over the past decade. The aim of this study was to perform a population-based analysis of incidence, demographics, stage, treatments and outcomes of patients diagnosed with oropharyngeal squamous cell carcinoma (OPSCC), with a particular focus on HPV-associated disease., Methods: This was a retrospective analysis of prospectively collected data within the Queensland Oncology Repository (QOR) and analysed by the Queensland Cancer Control Analysis Team. The cohort included patients diagnosed in Queensland between 1 January 2015 and 31 December 2019. Outcome measures included incidence of new OPSCC cases, age-standardised rates (ASR) (3-year average), demographics, p16 status, stage (8th Edition American Joint Commission on Cancer), treatments, and 2- and 5-year overall survival., Results: There were 1527 newly diagnosed OPSCC, representing 96% (1527/1584) of all oropharyngeal cancers. It was the most common head and neck cancer diagnosed, with oral cavity cancer being the second most common (n = 1171). Seventy-seven percent were p16 positive (1170/1527), of which 87% (1019/1170) were male. The median age was 61 years and 49% (568/1170) presented with Stage I disease. The ASR was 6.3/100,000, representing a 144% incidence increase since 1982 (2.6/100,000). Radiotherapy was utilised in 91% of p16+ cases with 2- and 5- year overall survival of 89% and 79%, respectively., Conclusion: OPSCC is now the most common mucosal head and neck cancer diagnosed in Queensland, having surpassed oral cavity cancer. The majority are HPV-associated (p16+), presenting with early-stage disease with a favourable prognosis., (© 2024 The Authors. Journal of Medical Imaging and Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Radiologists.)

Patients with head and neck squamous cell carcinoma (HNSCC) are at a high risk of developing recurrence and secondary cancers. This study evaluates the prognostic and surveillance utilities of circulating tumour cells (CTCs) in HNSCC. A total of 154 HNSCC patients were recruited and followed up for 4.5 years. Blood samples were collected at baseline and follow-up. CTCs were isolated using a spiral microfluid device. Recurrence and death due to cancer were assessed during the follow-up period. In patients with HNSCC, the presence of CTCs at baseline was a predictor of recurrence (OR = 8.40, p < 0.0001) and death (OR= ∞, p < 0.0001). Patients with CTCs at baseline had poor survival outcomes (p < 0.0001). Additionally, our study found that patients with CTCs in a follow-up appointment were 2.5 times more likely to experience recurrence or death from HNSCC (p < 0.05) prior to their next clinical visit. Our study highlights the prognostic and monitoring utilities of CTCs' in HNSCC patients. Early identification of CTCs facilitates precise risk assessment, guiding treatment choices and ultimately enhancing patient outcomes., (© 2024. The Author(s).)

Despite the rising incidence, currently, there are no early detection methods for HPV-driven HNC (HPV-HNC). Cervical cancer studies suggest that HPV DNA methylation changes can be used as a biomarker to discriminate cancer patients from HPV-infected individuals. As such, this study was designed to establish a protocol to evaluate DNA methylation changes in HPV late genes and long control region (LCR) in saliva samples of HPV-HNC patients and HPV-positive controls. Higher methylation levels were detected in HPV late genes (L1 and L2) in both tumour and saliva samples of HPV-HNC patients compared with HPV-positive controls. Moreover, methylation patterns between tumours and corresponding saliva samples were observed to have a strong correlation (Passing-Bablok regression analysis; τ = 0.7483, P < 0.0001). Considering the differences between HNC and controls in methylation levels in late genes, and considering primer amplification efficiencies, 13 CpG sites located at L1 and L2 genes were selected for further evaluation. A total of 18 HNC saliva samples and 10 control saliva samples were assessed for the methylation levels in the selected sites. From the CpG sites evaluated statistically significant differences were identified for CpG sites at L2-CpG 6 (P = 0.0004), L1-CpG 3 (P = 0.0144), L1-CpG 2 (P = 0.0395) and L2-CpG 19 (P = 0.0455). Our pilot data indicate that higher levels of DNA methylation in HPV late genes are indicative of HPV-HNC risk, and it is a potential supplementary biomarker for salivary HPV detection-based HPV-HNC screening., (© The Author(s) 2024. Published by Oxford University Press.)

The spatial localisation of immune cells within tumours are key to understand the intercellular communications that can dictate clinical outcomes. Here, we demonstrate an analysis pipeline for highly multiplexed CODEX data to phenotype and profile spatial features and interactions in NSCLC patients that subsequently received PD1 axis immunotherapy. We found that regulatory T cells (Tregs) are enriched in non-responding patients and this was consistent with their localization within stromal and peripheral tumour-margins. Proximity-based interactions between Tregs and both monocytes (p = 0.009) and CD8 + T cells (p = 0.009) were more frequently found in non-responding patients, while macrophages were more frequently located in proximity to HLADR + tumour cells (p = 0.01) within responding patients. Cellular neighbourhoods analysis indicated that both macrophages (p = 0.003) and effector CD4 + T cells (p = 0.01) in mixed tumour neighbourhoods, as well as CD8 + T cells (p = 0.03) in HLADR + tumour neighbourhoods were associated with favorable clinical response. Evaluation of the inferred regulatory functions between immune cells relative to the tumour suggested that macrophages exhibit an immunosuppressive phenotype against both CD4 + and CD8 + T cells, and that this association scores more highly in ICI refractory patients. These spatial patterns are associated with overall survival in addition to ICI response and may thus indicate features for the functional understanding of the tumour microenvironment., (© 2024. The Author(s).)

Objectives: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials., Study Design: Retrospective observational study; review of patient records in fifteen Australian institutions., Setting, Participants: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 - 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme., Main Outcome Measures: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival., Results: A total of 286 people with advanced CSCC received ICI therapy during May 2017 - May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3-97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5-20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72-83%); progression-free survival was 65% (95% CI, 58-70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0-4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8-3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1-3.0; progression-free: aHR, 1.8; 95% CI, 1.2-2.7). Fifty-five people (19%) reported immune-related adverse events of grade 2 or higher; there were no treatment-related deaths., Conclusion: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials., (© 2024 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Background: Cardiac metastases from neuroendocrine neoplasms (NENs) are being detected with increasing frequency, although the optimal imaging strategy remains unclear. We performed a single-center retrospective study to explore the role of somatostatin receptor positron emission tomography/computed tomography (SSTR PET/CT) and cardiac magnetic resonance imaging (CMR) in NEN cardiac metastases, determine the degree of concordance between the findings of these imaging modalities, and examine the advantages and disadvantages of each imaging technique. A secondary aim was to determine if cardiac metastases were associated with adverse cardiac events during peptide receptor radionuclide therapy (PRRT)., Methods and Results: 19 patients with NEN cardiac metastases were identified. A retrospective review of electronic medical records was performed, and if available SSTR PET/CT and CMR were blindly re-reviewed by imaging specialists, documenting the number and location of cardiac metastases. All 19 patients had SSTR PET/CT, and 10/19 patients had CMR. SSTR PET/CT identified more metastases than CMR. When identified on CMR, metastases were more accurately localized. 12/19 patients received PRRT, with no cardiac adverse effects., Conclusion: SSTR PET/CT and CMR are complementary investigations in the imaging of NEN cardiac metastases. SSTR PET/CT appears more sensitive for lesion detection, and CMR offers better lesion characterization. Both investigations present useful information for the planning of treatment including PRRT, which was administered safely., (© 2023. The Author(s).)

Background: Programmed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab., Methods: In this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety., Results: Objective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported., Conclusions: Cosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile., Trial Registration Number: NCT03212404., Competing Interests: Competing interests: PC has nothing to disclose. RL has received honoraria from AstraZeneca/MedImmune, Bristol Myers Squibb Foundation, MSD, and Sanofi; has served as a consultant and/or scientific advisor for AstraZeneca/MedImmune and Roche; and has received compensation for travel, accommodations, and other expenses from MSD. DB has nothing to disclose. DLH has served as a consultant and/or scientific advisor for Checkpoint Therapeutics. MM has nothing to disclose. SA has nothing to disclose. JC has nothing to disclose. SF has nothing to disclose. AK has nothing to disclose. DRM has nothing to disclose. AM has nothing to disclose. VSh has served as a speaker for Elekta. HS has nothing to disclose. AT has nothing to disclose. M-AB-G has served as a consultant and/or scientific advisor for BMS, Eisai, MSD, Novartis, and Pierre Fabre and has received research funding from Novartis. CC has received grant/research support from AstraZeneca, Novartis, and Roche. SD has received institutional research grants from BMS and MSD; has served as a consultant and/or scientific advisor for BMS, MSD, and Pierre Fabre; and has received compensation for congress attendance from BMS and MSD. AD has nothing to disclose. OD has nothing to disclose. PK has nothing to disclose. IL has financial or non-financial interests in Agenus, BMS, Janssen, MacroGenics, MSD, Pfizer, and Roche. HM has received honoraria from BMS, Merck Serono, MSD, Novartis, and Pierre Fabre; has received institutional support from BMS, Canceropole PACA, and Société Française de Dermatologie; has served as a consultant for BMS, Merck Serono, MSD, Novartis, and Pierre Fabre; has served on a data safety monitoring board/advisory board for Novartis and Pierre Fabre; and has received travel grants from Novartis and Pierre Fabre. EM-C has served as a consultant and/or scientific advisor for MBS, MSD, Novartis, Pierre Fabre, and Sanofi; has received honoraria from MBS, MSD, Novartis, Pierre Fabre, and Sanofi; and has received compensation for travel, accommodations, and other expenses from MSD. VSr has nothing to disclose. JO is an employee of Checkpoint Therapeutics and holds stocks and other ownership interests in the company; has served in leadership roles at Checkpoint Therapeutics; and has received compensation for travel, accommodations, and other expenses from Checkpoint Therapeutics. JD has served as a consultant and/or scientific advisor for Amgen, Bayer, BeiGene, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Merck KGaA, Novartis, Novotech, Pfizer, Pierre Fabre, and Roche/Genentech; has served on a data safety monitoring board/advisory board for Boehringer Ingelheim and Pfizer; has served as a board director for Cancer Trials Australia and ANZSA; and has received institutional grant/research support from AstraZeneca/MedImmune, BeiGene, BMS, GlaxoSmithKline, Lilly, Novartis, and Roche., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint inhibitor (ICI) therapy has had limited success (<30%) in treating metastatic recurrent Head and Neck Oropharyngeal Squamous Cell Carcinomas (OPSCCs). We postulate that spatial determinants in the tumor play a critical role in cancer therapy outcomes. Here, we describe the case of a male patient diagnosed with p16 + OPSCC and extensive lung metastatic disease who failed Nivolumab and Pembrolizumab/Lenvatinib therapies. Using advanced integrative spatial proteogenomic analysis on the patient's recurrent OPSCC tumors we demonstrate that: (i) unbiased tissue clustering based on spatial transcriptomics (ST) successfully detected tumor cells and enabled the investigation of phenotypic traits such as proliferation or drug-resistance genes in the tumor's leading-edge and core; (ii) spatial proteomic imagining used in conjunction with ST (SpiCi, Spatial Proteomics inferred Cell identification) can resolve the profiling of tumor infiltrating immune cells, (iii) ST data allows for the discovery and ranking of clinically relevant alternative medicines based on their interaction with their matching ligand-receptor. Importantly, when the spatial profiles of ICI pre- and post-failure OPSCC tumors were compared, they exhibited highly similar PD-1/PD-L1 low and VEGFA high expression, suggesting that these new tumors were not the product of ICI resistance but rather of Lenvatinib dose reduction due to complications. Our work establishes a path for incorporating spatial-omics in clinical settings to facilitate treatment personalization., (© 2023. Nature Publishing Group UK.)

The composition and activation status of the cellular milieu contained within the tumour microenvironment (TME) is becoming increasingly recognized as a driving factor for immunotherapy response. Here, we employed multiplex immunohistochemistry (mIHC), and digital spatial profiling (DSP) to capture the targeted immune proteome and transcriptome of tumour and TME compartments from an immune checkpoint inhibitor (ICI)-treated (n = 41) non-small cell lung cancer (NSCLC) patient cohort. We demonstrate by mIHC that the interaction of CD68 + macrophages with PD1 + , FoxP3 + cells is enriched in ICI refractory tumours (p = 0.012). Patients responsive to ICI therapy expressed higher levels of IL2 receptor alpha (CD25, p = 0.028) within their tumour compartments, which corresponded with increased IL2 mRNA (p = 0.001) within their stroma. In addition, stromal IL2 mRNA levels positively correlated with the expression of pro-apoptotic markers cleaved caspase 9 (p = 2e -5 ) and BAD (p = 5.5e -4 ) and negatively with levels of memory marker, CD45RO (p = 7e -4 ). Immuno-inhibitory markers CTLA-4 (p = 0.021) and IDO-1 (p = 0.023) were suppressed in ICI-responsive patients. Tumour expression of CD44 was depleted in the responsive patients (p = 0.02), while higher stromal expression of one of its ligands, SPP1 (p = 0.008), was observed. Cox survival analysis also indicated tumour CD44 expression was associated with poorer prognosis (hazard ratio [HR] = 1.61, p = 0.01), consistent with its depletion in ICI-responsive patients. Through multi-modal approaches, we have dissected the characteristics of NSCLC immunotherapy treatment groups and provide evidence for the role of several markers including IL2, CD25, CD44 and SPP1 in the efficacy of current generations of ICI therapy., (© 2023 The Authors. Immunology published by John Wiley & Sons Ltd.)

Background: Despite the rising incidence, particularly of the human papillomavirus (HPV)-associated fraction of oropharyngeal cancer (OPC), there are no early detection methods for OPC. Considering the close association between saliva and head and neck cancers, this study was designed to investigate salivary micro RNA (miRNAs) associated with OPC, especially focusing on HPV-positive OPC., Methods: Saliva was collected from OPC patients at diagnosis and patients were clinically followed up ≤5 years. Salivary small RNA isolated from HPV-positive OPC patients (N = 6), and HPV-positive (N = 4) and negative controls (N = 6) were analysed by next-generation sequencing to identify dysregulated miRNAs. Discovered miRNAs were validated by quantitative PCR using two different assays in a separate cohort of patients (OPC = 91, controls = 92). The relative expression was calculated considering SNORD-96A as the normalizer. Candidate miRNAs with diagnostic and prognostic potential were evaluated by generalized logistic regression., Results: A panel consisting of nine miRNAs was identified to have the best diagnostic performance to discriminate HPV-positive OPC from HPV-positive controls (AUC- validation-1 = 94.8%, validation-2 = 98%). Further, a panel consisting of six miRNAs were identified to discriminate OPC from controls regardless of the HPV status (AUC- validation-1 = 77.2%, validation-2 = 86.7%). In addition, the downregulation of hsa-miR-7-5p was significantly associated with poor overall survival of OPC patients (HR = 0.638). A panel consisting of nine miRNAs were identified for the prediction of the overall survival of the OPC patients (log-rank test-p = 0.0008)., Conclusion: This study highlights that salivary miRNAs can play an essential role in the detection and prognostication of OPC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aims: The frailty index (FI) is one way in which frailty can be quantified. While it is measured as a continuous variable, various cut-off points have been used to categorise older adults as frail or non-frail, and these have largely been validated in the acute care or community settings for older adults without cancer. This review aimed to explore which FI categories have been applied to older adults with cancer and to determine why these categories were selected by study authors., Methods: This scoping review searched Medline, EMBASE, Cochrane, CINAHL, and Web of Science databases for studies which measured and categorised an FI in adults with cancer. Of the 1994 screened, 41 were eligible for inclusion. Data including oncological setting, FI categories, and the references or rationale for categorisation were extracted and analysed., Results: The FI score used to categorise participants as frail ranged from 0.06 to 0.35, with 0.35 being the most frequently used, followed by 0.25 and 0.20. The rationale for FI categories was provided in most studies but was not always relevant. Three of the included studies using an FI > 0.35 to define frailty were frequently referenced as the rationale for subsequent studies, however, the original rationale for this categorisation was unclear. Few studies sought to determine or validate optimum FI categorises in this population., Conclusion: There is significant variability in how studies have categorised the FI in older adults with cancer. An FI ≥ 0.35 to categorise frailty was used most frequently, however an FI in this range has often represented at least moderate to severe frailty in other highly-cited studies. These findings contrast with a scoping review of highly-cited studies categorising FI in older adults without cancer, where an FI ≥ 0.25 was most common. Maintaining the FI as a continuous variable is likely to be beneficial until further validation studies determine optimum FI categories in this population. Differences in how the FI has been categorised, and indeed how older adults have been labelled as 'frail', limits our ability to synthesise results and to understand the impact of frailty in cancer care., (© 2023. Crown.)

Mucosal head and neck squamous cell carcinoma (HNSCC) are the seventh most common cancer, with approximately 50% of patients living beyond 5 years. Immune checkpoint inhibitors (ICIs) have shown promising results in patients with recurrent or metastatic (R/M) disease, however, only a subset of patients benefit from immunotherapy. Studies have implicated the tumor microenvironment (TME) of HNSCC as a major factor in therapy response, highlighting the need to better understand the TME, particularly by spatially resolved means to determine cellular and molecular components. Here, we employed targeted spatial profiling of proteins on a cohort of pre-treatment tissues from patients with R/M disease to identify novel biomarkers of response within the tumor and stromal margins. By grouping patient outcome categories into response or non-response, based on Response Evaluation Criteria in Solid Tumors (RECIST) we show that immune checkpoint molecules, including PD-L1, B7-H3, and VISTA, were differentially expressed. Patient responders possessed significantly higher tumor expression of PD-L1 and B7-H3, but lower expression of VISTA. Analysis of response subgroups indicated that tumor necrosis factor receptor (TNFR) superfamily members including OX40L, CD27, 4-1BB, CD40, and CD95/Fas, were associated with immunotherapy outcome. CD40 expression was higher in patient-responders than non responders, while CD95/Fas expression was lower in patients with partial response (PR) relative to those with stable disease (SD) and progressive disease (PD). Furthermore, we found that high 4-1BB expression in the tumor compartment, but not in the stroma, was associated with better overall survival (OS) (HR= 0.28, p-adjusted= 0.040). Moreover, high CD40 expression in tumor regions (HR= 0.27, p-adjusted= 0.035), and high CD27 expression in the stroma (HR= 0.2, p-adjusted=0.032) were associated with better survival outcomes. Taken together, this study supports the role of immune checkpoint molecules and implicates the TNFR superfamily as key players in immunotherapy response in our cohort of HNSCC. Validation of these findings in a prospective study is required to determine the robustness of these tissue signatures., Competing Interests: NM, BC, NJ, and OB are employees of Akoya Biosciences. BH, advisory board member of Merck Sharpe and Dohme, Bristol Myers Squibb, Astra Zeneca, Pfizer, Takeda, Sanofi, Eisai. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sadeghirad, Liu, Monkman, Ma, Cheikh, Jhaveri, Tan, Warkiani, Adams, Nguyen, Ladwa, Braubach, O’Byrne, Davis, Hughes and Kulasinghe.)

Background: There are limited real world data on the IMpower150 regimen in oncogene driven tumors and central nervous system metastases; this study aims to address this gap., Materials and Methods: Retrospective analysis of patients with advanced non-small cell lung cancer treated with the IMpower150 regimen across 12 Australian sites between July 2018 and April 2021. Clinicopathologic and treatment parameters were correlated with efficacy and toxicity., Results: A total of 106 patients identified with median follow up of 8 months (range 0-72). Median age was 61 years (range 33-83), 34% Asian and 58% never-smokers. An oncogene was reported in 94 (89%) patients, EGFR in 72 (68%). At treatment commencement, 50 (47%) patients had brain metastases, 21 (20%) leptomeningeal disease (LMD) and 47 (44%) liver metastases. 27% were treatment-naïve and pemetrexed was substituted for paclitaxel in 44 (42%). The overall response rate was 51% for all patients; 52% in patients with EGFR mutations. Patients with untreated brain metastases prior to commencing IMpower150 had a similar intracranial response as those with treated brain metastases (55% vs. 53%). The median time to treatment failure and overall survival from commencement of IMpower150 was 5.7 and 11.4 months respectively for the entire cohort and 5.2 and 10.5 months in those with an EGFR sensitizing mutation. Overall survival in patients with liver, brain metastases and LMD was 11.0, 11.4, and 7.1 months respectively. No new safety signals seen., Conclusion: In this largely oncogene positive, pre-treated population the IMpower150 regimen demonstrated clinically-meaningful responses, including in patients with CNS disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Local recurrence and metastasis remain the major causes of death in head and neck cancer (HNC) patients. Circulating tumour cells (CTCs) are shed from primary and metastatic sites into the circulation system and have been reported to play critical roles in the metastasis and recurrence of HNC. Here, we explored the use of CTCs to predict the response to treatment and disease progression in HNC patients., Methods: Blood samples were collected at diagnosis from HNC patients (n = 119). CTCs were isolated using a spiral microfluidic device and were identified using immunofluorescence staining. Correlation of baseline CTC numbers to 13-week PET-CT data and multidisciplinary team consensus data were conducted., Results: CTCs were detected in 60/119 (50.4%) of treatment naïve HNC patients at diagnosis. Baseline CTC numbers were higher in stage III vs. stage I-II p16-positive oropharyngeal cancers (OPCs) and other HNCs (p = 0.0143 and 0.032, respectively). In addition, we found that baseline CTC numbers may serve as independent predictors of treatment response, even after adjusting for other conventional prognostic factors. CTCs were detected in 10 out of 11 patients exhibiting incomplete treatment responses., Conclusions: We found that baseline CTC numbers are correlated with treatment response in patients with HNC. The expression level of cell-surface vimentin (CSV) on CTCs was significantly higher in patients with persistent or progressive disease, thus providing additional prognostic information for stratifying the risk at diagnosis in HNC patients. The ability to detect CTCs at diagnosis allows more accurate risk stratification, which in the future may be translated into better patient selection for treatment intensification and/or de-intensification strategies., (© 2022. The Author(s).)

Background: Non-small cell lung cancer (NSCLC) often presents at an incurable stage, and majority of patients will be considered for palliative treatment at some point in their disease. Despite recent advances, the prognosis remains poor, with a median overall survival of 12-18 months. Liquid biopsy-based biomarkers have emerged as potential candidates for predicting prognosis and response to therapy in NSCLC patients. This pilot study evaluated whether combining circulating tumour cells and clusters (CTCs) and cell-free DNA (cfDNA) can predict progression-free survival (PFS) in NSCLC patients., Methods: CTC and cfDNA/ctDNA from advanced stage NSCLC patients were measured at study entry (T 0 ) and 3-months post-treatment (T 1 ). CTCs were enriched using a spiral microfluidic chip and characterised by immunofluorescence. ctDNA was assessed using an UltraSEEK® Lung Panel. Kaplan-Meier plots were generated to investigate the contribution of the presence of CTC/CTC clusters and cfDNA for PFS. Cox proportional hazards analysis compared time to progression versus CTC/CTC cluster counts and cfDNA levels., Results: Single CTCs were found in 14 out of 25 patients, while CTC clusters were found in 8 out of the 25 patients at T 0 . At T 1 , CTCs were found in 7 out of 18 patients, and CTC clusters in 1 out of the 18 patients. At T 0 , CTC presence and the combination of CTC cluster counts with cfDNA levels were associated with shorter PFS, p = 0.0261, p = 0.0022, respectively., Conclusions: Combining CTC cluster counts and cfDNA levels could improve PFS assessment in NSCLC patients. Our results encourage further investigation on the combined effect of CTC/cfDNA as a prognostic biomarker in a large cohort of advanced stage NSCLC patients., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of tumors. While significant progress has been made using multimodal treatment, the 5-year survival remains at 50%. Developing effective therapies, such as immunotherapy, will likely lead to better treatment of primary and metastatic disease. However, not all HNSCC tumors respond to immune checkpoint blockade therapy. Understanding the complex cellular composition and interactions of the tumor microenvironment is likely to lead to new knowledge for effective therapies and treatment resistance. In this review, we discuss HNSCC characteristics, predictive biomarkers, factors influencing immunotherapy response, with a focus on the tumor microenvironment., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Head and neck squamous cell carcinoma (HNSCC) often presents with locoregional or distant disease, despite multimodal therapeutic approaches, which include surgical resection, chemoradiotherapy, and more recently, immunotherapy for metastatic or recurrent HNSCC. Therapies often target the primary and nodal regional HNSCC sites, and their efficacy at controlling occult distant sites remains poor. While our understanding of the tumor microenvironment conducive to effective therapies is increasing, the biology underpinning locoregional sites remains unclear. Here, we applied targeted spatial proteomic approaches to primary and lymph node metastasis from an oropharyngeal SCC (OPSCC) cohort to understand the expression of proteins within tumors, and stromal compartments of the respective sites in samples of both matched and unmatched patients. In unmatched analyses of n = 43 primary and 11 nodal metastases, our data indicated that tumor cells in nodal metastases had higher levels of Ki-67, PARP, BAD, and cleaved caspase 9, suggesting a role for increased proliferation, DNA repair, and apoptosis within these metastatic cells. Conversely, in matched analyses (n = 7), pro-apoptotic markers BIM and BAD were enriched in the stroma of primary tumors. Univariate, overall survival (OS) analysis indicated CD25 in tumor regions of primary tumors to be associated with reduced survival (HR = 3.3, p = 0.003), while progesterone receptor (PR) was associated with an improved OS (HR = 0.33, p = 0.015). This study highlights the utility of spatial proteomics for delineating the tumor and stromal compartment composition, and utility toward understanding these properties in locoregional metastasis. These findings indicate unique biological properties of lymph node metastases that may elucidate further understanding of distant metastatic in OPSCC., Competing Interests: AM is employed by QCIF Bioinformatics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sadeghirad, Monkman, Mehdi, Ladwa, O’Byrne, Hughes and Kulasinghe.)

Introduction: Cancer-related fatigue (CRF) is one of the most common and debilitating adverse effects of cancer and its treatment reported by cancer survivors. Physical activity, psychological interventions and management of concurrent symptoms have been shown to be effective in alleviating CRF. This pilot randomised controlled trial (RCT) will determine the feasibility of a telehealth CRF clinic intervention (T-CRF) to implement evidence-based strategies and assess the impact of the intervention on CRF and other clinical factors in comparison to usual care., Methods and Analysis: A parallel-arm (intervention vs usual care) pilot RCT will be conducted at the Princess Alexandra Hospital in Queensland, Australia. Sixty cancer survivors aged 18 years and over, who report moderate or severe fatigue on the Brief Fatigue Inventory and meet other study criteria will be recruited. Participants will be randomised (1:1) to receive the T-CRF intervention or usual care (ie, specialist-led care, with a fatigue information booklet). The intervention is a 24-week programme of three telehealth nurse-led consultations and a personalised CRF management plan. The primary objective of this pilot RCT is to determine intervention feasibility, with a secondary objective to determine preliminary clinical efficacy. Feasibility outcomes include the identification of recruitment methods; recruitment rate and uptake; attrition; adherence; fidelity; apathy; and intervention functionality, acceptability and satisfaction. Clinical and resource use outcomes include cancer survivor fatigue, symptom burden, level of physical activity, productivity loss, hospital resource utilisation and carer's fatigue and productivity loss. Descriptive statistics will be used to report on feasibility and process-related elements additional to clinical and resource outcomes., Ethics and Dissemination: This trial is prospectively registered (ACTRN12620001334998). The study protocol has been approved by the Metro South Health and Hospital Services Human Research Ethics Committee (MSHHS HREC/2020/QMS/63495). Findings will be disseminated through peer-reviewed publications, national and international conferences and seminars or workshops., Trial Registration Number: Australian New Zealand Clinical Trials Registry ID: ACTRN12620001334998; Pre-results. Trial Version: Version 1.1. Last updated 10 December 2020., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although the majority of human papillomavirus (HPV) infections are cleared by the immune system, a small percentage of them progress to develop HPV-driven cancers. Cervical cancer studies highlight that HPV persistence and cancer risk are associated with genetic factors, especially at the human leukocyte antigen (HLA) genes. This study was conducted to investigate such associations in head and neck cancer (HNC)., Methods: In all, 192 patients with HNC and 384 controls were genotyped with the Infinium Global Screening Array (Illumina, Inc). HLA variants were imputed with SNP2HLA, and an association analysis was performed by logistic regression., Results: HPV-positive HNCs were significantly associated with single-nucleotide polymorphisms (SNPs) at DRB1&#95;32660090 (P = 1.728 × 10 -6 ) and DRB1&#95;32660116 (P = 1.728 × 10 -6 ) and with the amino acid variant DRB1&#95;11&#95;32660115 (P = 1.728 × 10 -6 ). None of these associations were observed in the HPV-negative cohort, and this suggested their specificity to convey risk for HPV-associated HNCs. In general, associations observed for HPV-negative HNC were relatively weak, and variants in the HLA-DPA1 region were the strongest among them (P = 4.531 × 10 -4 ). Several lead signals reported by previous HNC genome-wide association studies, including SNPs rs3135001 (P = .012), rs1049055 (P = .012), and rs34518860 (P = .029) and allele HLA-DQB1*06 (P = .009), were replicated in the current study. However, these associations were limited to the HPV-positive HNC group. Several cervical cancer-associated HLA variants, including SNPs rs9272143 (P = .002) and rs9271858 (P = .002) and alleles HLA-B-1501 (P = .009) and HLA-B-15 (P = .015), were also exclusively associated with HPV-positive HNC., Conclusions: HPV-positive HNC risk is associated with distinct HLA variants, and some of them are shared by both cervical cancer and HPV-positive HNC. Human papillomavirus (HPV)-positive head and neck cancer (HNC) risk is associated with distinct human leukocyte antigen variants, and some of them are shared by both cervical cancer and HPV-positive HNC., Lay Summary: Cervical cancer studies highlight that human papillomavirus (HPV)-driven cancer risk is linked with human leukocyte antigen (HLA) polymorphism. Hence, the current study was designed to investigate the HLA associations in HPV-positive and HPV-negative head and neck cancer (HNC) and compare these associations with cervical cancer. Several lead signals reported by previous HNC and cervical genome-wide association studies were replicated in the current study. However, these associations were limited to the HPV-positive HNC group, and this suggests that HPV-positive HNC risk is associated with distinct HLA variants, and some of them are shared by both cervical cancer and HPV-positive HNC., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Immune checkpoint inhibitors have shown promising antitumour activity. Application in head and neck cutaneous squamous cell carcinoma (cSCC) large nerve perineural spread (PNS) is limited., Methods: Retrospective review of 13 patients with PNS receiving anti-PD-1 therapy from September 2017 to May 2021 is presented. Primary endpoints were objective response (complete or partial response) and median time to progression, determined by Head and Neck Multi-Disciplinary Team (MDT) and independent radiology review of magnetic resonance imaging (MRI) and/or computed tomography/positron emission tomography (CT/PET)., Results: Objective response was observed in 9/13 patients (69%), with complete response in 6 (46%) and partial response in 3 patients (23%). Median time to response was 2.1 months (IQR 1.8-2.7 months). There were 3 (23%) patients with progressive disease, with median time to progression of 3.5 months. There were no grade 3-4 treatment related adverse events., Conclusions: This case series supports developing evidence for anti-PD-1 checkpoint inhibitor therapy for perineural spread, supporting future prospective clinical trials in this patient population., (© 2022 Wiley Periodicals LLC.)

The discovery of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 represents a significant breakthrough in the field of cancer immunotherapy. Therefore, humanized monoclonal antibodies, targeting these immune checkpoint proteins have been utilized successfully in patients with metastatic melanoma, renal cell carcinoma, head and neck cancers and non-small lung cancer. The US FDA has successfully approved three different categories of immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and Avelumab), and CTLA-4 inhibitor (Ipilimumab). Unfortunately, not all patients respond favourably to these drugs, highlighting the role of biomarkers such as Tumour mutation burden (TMB), PDL-1 expression, microbiome, hypoxia, interferon-γ, and ECM in predicting responses to ICIs-based immunotherapy. The current study aims to review the literature and updates on ICIs in cancer therapy.

Despite efforts to improve earlier diagnosis of non-small cell lung cancer (NSCLC), most patients present with advanced stage disease, which is often associated with poor survival outcomes with only 15% surviving for 5 years from their diagnosis. Tumour tissue biopsy is the current mainstream for cancer diagnosis and prognosis in many parts of the world. However, due to tumour heterogeneity and accessibility issues, liquid biopsy is emerging as a game changer for both cancer diagnosis and prognosis. Liquid biopsy is the analysis of tumour-derived biomarkers in body fluids, which has remarkable advantages over the use of traditional tumour biopsy. Circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) are two main derivatives of liquid biopsy. CTC enumeration and molecular analysis enable monitoring of cancer progression, recurrence, and treatment response earlier than traditional biopsy through a minimally invasive liquid biopsy approach. CTC-derived ex-vivo cultures are essential to understanding CTC biology and their role in metastasis, provide a means for personalized drug testing, and guide treatment selection. Just like CTCs, ctDNA provides opportunity for screening, monitoring, treatment evaluation, and disease surveillance. We present an updated review highlighting the prognostic and therapeutic significance of CTCs and ctDNA in NSCLC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kapeleris, Ebrahimi Warkiani, Kulasinghe, Vela, Kenny, Ladwa, O’Byrne and Punyadeera.)

Lung cancer is the leading cause of cancer morbidity and mortality worldwide and early diagnosis is crucial for the management and treatment of this disease. Non-invasive means of determining tumour information is an appealing diagnostic approach for lung cancers as often accessing and removing tumour tissue can be a limiting factor. In recent years, liquid biopsies have been developed to explore potential circulating tumour biomarkers which are considered reliable surrogates for understanding tumour biology in a non-invasive manner. Most common components assessed in liquid biopsy include circulating tumour cells (CTCs), cell-free DNA (cfDNA), circulating tumour DNA (ctDNA), microRNA and exosomes. This review explores the clinical use of circulating tumour biomarkers found in liquid biopsy for screening, early diagnosis and prognostication of lung cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Herath, Sadeghi Rad, Radfar, Ladwa, Warkiani, O’Byrne and Kulasinghe.)

Background: Frailty is prevalent in older adults with lung cancer, however the impact of frailty in this population is not well understood. The aim of this review was to evaluate the outcomes that are measured in frail older adults with lung cancer, and to determine the associations between frailty and these outcomes., Methods: A systematic online search of PubMed, EMBASE, and Cochrane databases was conducted to identify all English-language studies between January 2015 and May 2022 prospectively evaluating frailty and outcomes in older adults (median age > 65 years) with lung cancer. Studies were excluded if frailty was defined by a single domain assessment or not clearly defined. Quality was assessed using the Newcastle-Ottawa Scale., Results: Of 1891 studies screened, 16 met inclusion criteria. The median number of patients was 96 (range 26-494) and the mean age was 76.6 years. Eight different frailty assessments were used, and frailty definitions varied widely. The most frequently assessed outcomes were overall survival (n = 13,81%), treatment-related toxicity (n = 8,50%), hospitalisation (n = 5,31%), and treatment completion/discontinuation (n = 4,25%). Quality of life (n = 3,19%), function (n = 1,6%), frailty trajectory (n = 1,6%), and emergency visits (n = 1,6%) were infrequently assessed. Frailty had a strong and consistent association with mortality (Hazard Ratio range: 3.5-11.91). It was also associated with treatment-related toxicity and treatment selection. The remaining outcomes were not statistically significant., Conclusion: These data support frailty as an important predictor of mortality in older adults with lung cancer, however further research is warranted to determine the association between frailty and other meaningful endpoints for this vulnerable population., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr James Fletcher reports honorarium from Astra Zeneca. Dr Rahul Ladwa reports honorarium from Astra Zeneca, Bristol Myers Squibb and MSD, and consulting fees from Roche and Astra Zeneca. The remaining authors report no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Objectives: Attaining tumour material from lung cancer patients can be challenging with limited sample availability. Therefore, non-invasive means of assessing tumour material is becoming increasingly more important. Circulating tumour DNA (ctDNA), extracted from a blood sample is appealing for the patient, and can be performed serially over the course of treatment., Materials and Methods: Here, we describe an approach for profiling the blood samples of 103 NSCLC patients for 73 variants in ctDNA across a panel of actionable lung cancer mutations using the UltraSEEK lung Panel (Agena Biosciences)., Results: Our cross-sectional study showed tumour and blood concordance in the detection of KRAS mutations (G12C, G12D, G12A/V, G12R, G12RC, Q61H) in 17/27 (63%), EGFR mutations (e746&#95;a750del, e747&#95;A750, T790M, L861Q) in 16/20 (80%) with additional PIK3CA&#95;p545K mutations across both cohorts. In patients without reported tumour mutations, 11/56 (19.6%) presented with plasma mutations across EGFR, KRAS and PIK3CA. Where ctDNA mutations were measured longitudinally (n = 4 patients), the individual mutations mirrored the response to therapy/progression of disease., Conclusion: Whilst preliminary, this study demonstrates the utility of detecting clinically actionable mutations in the blood samples of NSCLC patients at the time of presentation, and over the course of therapy., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

PET scans using 18 F-FDG and somatostatin receptor imaging agents are both used in imaging of neuroendocrine neoplasms (NENs). We have suggested the "NETPET score," using uptake of both PET tracers, as a prognostic biomarker in NENs. The name NETPET score was suggested previously to capture the score's intent to summarize information from dual PET imaging in neuroendocrine tumors. We previously demonstrated the effectiveness of the NETPET score in gastroenteropancreatic NENs (GEPNENs). Its prognostic relevance in bronchial NENs remains undetermined. Methods: This is a retrospective multicenter study (2011-2018) assessing patients who had advanced bronchial NEN and who underwent both 18 F-FDG and 68 Ga-DOTATATE PET within 60 d of each other. The NETPET score was assigned by experienced nuclear medicine physicians and compared with other clinical data such as World Health Organization grade. The primary outcome was overall survival; NETPET score and other prognostic variables were analyzed using univariate and multivariate analyses by the Cox proportional-hazards model. Results: Thirty-eight patients were included for review. The NETPET score and histology were significantly correlated with overall survival in univariate analyses ( P = 0.003, P = 0.01). On multivariate analysis, only the NETPET score remained significant ( P = 0.03). The NETPET score was significantly associated with histologic grade ( P = 0.006, χ 2 test). Conclusion: The NETPET score is a prognostic biomarker in bronchial NENs as well as GEPNENs. Although it needs to be validated in prospective studies, it holds significant promise as a biomarker for a wide range of NENs., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Doublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a "lighter" treatment approach is limited to mono-chemotherapy plus bevacizumab in the RAS unselected population. Anti-EGFR antibodies have activity as monotherapy or in combination with chemotherapy in RAS wildtype metastatic colorectal cancer; however their role in first-line treatment in combination with 5-fluorouracil monotherapy or when given alone has not been well studied. MONARCC aims to investigate this approach in an elderly population., Methods/design: MONARCC is a prospective, open-label, multicentre, non-comparative randomised phase II trial. Eligible patients aged ≥70 with unresectable metastatic, untreated, RAS/BRAF wildtype metastatic colorectal cancer will be randomised 1:1 to receive panitumumab alone or panitumumab plus infusional 5-fluorouracil. RAS and BRAF analyses will be performed in local laboratories. Comprehensive Health Assessment and Limited Health Assessments will be performed at baseline and at 16 weeks, respectively, to assess frailty. The Patient Symptom Questionnaire and Overall Treatment Utility are to be undertaken at different timepoints to assess the impact of treatment-related toxicities and quality of life. Treatment will be delivered every 2 weeks until disease progression, unacceptable toxicity (as determined by treating clinician or patient), delay of treatment of more than 6 weeks, or withdrawal of consent. The primary end point is 6-month progression-free survival in both arms. Secondary end points include overall survival, time to treatment failure, objective tumour response rate as defined by RECIST v1.1 and safety (adverse events). Tertiary and correlative endpoints include the feasibility and utility of a comprehensive geriatric assessment, quality of life and biological substudies., Discussion: MONARCC investigates the activity and tolerability of first-line panitumumab-based treatments with a view to expand on current treatment options while maximising progression-free and overall survival and quality of life in molecularly selected elderly patients with metastatic colorectal cancer., Trial Registration: Australia New Zealand Clinical Trials Registry: ACTRN12618000233224 , prospectively registered 14 February 2018., (© 2021. The Author(s).)

Background: Cancer-related fatigue (CRF) is one of the most common and distressing symptoms in people with cancer. Although efficacy of interventions for CRF have been extensively investigated, less has been done to ensure successful translation into routine clinical practice. The aim of this systematic scoping review was to synthesise knowledge surrounding the implementation of CRF interventions, summarise the processes and outcomes of implementation strategies used, and identify opportunities for further research., Methods: PubMed, Cochrane CENTRAL, EMBASE and CINAHL databases were searched (up to December 2020). The Cochrane Effective Practice and Organisation of Care (EPOC) Group taxonomy and the RE-AIM Framework were used to guide the evaluation of implementation strategies and outcomes, respectively., Results: Six studies were included. Three used an implementation framework (PARIHS, KTA, Cullens & Adams' Implementation Guide) to guide implementation. Overall, the implementation strategies used across all studies were reported to have directly resulted in immediate changes at the clinician level (e.g., increased clinician behaviours, self-efficacy, attitudes, knowledge of CRF management). No clear relationship was found between the use of implementation models and the number or type of implementation strategies used. For outcomes, Effectiveness and Implementation were the most highly reported RE-AIM measures followed by Reach then Maintenance. Adoption was the least reported., Conclusions: Despite the high prevalence of CRF and evidence-based interventions for managing CRF, there is limited evidence informing the sustainable implementation of these interventions. This systematic scoping review emphasises the lack of quality CRF implementation studies presently available in the literature leading to a disconnect between effective CRF interventions, routine clinical care, and cancer survivors at present. This review highlights the need for robust study designs guided by established frameworks to methodically design and evaluate the implementation of CRF management interventions in the future., (© 2021. The Author(s).)

The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these immunotherapies and allowed the development of promising cancer vaccine candidates. Numerous clinical trials testing the response evoked by tumour antigens, differing in origin and nature, have shed light on the desirable target characteristics capable of inducing strong tumour-specific non-toxic responses with increased potential to bring clinical benefit to patients. Novel delivery methods, ranging from a patient's autologous dendritic cells to liposome nanoparticles, have exponentially increased the abundance and exposure of the antigenic payloads. Furthermore, growing knowledge of the mechanisms by which tumours evade the immune response has led to new approaches to reverse these roadblocks and to re-invigorate previously suppressed anti-tumour surveillance. The use of new drugs in combination with antigen-based therapies is highly targeted and may represent the future of cancer vaccines. In this review, we address the main antigens and delivery methods used to develop cancer vaccines, their clinical outcomes, and the new directions that the vaccine immunotherapy field is taking.

Background: Smoking status at point of diagnosis is not used in defining risk groups for human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) despite its prognostic value in head and neck cancer., Methods: Retrospective analysis of consecutive patients treated with chemoradiotherapy between January 2005 and July 2017 was performed with multivariable analysis to explore the impact of smoking status at diagnosis (current/former/never) on overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS)., Results: Median follow-up was 61 months. Four hundred and four patients were included. Current smokers had inferior OS versus never and former smokers [adjusted HR 2.37 (95% CI 1.26-4.45, p < 0.01) and 2.58 (95% CI 1.40-4.73, p < 0.01), respectively] and inferior PFS versus never smokers [adjusted HR 1.83 (95% CI 1.00-3.35, p = 0.04)]. Smoking status did not predict for CSS., Conclusion: Detailed smoking behavior should be considered in refining risk groups in HPV-associated OPC treated with radiotherapy and in future trial design eligibility and stratification., (© 2021 Wiley Periodicals LLC.)

Advances in immunotherapy have led to durable and long-term benefits in a subset of patients across a number of solid tumor types. Understanding of the subsets of patients that respond to immune checkpoint inhibitors at the cellular level, and in the context of their tumor microenvironment (TME) is becoming increasingly important. The TME is composed of a heterogeneous milieu of tumor and immune cells. The immune landscape of the TME can inhibit or promote tumor initiation and progression; thus, a deeper understanding of tumor immunity is necessary to develop immunotherapeutic strategies. Recent developments have focused on characterizing the TME immune contexture (type, density, and function) to discover mechanisms and biomarkers that may predict treatment outcomes. This has, in part, been powered by advancements in spatial characterization technologies. In this review article, we address the role of specific immune cells within the TME at various stages of tumor progression and how the immune contexture determinants affecting tumor growth are used therapeutically., (© 2020 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.)

The natural history of adenoid cystic carcinoma (ACC) is relentless, defined by treatment failure heralded by locoregional recurrence and distant metastatic disease. In this review, we present an update of clinical features, molecular classification, current targeted therapies, immune landscapes and novel treatment targets with their respective clinical trials. The presented results are defined by a lack of overall response rate and limited progression free survival, with restriction to stable disease. In addition, ACC is resistant to immune checkpoint inhibition due to low tumour immunogenicity and lack of PD-L1 expression. Here we present a new prospective research paradigm for ACC, including the potential to target prostate specific membrane antigen (PSMA) and the potential for manipulation of target receptors in the clinic. The presentation of this review aims to promote future research to improve response rates and outcomes for therapeutics undergoing clinical trial in ACC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Profiling the tumour microenvironment (TME) has been informative in understanding the underlying tumour-immune interactions. Multiplex immunohistochemistry (mIHC) coupled with molecular barcoding technologies have revealed greater insights into the TME. In this study, we utilised the Nanostring GeoMX Digital Spatial Profiler (DSP) platform to profile a non-small-cell lung cancer (NSCLC) tissue microarray for protein markers across immune cell profiling, immuno-oncology (IO) drug targets, immune activation status, immune cell typing, and pan-tumour protein modules. Regions of interest (ROIs) were selected that described tumour, TME, and normal adjacent tissue (NAT) compartments. Our data revealed that paired analysis ( n = 18) of matched patient compartments indicate that the TME was significantly enriched in CD27, CD3, CD4, CD44, CD45, CD45RO, CD68, CD163, and VISTA relative to the tumour. Unmatched analysis indicated that the NAT ( n = 19) was significantly enriched in CD34, fibronectin, IDO1, LAG3, ARG1, and PTEN when compared to the TME ( n = 32). Univariate Cox proportional hazards indicated that the presence of cells expressing CD3 (hazard ratio (HR): 0.5, p = 0.018), CD34 (HR: 0.53, p = 0.004), and ICOS (HR: 0.6, p = 0.047) in tumour compartments were significantly associated with improved overall survival (OS). We implemented both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy samples, and demonstrate the power of such tools for a new generation of pathology research.