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Integration of high-dimensional tumor gene expression data with clinicopathological data can increase our understanding of disease diversity, enable retrospective patient stratification, and identify new potential biomarkers and therapeutic targets. Using a systems biology approach, we provide a holistic overview of gene co-expression networks in head and neck squamous cell carcinomas (HNSCC). Weighted gene co-expression network analysis of HNSCC RNA sequencing data from 519 patients from The Cancer Genome Atlas (TCGA) was used to determine correlates of 5-year survival, using regression tree-based optimal threshold calculations. Survival-associated gene sets were transformed to gene set scores that were assessed for correlation with clinicopathological data. We identified 8 gene co-expression modules for HNSCC tumors, each of which contained co-expressed genes associated significantly with 5-year survival. Survival-associated co-expression gene signatures correlated dominantly with tumor HPV and p16 status. Network analysis identified that survival was associated with signaling networks of infection, immunity, epithelial-mesenchymal transition (EMT), hypoxia, glycolysis, focal adhesion, extracellular matrix, MYC signaling, autophagy and transcriptional regulation. EMT-associated gene signatures were expressed dominantly in fibroblasts, and cancer-associated fibroblasts were inversely correlated with immune activity. Interestingly, a high Immune Suppression Score based on expression of 21 genes associated with immune inhibition and including immune checkpoints, cytokines and regulatory T cell factors, was also associated with increased survival probability, and was significantly higher in HPV+ HNSCC. Networks associated with HNSCC survival were further associated with survival in cervical cancer, melanoma and lung cancer. This study defines 5129 genes associated with HNSCC survival, organized into co-expressed networks, their correlation with clinicopathological data, and with gene expression data from other malignant diseases, and provides a source for the discovery of biomarkers and novel therapies for HNSCC.

Research has shown that electronic platforms can assist data capture of patient‐reported outcome measures (PROMs) to guide clinical care. In comparison, routine collection of carer‐reported outcome measures (CROMs) to support the patient–carer dyad during cancer treatment has had limited attention. The current study utilised a novel electronic CROM (eCROM) system, ScreenIT Carer, to monitor the prevalence and nature of distress in carers of patients undergoing (chemo)radiotherapy ((C)RT) for head/neck cancer (HNC), and explore factors associated with carer distress. Carers completed ScreenIT Carerweekly when attending patients’ (C)RT treatment sessions from planning to 2 weeks post‐treatment. ScreenIT Carerincluded the Distress Thermometer (DT) and Problem List, and a purpose‐built Mealtime‐Specific DT and Problem list. Data were first examined descriptively, then associations between demographic/treatment‐related factors and distress severity were analysed using mixed‐effects general linear modelling. 135 carers provided 434 ScreenIT Carerentries during the study period (mean entries = three/carer; yielding average adherence rate of 41% (range 11–100%)). A high prevalence of general (59%) and mealtime‐specific distress (46%) was reported by carers. Nature of distress was multifactorial, with emotional problems and the patients’ physical condition/symptoms common contributing factors. Based on multivariate analysis, tumour site, geographical location of residence and time during (C)RT when ScreenIT Carerwas completed were significant predictors of carer distress severity. Carer distress is prevalent and multifactorial during (C)RT. This study highlights the feasibility of utilising eCROM platforms such as ScreenIT Carer, to monitor carer wellbeing and guide supportive care services as part of a holistic care pathway. The current study utilised a novel electronic CROM (eCROM) system, ScreenIT Carer, to monitor prevalence and nature of distress in carers of patients undergoing (chemo)radiotherapy ((C)RT) for head/neck cancer (HNC), and explore factors associated with carer distress. Findings demonstrated that carer distress is highly prevalent and multifactorial during (C)RT. This study highlights the feasibility of utilising eCROM platforms, to monitor carer wellbeing and guide supportive care services as part of a holistic care pathway.

EGFR overexpression is associated with squamous cell carcinoma development. Altered endocytosis and polarization of receptor tyrosine kinases, including EGFR, affect migration and invasion in three-dimensional culture. These studies have been completed via genetic sequencing, cell line, or three-dimensional in vitro and in vivo murine models. Here, we describe an imaging method that allows ex vivo examination of ligand-induced endocytosis of EGFR in non-dissociated human tumors. We analyzed sets of tumor samples from advanced cutaneous squamous cell carcinoma and head and neck squamous cell carcinoma, actinic keratosis, intraepidermal carcinoma, and cutaneous squamous cell carcinoma. We show that EGFR endocytosis is dysregulated in advanced SCC and correlates with anti-EGFR monoclonal antibody therapy outcomes. In actinic keratosis, intraepidermal carcinoma, and well-differentiated cutaneous squamous cell carcinoma, different patterns of epidermal growth factor ligand uptake and binding were observed at the leading edge of different dysplastic lesions, suggesting that these differences in EGFR endocytosis might influence the metastatic potential of dysplastic squamous epithelium. These studies in live ex vivo human tumors confirm that endocytosis dysregulation is a physiological event in human tumors and has therapeutic implications.

While use of a thermoplastic mask during radiotherapy (RT) treatment for head and neck cancer (HNC) is an essential component of safe patient care, there is little understanding of the extent to which this evokes anxiety (i.e. “mask anxiety”) for the person undergoing treatment. A mixed method, convergent design was used to examine the prevalence and experience of mask anxiety using two clinical cohorts. In phase one, a cohort of 100 patients undergoing RTfor HNCwere assessed for self‐perceived mask anxiety using a modified distress thermometer screening tool. In phase two, a separate cohort of 20 patients who identified as having mask anxiety participated in individual interpretative descriptive interviews to explore the nature of their experience. In phase one, 26% of participants self‐identified as being anxious about the use of a thermoplastic mask. In phase two thematic analysis of the interviews revealed two over‐arching themes relating to the person's experience of mask anxiety: contributors to the mask anxiety (vulnerability, response to experience and expectations); and how the person was going to manage the mask anxiety during treatment (strategies and mindset). Mask anxiety impacted a quarter of participants undergoing radiotherapy for HNC. In line with the themes elicited from the participants, implementation of routine screening to ensure early identification, and patient education to assist preparation for wearing the mask during RTare strategies that could improve current management of mask anxiety. While use of a thermoplastic mask during radiotherapy (RT) treatment for head and neck cancer (HNC) is an essential component of safe patient care, there is little understanding of the extent to which this evokes anxiety (i.e. “mask anxiety”) for the person undergoing treatment. A mixed method, convergent design was used to examine the prevalence and experience of mask anxiety using two clinical cohorts. Mask anxiety impacted 26% of participants undergoing radiotherapy for HNC. In line with the themes elicited from the participants, implementation of routine screening to ensure early identification, and patient education to assist preparation for wearing the mask during RTare strategies that could improve current management of mask anxiety.

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Head and neck lymphoedema (HNL) is a persistent symptom for many patients following head and neck cancer treatment. There is limited research into the benefits of lymphoedema treatment with this population. This pilot study (n=8) employs the Assessment of Lymphoedema of Head and Neck (ALOHA) system to evaluate treatment changes in this clinical population. The ALOHA assessment combines the use of the Princess Alexandra Hospital tape measurement system and the use of Tissue Dielectric Constant (MoistureMeterD) to measure HNL. Baseline measures were taken at the start of treatment and were repeated when the participants had reduced one level on the MD Anderson Cancer Centre HNL rating scale. The MoistureMeterD and three of the four tape measurement points showed a statistically significant change over time. This indicates the ALOHA system was useful in objectively detecting changes associated with clinical improvements.

Aims:The purpose of this study was to review the treatment policy for locally advanced stage III and IV squamous cell carcinoma (SCC) of the tonsil at the Princess Alexandra Hospital Head and Neck Unit, Brisbane, Australia.

Head and neck cancer consists of a diverse group of cancers that ranges from cutaneous, lip, salivary glands, sinuses, oral cavity, pharynx and larynx. Each group dictates different management. In this review, the primary focus is on head and neck squamous cell carcinoma (HNSCC) arising from the mucosal lining of the oral cavity and pharynx, excluding nasopharyngeal cancer. Presently, HNSCC is the sixth most prevalent neoplasm in the world, with approximately 900,000 cases diagnosed worldwide. Prognosis has improved little in the past 30 years. In those who have survived, pain, disfigurement and physical disability from treatment have had an enormous psychosocial impact on their lives. Management of these patients remains a challenge, especially in developing countries where this disease is most common. Of all human cancers, HNSCC is the most distressing since the head and neck is the site of the most complex functional anatomy in the human body. Its areas of responsibility include breathing, the CNS, vision, hearing, balance, olfaction, taste, swallowing, voice, endocrine and cosmesis. Cancers that occur in this area impact on these important human functions. Consequently, in treating cancers of the head and neck, the effects of the treatment on the functional outcome of the patient need the most serious consideration. In assessing the success of HNSCC treatment, consideration of both the survival and functional deficits that the patient may suffer as a consequence of their treatment are of paramount importance. For this reason, the modern-day management of head and neck patients should be carried out in a multidisciplinary head and neck clinic.

Sinonasal undifferentiated carcinoma (SNUC) is an uncommon malignancy associated with poor prognosis. The optimal treatment approach for SNUC has not been established was performed. A retrospective review of all patients with SNUC seen at the Peter MacCallum Cancer Centre over a 12-year period. Ten patients with SNUC were identified, with nine having locally advanced disease (T4). Seven were treated with three cycles of platinum and 5-fluorouracil followed by radiation with two cycles of concurrent platinum. In these seven patients, the 2-year progress on-free survival was 43% (95% CI, 11% to 82%) and 2-year overall survival was 64% (95% CI, 23% to 91%). One patient with a T1N0 nasal cavity tumor treated with radiation alone has not relapsed. Two patients who were treated with initial surgical resection, prior to referral to our institution, received postoperative radiation, but they subsequently had relapses and died. Induction chemotherapy followed by concurrent chemoradiation is promising treatment strategy for SNUC. © 2004 Wiley Periodicals, Inc. Head Neck 26: 435–441, 2004.

The purpose of this study was to evaluate the local control, pattern of recurrence, overall survival, and prognostic factors of patients with squamous cell carcinoma (SCC), adenocarcinoma, and undifferentiated carcinoma of the paranasal sinuses (PNS) and nasal cavity (NC) presenting to our center for curative treatment over a 10-year period. Between 1991 and 2000, 60 patients with SCC (n = 32), adenocarcinoma (n = 25), and undifferentiated carcinoma (n = 3) of the PNS or NC were identified. Forty patients received surgery and postoperative radiotherapy, four surgery alone; 11, radiotherapy alone; three radical radiotherapy after surgical recurrence; one, chemoradiotherapy and surgery; and one, induction chemotherapy followed by radiotherapy. Forty-seven patients (78%) were seen with T3–4 disease; however, most (92%) were node negative on initial assessment. The predominant failure pattern was local disease persistence or recurrence. The estimated 2- and 5-year local control rates were 63% and 49%, respectively. Orbital and neural invasion significantly affected local control. The estimated 2- and 5 year overall survival rates were 57% and 40%, respectively. Local failure remains the dominant cause for poor outcome in this group of patients. Because of the proximity of critical normal structures, the ability to perform adequate surgery and to deliver effective radiotherapy is limited in many cases. The use of postoperative concurrent chemoradiotherapy warrants further investigation. © 2004 Wiley Periodicals, Inc. Head Neck 26: 322–330, 2004.

Cellular immunotherapeutics targeting the human papillomavirus (HPV)–16 E6 and E7 proteins have achieved limited success in HPV-positive oropharyngeal cancer (OPC). Here we have conducted proteome-wide profiling of HPV-16–specific T cell responses in a cohort of 66 patients with HPV-associated OPC and 22 healthy individuals. Unexpectedly, HPV-specific T cell responses from OPC patients were not constrained to the E6 and E7 antigens; they also recognized E1, E2, E4, E5, and L1 proteins as dominant targets for virus-specific CD8+ and CD4+ T cells. Multivariate analysis incorporating tumor staging, treatment status, and smoking history revealed that treatment status had the most significant impact on HPV-specific CD8+ and CD4+ T cell immunity. Specifically, the breadth and overall strength of HPV-specific T cell responses were significantly higher before the commencement of curative therapy than after therapy. These data provide the first glimpse of the overall human T cell response to HPV in a clinical setting and offer groundbreaking insight into future development of cellular immunotherapies for HPV-associated OPC patients.

ABSTRACTAdoptive T cell therapy has emerged as a powerful strategy to treat human cancers especially haematological malignancies. Extension of these therapies to solid cancers remains a significant challenge especially in the context of defining immunological correlates of clinical responses. Here we describe results from a clinical study investigating autologous Epstein-Barr virus (EBV)-specific T cells generated using a novel AdE1-LMPpoly vector to treat patients with nasopharyngeal carcinoma (NPC) either pre-emptively in at-risk patients with no or minimal residual disease (N/MRD) or therapeutically in patients with active recurrent/metastatic disease (ARMD). Tolerability, safety and efficacy, including progression-free survival (PFS) and overall survival (OS), were evaluated following adoptive T-cell immunotherapy. Twenty-nine patients, including 20 with ARMD and nine with N/MRD, successfully completed T-cell therapy. After a median follow-up of 18.5 months, the median PFS was 5.5 months (95% CI 2.1 to 9.0 months) and the median OS was 38.1 months (95% CI 17.2 months to not reached). Post-immunotherapy analyses revealed that disease stabilization in ARMD patients was significantly associated with the functional and phenotypic composition of in vitro-expanded T cell immunotherapy. These included a higher proportion of effector CD8+T-cells and an increased number of EBV-specific T-cells with broader antigen specificity. These observations indicate that adoptive immunotherapy with AdE1-LMPpoly-expanded T cells stabilizes relapsed, refractory NPC without significant toxicity. Promising clinical outcomes in N/MRD patients further suggest a potential role for this approach as a consolidation treatment following first-line chemotherapy.

Aim The aggressive nature of cutaneous SCC in CLL, specifically presentation with locally invasive, regional metastatic or loco-regionally recurrent disease, is not well documented. We describe a series of patients with CLL who have developed aggressive SCC. Methods Patients with CLL with aggressive SCC were identified from existing databases in the Department of Haematology and Oncology, Princess Alexandra Hospital, Australia from August 2001–May 2005. Patient demographics, tumour characteristics and treatment received were reviewed from the clinical records. Results We identified 12 patients with CLL with aggressive head and neck SCC: 11 locally invasive, 7 with lymph node metastases and 5 with loco-regional recurrence. The median age was 73 (range 49–88) and 9 patients were male. 8 patients were Rai stage III or IV. 8 of 9 patients with documented IgG levels had hypogammaglobulinemia (median 3.4g/L). 143 patients with CLL were seen in the hematology department during this time. The median time from CLL diagnosis to SCC development was 55 months (range 0–169). Median time from chemotherapy to aggressive SCC was 48 months (range 22–110) with alkylating agent chemotherapy (seven patients) and 12.5 months (range 1–46) with purine analogue chemotherapy (six patients). Four patients had received no treatment for CLL. All patients had extensive surgical resection and 11 had, or are planned for, post-operative radiotherapy. Five developed loco-regional recurrence at a median of 12 months (range 4–14). 10 patients had numerous SCC (>5) excised prior to the diagnosis of aggressive SCC. Conclusions The risk of patients with CLL developing aggressive cutaneous SCC, with its attendent morbidity, is underappreciated. Cellular and humoral immunodeficiencies from CLL and its chemotherapy treatment may predispose patients to aggressive SCC.

Aim