Publications by authors named "Bruce Ashford"

43 Publications

Assessment of post-surgical donor-site morbidity in vastus lateralis free flap for head and neck reconstructive surgery: An observational study.

ANZ J Surg 2021 Sep 3. Epub 2021 Sep 3.

Illawarra Shoalhaven Local Health District, Wollongong Hospital, Wollongong, New South Wales, Australia.

Background: Vastus lateralis (VL) can be used to reconstruct defects of the head and neck. Whilst the advantages are documented, donor-site morbidity is not well described. This study aimed to assess donor-site morbidity after VL flap harvest. Results will determine future directions for preventative and post-operative care to improve patient health outcomes.

Methods: Ten participants (mean age 55 years) were assessed for the presence of donor-site morbidity after VL harvest. Musculoskeletal (pain, muscle strength, muscle length and tactile sensation), quality of life (SF-12), lower extremity function, gait (function and speed) and sit to stand were assessed using validated and standardized procedures. The outcomes were compared to age-matched healthy reference values or to the non-operative side. Analyses were conducted using descriptive statistics and non-parametric tests.

Results: There was no difference in muscle strength (knee extension), muscle length, ability to sit-to-stand, or gait function (all P > 0.05). Knee flexor muscle strength was significantly less on the operated leg compared to the non-operated leg (P = 0.02) and walking speed was slower than age-matched healthy values (P < 0.001). Thigh tactile sensation was impaired in 89% of participants. Quality of life was significantly less for the physical health component of the SF-12 (P < 0.001). The mental health component of the SF-12 was similar to healthy controls (P = 0.256).

Conclusion: There was no effect on donor site morbidity with regards to knee extensor strength, pain, walking function, ability to sit-to-stand and muscle length. VL harvest affected donor-site knee flexion strength, walking speed, tactile sensation and physical health-related quality of life.
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http://dx.doi.org/10.1111/ans.17187DOI Listing
September 2021

Demystifying emerging bulk RNA-Seq applications: the application and utility of bioinformatic methodology.

Brief Bioinform 2021 Jul 30. Epub 2021 Jul 30.

University of Wollongong, Wollongong, Australia.

Significant innovations in next-generation sequencing techniques and bioinformatics tools have impacted our appreciation and understanding of RNA. Practical RNA sequencing (RNA-Seq) applications have evolved in conjunction with sequence technology and bioinformatic tools advances. In most projects, bulk RNA-Seq data is used to measure gene expression patterns, isoform expression, alternative splicing and single-nucleotide polymorphisms. However, RNA-Seq holds far more hidden biological information including details of copy number alteration, microbial contamination, transposable elements, cell type (deconvolution) and the presence of neoantigens. Recent novel and advanced bioinformatic algorithms developed the capacity to retrieve this information from bulk RNA-Seq data, thus broadening its scope. The focus of this review is to comprehend the emerging bulk RNA-Seq-based analyses, emphasizing less familiar and underused applications. In doing so, we highlight the power of bulk RNA-Seq in providing biological insights.
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http://dx.doi.org/10.1093/bib/bbab259DOI Listing
July 2021

Gene expression profiling of perineural invasion in head and neck cutaneous squamous cell carcinoma.

Sci Rep 2021 Jun 23;11(1):13192. Epub 2021 Jun 23.

School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia.

Perineural invasion (PNI) is frequently associated with aggressive clinical behaviour in head and neck cutaneous squamous cell carcinoma (HNcSCC) leading to local recurrence and treatment failure. This study evaluates the gene expression profiles of HNcSCC with PNI using a differential expression analysis approach and constructs a tailored gene panel for sensitivity and specificity analysis. 45 cases of HNcSCC were stratified into three groups (Extensive, Focal and Non PNI) based on predefined clinicopathological criteria. Here we show HNcSCC with extensive PNI demonstrates significant up- and down-regulation of 144 genes associated with extracellular matrix interactions, epithelial to mesenchymal transition, cell adhesion, cellular motility, angiogenesis, and cellular differentiation. Gene expression of focal and non PNI cohorts were indistinguishable and were combined for further analyses. There is clinicopathological correlation between gene expression analysis findings and disease behaviour and a tailored panel of 10 genes was able to identify extensive PNI with 96% sensitivity and 95% specificity.
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http://dx.doi.org/10.1038/s41598-021-92335-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222302PMC
June 2021

Targeted ordering of investigations reduces costs of treatment for surgical inpatients.

Int J Qual Health Care 2021 May;33(2)

Department of Surgery, Wollongong Public Hospital, 252 Loftus Street, Wollongong, NSW 2500, Australia.

Background: Laboratory testing forms an important part of diagnostic investigation in modern medicine; however, the overuse of 'routine blood tests' can result in significant potential harm and financial cost to the patient and the healthcare system. In 2018, a new protocol targeting the ordering of investigations was implemented within the General Surgical Teams of Wollongong Hospital in New South Wales, an Australian tertiary referral hospital, to reduce the number of 'routine blood tests' as a quality improvement initiative.

Objective: To identify whether there was a reduction in the number of 'routine blood tests' and associated costs following implementation of the new protocol.

Methods: The protocol involved regular review of the laboratory investigations being ordered for the following day with a senior team member. The medical records of all patients admitted under the general surgery service at Wollongong Hospital were retrospectively reviewed over two 10-week periods in 2017 and 2018 (control and study, respectively). The casemix was categorized into Minor, Intermediate, Major or Unscored, depending on case complexity coding.

Results: A total of 838 patients were identified during the control period (2017) and 805 patients were identified during the study period (2018). Ten thousand and thirty tests were included in the control period, compared to 8610 over the study period, resulting in a 16% (or greater) reduction in 'routine blood tests' per patient, per day of admission and a 6% reduction in costs in the study group (P < 0.001).

Conclusion: Targeted ordering of investigations with personalized education and feedback to junior staff during review of clinical status of each patient as a part of normal workflow can reduce inappropriate ordering of 'routine blood tests' and associated costs to the patient and the healthcare system.
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http://dx.doi.org/10.1093/intqhc/mzab083DOI Listing
May 2021

The experience of nutritional care according to patients with head and neck cancer involved with a combined dietitian, specialist nurse and speech pathologist clinic in a regional Australia: a qualitative longitudinal study.

Support Care Cancer 2021 Aug 7;29(8):4329-4337. Epub 2021 Jan 7.

Wollongong Hospital, Illawarra Shoalhaven Local Health District, Wollongong, NSW, 2500, Australia.

Purpose: Malnutrition is a co-morbidity of head and neck cancer (HNC) that has negative consequences for patients. Evidence-based guidelines (EBGs) provide recommendations to prevent and manage malnutrition. A clinic that combines the services of a dietitian, specialist oncology nurse and speech pathologist may promote the implementation of nutritional EBGs in regional Australia. This study aimed to explore the nutritional care experience that patients with HNC had in this setting.

Methods: A qualitative longitudinal study collected data via semi-structured interviews with HNC patients who were treated in one regional cancer care network in Australia. Interviews were conducted at key points in their HNC journey from diagnosis to 4 months post-radiotherapy. Data was analysed using a grounded theory approach.

Results: Ten participants completed a total of thirty-six interviews. The findings were grouped into four categories: "preparing for nutritional challenges", "multidisciplinary care directed by patient needs", "the battle to eat", and "incongruence between patient values and nutritional priorities".

Conclusion: These findings highlight the nutritional burden associated with HNC and barriers to patients accepting nutritional support from healthcare professionals. Information provided by doctors and nurses prior to treatment may help patients prepare for the nutritional challenges ahead and accept support from dietitians. Furthermore, clinics that promote continuity through treatment and allow dietitians to lead aspects of nutritional care, in collaboration with nurses, speech pathologists and doctors, may also enhance the nutritional care experience. More qualitative research within HNC teams would provide further insight on enhancing the implementation of nutritional EBGs to improve outcomes for these patients.
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http://dx.doi.org/10.1007/s00520-020-05917-9DOI Listing
August 2021

Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities.

Int J Mol Sci 2020 Dec 15;21(24). Epub 2020 Dec 15.

Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer. Most patients who develop metastases (2-5%) present with advanced disease that requires a combination of radical surgery and adjuvant radiation therapy. There are few effective therapies for refractory disease. In this study, we describe novel patient-derived cell lines from cSCC metastases of the head and neck (designated UW-CSCC1 and UW-CSCC2). The cell lines genotypically and phenotypically resembled the original patient tumor and were tumorogenic in mice. Differences in cancer-related gene expression between the tumor and cell lines after various culturing conditions could be largely reversed by xenografting and reculturing. The novel drug susceptibilities of UW-CSCC1 and an irradiated subclone UW-CSCC1-R to drugs targeting cell cycle, PI3K/AKT/mTOR, and DNA damage pathways were observed using high-throughput anti-cancer and kinase-inhibitor compound libraries, which correlate with either copy number variations, targetable mutations and/or the upregulation of gene expression. A secondary screen of top hits in all three cell lines including -targeting drugs supports the utility of targeting the PI3K/AKT/mTOR pathway in this disease. UW-CSCC cell lines are thus useful preclinical models for determining targetable pathways and candidate therapeutics.
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http://dx.doi.org/10.3390/ijms21249536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765308PMC
December 2020

Gallstone Ileus Decades after Cholecystectomy and Pylorus-Preserving Whipples.

Case Rep Surg 2020 27;2020:8866254. Epub 2020 Nov 27.

Division of Surgery, Wollongong Hospital, Illawarra Shoalhaven Local Health District, Wollongong NSW, Australia.

We report a case of small bowel obstruction due to gallstone ileus found in a patient with previous pancreaticoduodenectomy (Whipple procedure). Investigation by computed tomography of the abdomen showed a transition point in the midjejunum due to a radioopaque intraluminal mass. Following resuscitation, the patient underwent laparotomy to remove the offending mass from the midjejunum. Subsequent stone analysis confirmed a cholesterol-rich gallstone. This is thus the first description of gallstone ileus following Whipple procedure. The rarity of this presentation and a literature review is presented.
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http://dx.doi.org/10.1155/2020/8866254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718047PMC
November 2020

Thulium oxide nanoparticles as radioenhancers for the treatment of metastatic cutaneous squamous cell carcinoma.

Phys Med Biol 2020 11 5;65(21):215018. Epub 2020 Nov 5.

Illawarra Health and Medical Research Institute (IHMRI), Wollongong, NSW 2522, Australia. School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia. Centre for Oncology Education and Research Translation (CONCERT), NSW 2170, Australia.

Metastases from cutaneous squamous cell carcinoma (cSCC) occur in 2%-5% of cases. Surgery is the standard treatment, often combined with adjuvant radiotherapy. Concurrent carboplatin treatment with post-operative radiotherapy may be prescribed, although it has not shown benefit in recent clinical trials in high-risk cSCC patients. The novel high-Z nanoparticle thulium (III) oxide has been shown to enhance radiation dose delivery to brain tumors by specific uptake of these nanoparticles into the cancerous tissue. As the dose-enhancement capacity of thulium oxide nanoparticles following radiotherapy against metastatic cSCC cells is unknown, its efficacy as a radiosensitizer was evaluated, with and without carboplatin. Novel and validated human patient-derived cell lines of metastatic cSCC were used. The sensitivity of the cells to radiation was investigated using short-term proliferation assays as well as clonogenic survival as the radiobiological endpoint. Briefly, cells were irradiated with 125 kVp orthovoltage x-rays (0-6 Gy) with and without thulium oxide nanoparticles (99.9% trace metals basis; 50 µg ml) or low dose carboplatin pre-sensitization. Cellular uptake of the nanoparticles was first confirmed by microscopy and found to have no impact on short-term cell survival for the cSCC cells, highlighting the biocompatibility of thulium oxide nanoparticles. Clonogenic cell survival assays confirmed radio-sensitization when exposed to thulium nanoparticles, with the cell sensitivity increasing by a factor of 1.24 (calculated at the 10% survival fraction) for the irradiated cSCC cells. The combination of carboplatin with thulium oxide nanoparticles with irradiation did not result in significant further reductions in survival compared to nanoparticles alone. This is the first study to provide in vitro data demonstrating the independent radiosensitization effect of high-Z nanoparticles against metastatic cSCC with or without carboplatin. Further preclinical investigations with radiotherapy plus high-Z nanoparticles for the management of metastatic cSCC are warranted.
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http://dx.doi.org/10.1088/1361-6560/abaa5dDOI Listing
November 2020

Chimeric Vastus Lateralis and Anterolateral Thigh Flap for Restoring Facial Defects and Dynamic Function following Radical Parotidectomy.

Plast Reconstr Surg 2019 11;144(5):853e-863e

From the Faculty of Medicine and the Central Clinical School, University of Sydney; Department of Head and Neck Surgery and Sydney Facial Nerve Service, The Chris O'Brien Lifehouse; the Illawarra Health and Medical Research Institute; and the Centre for Oncology Education and Research Translation.

Background: Extirpation of malignant tumors of the parotid results in creation of a complex facial defect often in combination with facial nerve palsy. This study presents the authors' experience using vastus lateralis muscle as a chimeric flap with anterolateral thigh flap to allow both soft-tissue reconstruction and dynamic reanimation in radical parotidectomy.

Methods: A retrospective review of the medical records of cancer patients who had undergone radical parotidectomy and reconstruction using a chimeric vastus lateralis and anterolateral thigh flap between March of 2013 and May of 2017 was performed using the Sydney Head and Neck Cancer Institute database. The return of dynamic midface movement was the primary outcome investigated. Electronic, clinician-graded facial function scale grades were used to formally assess postoperative outcomes.

Results: A total of 27 patients were included in the study with an average age of 72 years (range, 31 to 88 years). Thirteen patients (48 percent) had developed dynamic function by the end of the study period. Young age predicted a more rapid return to dynamic function (p = 0.018). Both being a woman and having an intact facial nerve before surgery improved dynamic midface movement (p = 0.005 and p = 0.036, respectively). On multivariable analysis, superior midface dynamic function was associated with neurotization using midface facial nerve branches as opposed to using nerve-to-masseter alone (p = 0.05).

Conclusion: The chimeric vastus lateralis and anterolateral thigh flap is a suitable option for restoring defects and dynamic function following radical parotidectomy.

Clinical Question/level Of Evidence: Therapeutic, IV.
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http://dx.doi.org/10.1097/PRS.0000000000006183DOI Listing
November 2019

Sentinel Node Biopsy in 105 High-Risk Cutaneous SCCs of the Head and Neck: Results of a Multicenter Prospective Study.

Ann Surg Oncol 2019 Dec 3;26(13):4481-4488. Epub 2019 Oct 3.

Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia.

Background: Regional nodal metastases from cutaneous squamous cell carcinoma (cSCC) is strongly associated with a poor prognosis, but these metastases are difficult to predict clinically. Sentinel node biopsy (SNB) has been used for a wide range of malignancies to assess for regional nodal metastasis, but is not widely used for cSCC.

Methods: Patients presenting with high-risk cSCC of the head and neck with clinically N0 necks were offered SNB at the time of primary cSCC excision or secondary wide local excision. Patients with positive sentinel nodes were offered completion lymph node dissection, and all the patients were followed up at regular intervals for up to 5 years.

Results: In this study, 105 lesions underwent SNB, and 10 sentinel nodes (9.5%) were positive. In an additional five patients, regional recurrence developed after a negative sentinel node, with a total subclinical nodal metastasis rate of 14.3%. Nodal metastases were significantly associated with reduced disease-specific survival. The significant predictors of metastasis were four or more high-risk features or tumors with a concurrent invasion deeper than 5 mm and PNI.

Conclusion: For high-risk cSCC, SNB is a safe and feasible staging technique. The total number of high risk features and certain combinations of high-risk features predicted metastasis better than individual high-risk features.
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http://dx.doi.org/10.1245/s10434-019-07865-zDOI Listing
December 2019

Is high-risk cutaneous squamous cell carcinoma of the head and neck a suitable candidate for current targeted therapies?

J Clin Pathol 2020 Jan 12;73(1):17-22. Epub 2019 Jul 12.

Molecular and Clinical Genetics, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

Objective: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy, most frequently affecting the head and neck. Treatment often requires surgery and can have significant functional morbidity. Research into disease pathogenesis and second line medical management of cSCC is limited. We assess genetic mutations in high-risk, primary head and neck cutaneous squamous cell carcinomas (HNcSCC) that may hinder or be beneficial for use of targeted therapy in disease management.

Methods: Genetic alterations and variant allele frequencies (VAFs) were analysed using a clinically relevant 48 gene panel in 10 primary high-risk non-metastatic treatment-naïve HNcSCC to evaluate applicability of targeted therapeutics. Variants present at all VAFs were evaluated for pathogenicity. Somatic mutation patterns of individual tumours were analysed.

Results: High-risk HNcSCC showed a high proportion (82%) of C to T transitions in keeping with ultraviolet-mediated damage. There was significant intratumour genetic heterogeneity in this cohort (MATH scores 20-89) with the two patients <45 years of age showing highest intratumour heterogeneity. was altered at VAF >22% in all cases, and mutations with highest VAF were observed in tumour suppressor genes in 80%. 70% of cases demonstrated at least one mutation associated with treatment resistance ( S821F, T670I, mutations at codons 12 and 13).

Conclusion: We demonstrate high proportion tumour suppressor loss of function mutations, high intratumour genetic heterogeneity, and presence of well recognised resistance mutations in treatment naïve primary HNcSCC. These factors pose challenges for successful utilisation of targeted therapies.
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http://dx.doi.org/10.1136/jclinpath-2019-206038DOI Listing
January 2020

Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma.

J Invest Dermatol 2019 07 23;139(7):1449-1458.e1. Epub 2019 Jan 23.

Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, Australia; Children's Cancer Institute, Kensington, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Sydney, Australia.

Cutaneous squamous cell carcinoma from the head and neck typically metastasize to the lymph nodes of the neck and parotid glands. When a primary is not identified, they are difficult to distinguish from metastases of mucosal origin and primary salivary gland squamous cell carcinoma. UV radiation causes a mutation pattern that predominantly features cytosine to thymine transitions at dipyrimidine sites and has been associated with cutaneous squamous cell carcinoma. In this study, we used whole genome sequencing data from 15 cutaneous squamous cell carcinoma metastases and show that a UV mutation signature is pervasive across the cohort and distinct from mucosal squamous cell carcinoma. The mutational burden was exceptionally high and concentrated in some regions of the genome, especially insulator elements (mean 162 mutations/megabase). We therefore evaluated the likely impact of UV-induced mutations on the dipyrimidine-rich binding site of the main human insulator protein, CCCTC-binding factor, and the possible implications on CCCTC-binding factor function and the spatial organization of the genome. Our findings suggest that mutation signature analysis may be useful in determining the origin of metastases in the neck and the parotid gland. Furthermore, UV-induced DNA damage to insulator binding sites may play a role in the carcinogenesis and progression of cutaneous squamous cell carcinoma.
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http://dx.doi.org/10.1016/j.jid.2019.01.008DOI Listing
July 2019

Prognostic implications of the 8th edition American Joint Committee on Cancer (AJCC) staging system in oral cavity squamous cell carcinoma.

Oral Oncol 2018 10 4;85:82-86. Epub 2018 Sep 4.

Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia; Central Clinical School, University of Sydney, Sydney, Australia; South West Clinical School, University of New South Wales, Sydney, Australia.

Background: The American Joint Committee on Cancer (AJCC) has changed the staging system of oral squamous cell carcinoma (OSCC) in the 8th edition of its staging manual to include depth of invasion (DOI) of the primary tumor as a modifier to the T category and extranodal extension (ENE) to upstage node positive OSCC. This study aims to evaluate the performance of the AJCC 8 pathologic staging system in OSCC and compare it to its predecessor (AJCC 7).

Methods: Analysis of 663 patients with OSCC from a prospective database was performed using the Cox proportional hazards competing risk model. The prognostic performance of the pathologic staging system was assessed using the Akaike Information Criterion (AIC) and Harrell's concordance index (C-index).

Results: AJCC 8 led to upstaging of 35.6% (N = 235) of patients in this cohort. Both AJCC 7 and 8 show limited monotonicity and poor stratification between stage groups I to III. The estimates for model performance reveal that AJCC 8 has modest predictive capacity for overall survival (OS) and disease specific survival (DSS) (Harrell's C of 0.70 and 0.74, respectively) but is superior to AJCC 7 (Harrell's C of 0.65 and 0.69, respectively).

Conclusions: The AJCC 8 staging system is more complex than its former version due to the inclusion of DOI and ENE. Compared with AJCC 7, it performs better in stratifying survival of OSCC patients by stage.
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http://dx.doi.org/10.1016/j.oraloncology.2018.08.013DOI Listing
October 2018

Metastases to the parotid gland - A review of the clinicopathological evolution, molecular mechanisms and management.

Surg Oncol 2018 Mar 2;27(1):44-53. Epub 2017 Dec 2.

Sydney Head and Neck Cancer Institute, Department of Head and Neck Surgery, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia; Central Clinical School, University of Sydney, New south Wales, Australia.

Metastases to the parotid gland are the commonest cause of parotid malignancies in many regions of the world including Australia. The most common etiology of these metastases is head and neck cutaneous squamous cell carcinoma (HNcSCC) followed by melanoma of the head and neck. This article focuses on the management of the aforementioned pathologies including Merkel cell carcinoma (MCC).
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http://dx.doi.org/10.1016/j.suronc.2017.11.007DOI Listing
March 2018

Lymph node ratio as a prognostic factor in metastatic cutaneous head and neck squamous cell carcinoma.

Head Neck 2018 05 23;40(5):993-999. Epub 2018 Jan 23.

Nepean Blue Mountains Local Health District, Sydney, Australia.

Background: The prognostic impact of the size and number of nodal metastases in head and neck cutaneous squamous cell carcinoma (SCC) is well established. The purpose of this study was to validate the prognostic significance of the lymph node ratio in metastatic head and neck cutaneous SCC.

Methods: A retrospective review of 326 patients with head and neck cutaneous SCC with parotid and/or cervical nodal metastases was performed. The primary endpoints were overall survival (OS) and disease-free survival (DFS). The minimal-P approach was used to investigate the optimal lymph node ratio threshold.

Results: Our data included 77 recurrences and 101 deaths. A lymph node ratio of 6% was a significant predictor of shorter DFS (hazard ratio [HR] 1.62; 95% confidence interval [CI] 1.11-2.38; P = .01) and OS (HR 1.63; 95% CI 1.03-2.58; P = 0.04) on multivariable analysis.

Conclusion: The lymph node ratio is an independent prognosticator of survival outcomes in patients presenting with metastatic head and neck cutaneous SCC. A lymph node ratio >6% is a significant threshold to categorize patients into low and high risk.
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http://dx.doi.org/10.1002/hed.25066DOI Listing
May 2018

Analysis and Comparison of the 8th Edition American Joint Committee on Cancer (AJCC) Nodal Staging System in Cutaneous and Oral Squamous Cell Cancer of the Head and Neck.

Ann Surg Oncol 2018 Jun 19;25(6):1730-1736. Epub 2018 Jan 19.

Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia.

Background: The American Joint Committee on Cancer (AJCC) uses the same nodal staging system for cutaneous and mucosal squamous cell carcinoma of the head and neck in its 8th edition (AJCC 8) despite differences in the etiology, risk factors, and clinical behavior of the two diseases. This study aims to evaluate the performance of the AJCC 8 nodal staging system by direct comparison of cutaneous (cSCC) versus oral squamous cell carcinoma (oSCC) patients.

Methods: Patients with metastatic cSCC (N = 382) and oSCC (N = 325) were identified from a prospective database (years 1987-2016). Multivariable analysis was performed using Cox proportional hazards competing risk model. To assess staging system performance, an explained variation measure (proportion of variation explained, PVE) as well as a discrimination measure (Harrell's concordance index, C-index) were used.

Results: Inclusion of extranodal extension (ENE) in AJCC 8 increased the proportion of patients in N3b category (48.7% in cSCC, 40.3% in oSCC). AJCC 8 stratified poorly with regards to risk of death from cSCC and oSCC and showed limited monotonicity of the nodal categories. Estimates of model performance revealed modest predictive capacity for overall survival (OS) and disease-specific survival (DSS) in oSCC (Harrell's C of 0.66 in both) and weak predictive capacity in cSCC (Harrell's C of 0.58 and 0.61, respectively).

Conclusions: The AJCC 8 nodal staging system performs poorly in terms of stratifying survival by N category, especially in cSCC. The data indicate that cSCC merits an independent nodal staging system from that for mucosal SCC.
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http://dx.doi.org/10.1245/s10434-018-6340-xDOI Listing
June 2018

Supraclavicular flap repair in the free flap era.

ANZ J Surg 2018 Jun 17;88(6):540-546. Epub 2017 Nov 17.

Division of Surgery, Wollongong Hospital, Wollongong, New South Wales, Australia.

Background: Supraclavicular flap (SCF) repair is widely reported in head and neck surgery in select patients and defects. The authors' objective is to present our series of 30 patients who underwent SCF repair for varying defects and to review the scope and outcome of SCF repair in the literature.

Methods: The authors contributed primary evidence of 30 cases of SCF repair. Our outcomes are compared with those reported in the last 5 years' literature; 33 articles published between January 2012 and January 2017 that present original clinical experience of 528 SCFs.

Results: SCF is suitable for a wide variety of oral cavity, pharyngeal, skull base and cutaneous defects. Consistent with our experience, SCF is highly reliable even in previously irradiated or dissected necks, so long as the supraclavicular artery is intact. Our case series shows minor complications in 3/30 (10%) and flap loss in 1/30 (3.3%) cases. The literature reports a similar rate of complete flap failure of 3.4% and a slightly higher average minor complication rate of 24.6%.

Conclusion: We add our experience of 30 cases of SCF repair to the international literature. We experienced a complication rate lower than the reported average, and maintain that the SCF is an excellent reconstructive option in patients with previously irradiated necks or comorbidities that affect microvasculature and anaesthetic resilience.
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http://dx.doi.org/10.1111/ans.14263DOI Listing
June 2018

Predictive value of the 8th edition American Joint Commission Cancer (AJCC) nodal staging system for patients with cutaneous squamous cell carcinoma of the head and neck.

J Surg Oncol 2018 Mar 19;117(4):765-772. Epub 2017 Oct 19.

Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.

Background: The 8th edition American Joint Committee on Cancer (AJCC8) provides the same nodal staging system for mucosal and cutaneous squamous cell carcinoma of the head and neck (HNcSCC) and includes extranodal extension (ENE) as an adverse prognostic criterion. This study evaluates the prognostic efficacy of the AJCC8 pathologic nodal staging system (pN) for HNcSCC.

Methods: Univariate analysis of 382 patients with metastatic HNcSCC staged according to both the 7th (AJCC7) and the 8th edition staging systems.

Results: The AJCC7 pN3 category was associated with reduced disease specific survival (DSS HR 5.49; 95% CI: 1.83-16.53; P = 0.002) and overall survival (OS HR 3.42; 95% CI: 1.54-7.58; P = 0.002) as compared with pN1. However, no difference was observed between pN1, pN2, and pN3 categories as defined by the AJCC8. Also, when comparing Stages III and IV as defined by AJCC8, there was no difference in DSS (HR 0.75; 95% CI: 0.34-1.67; P = 0.478) or OS (HR 0.88; 95% CI: 0.51-1.51; P = 0.648).

Conclusion: The AJCC8 performed poorly as a prognostic indicator for patients with metastatic HNcSCC in this cohort. HNcSCC would benefit from a staging system that accounts for its unique biologic characteristics distinct from mucosal SCC.
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http://dx.doi.org/10.1002/jso.24883DOI Listing
March 2018

Analysis of clinically relevant somatic mutations in high-risk head and neck cutaneous squamous cell carcinoma.

Mod Pathol 2018 02 6;31(2):275-287. Epub 2017 Oct 6.

Central Clinical School, The University of Sydney, Sydney, Australia.

Cutaneous squamous cell carcinoma is the second most prevalent malignancy, most frequently occurring in the head and neck (head and neck cutaneous squamous cell carcinoma). Treatment of locally advanced or metastatic disease is associated with functional morbidity and disfigurement. Underlying genetic mechanisms are poorly understood. Targeted sequencing of 48 clinically relevant genes was performed on DNA extracted from formalin-fixed and paraffin-embedded high-risk primary head and neck cutaneous squamous cell carcinomas that remained non-metastatic at minimum follow-up of 24 months. Associations of somatic mutations with clinicopathologic characteristics were evaluated and compared with those described in the literature for metastatic disease. Alterations in 44 cancer-associated genes were identified. TP53 was mutated in 100% of cases; APC, ATM, ERBB4, GNAQ, KIT, RB1 and ABL1 were altered in 60% of cases. FGFR2 mutations (40%) were exclusively seen in patients with perineural invasion. MLH1 mutations were exclusively seen in the two younger patients (<45 years). Lower incidences of NOTCH1 mutations were observed compared with that described in metastatic head and neck cutaneous squamous cell carcinoma in the literature. Somatic mutations susceptible to EGFR inhibitors, and other small molecular targeted therapeutics were seen in 60% of cases. This study provides insights into somatic mutations in non-metastatic, high-risk head and neck cutaneous squamous cell carcinoma and identifies potential therapeutic targets. Alterations in FGFR2 and NOTCH1 may have roles in local and distant disease progression.
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http://dx.doi.org/10.1038/modpathol.2017.128DOI Listing
February 2018

PD-L1 expression predicts longer disease free survival in high risk head and neck cutaneous squamous cell carcinoma.

Pathology 2017 Aug 27;49(5):499-505. Epub 2017 Jun 27.

Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia; Central Clinical School, University of Sydney, Sydney, Australia. Electronic address:

Programmed cell death (PD-1) and its ligand (PD-L1) inhibitors have shown clinical response in many tumours. PD-L1 data are limited in head and neck cutaneous squamous cell carcinoma (HNcSCC) and no clinical trials of PD-1/PD-L1 inhibitors are published. We performed PD-L1 immunohistochemistry on 74 cases of high risk HNcSCC with 38 matched metastases and evaluated clinicopathological associations, prognostic significance and heterogeneity in matched metastases. We observed PD-L1 expression in >5% of primary tumour cells in 29 cases (39.2%), primary tumour infiltrating lymphocytes (TILs) in 40 cases (70.2%), metastatic tumour cells in 15 cases (39.5%), and metastatic TILs in 18 cases (47.4%). PD-L1 expression in >5% of primary tumour cells was associated with an inflammatory phenotype (p = 0.04), and in primary TILs with clear margins (p = 0.05). PD-L1 expression in >5% of primary tumour cells (p = 0.01), primary TILs (p = 0.001), and metastatic TILs (p = 0.02) was associated with improved disease free survival. PD-L1 expression in >5% of tumour cells was heterogeneous between primary and metastatic tumours in 13 cases (34.2%). PD-L1 expression is common in HNcSCC supporting the rationale for a clinical trial of PD-1/PD-L1 inhibitors. PD-L1 expression in tumour cells or TILs predicts longer disease free survival and demonstrates temperospatial heterogeneity.
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http://dx.doi.org/10.1016/j.pathol.2017.04.004DOI Listing
August 2017

p16 expression in cutaneous squamous cell carcinoma of the head and neck is not associated with integration of high risk HPV DNA or prognosis.

Pathology 2017 Aug 26;49(5):494-498. Epub 2017 Jun 26.

Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia; Central Clinical School, University of Sydney, Sydney, NSW, Australia. Electronic address:

Head and neck cutaneous squamous cell carcinoma (HNcSCC) can present with cervical metastases without an obvious primary. Immunohistochemistry for p16 is established as a surrogate marker of human papillomavirus (HPV) in oropharyngeal cancer. p16 expression in HNcSCC needs to be elucidated to determine its utility in predicting the primary site. The aim of this study was to evaluate the rate of p16 expression in HNcSCC and its association with prognostic factors and survival. p16 immunohistochemistry was performed on 166 patients with high risk HNcSCC (2000-2013) following histopathology review. Chromogenic in situ hybridisation (CISH) for HPV was performed. Fifty-three (31.9%) cases showed strong, diffuse nuclear and cytoplasmic p16 expression including 14 (41%) non-metastatic and 39 (29.5%) metastatic tumours (p=0.21). HPV CISH was negative in all cases. p16 expression significantly increased with poorer differentiation (p=0.033), but was not associated with size (p=0.30), depth of invasion (p=0.94), lymphovascular invasion (p=0.31), perineural invasion (p=0.69), keratinisation (p=0.99), number of involved nodes (p=0.64), extranodal extension (p=0.59) or survival. Nearly 32% of HNcSCCs, particularly poorly differentiated HNcSCCs, show p16 expression. A primary HNcSCC should be considered in p16 positive neck node metastases in regions with high prevalence of HNcSCC. p16 expression is not associated with improved survival in HNcSCC.
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http://dx.doi.org/10.1016/j.pathol.2017.04.002DOI Listing
August 2017

Bone resection for facial cutaneous malignancies.

J Surg Oncol 2017 Sep 19;116(4):545-549. Epub 2017 Jun 19.

Sydney Head and Neck Cancer Institute, Department of Head and Neck Surgery, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia.

Background And Objectives: The aim of this study is to analyze the clinical outcomes of patients who underwent bone resection for cutaneous malignancy of the face and scalp.

Methods: We retrospectively collected patient data from 62 patients who underwent bone resection for craniofacial cutaneous malignancy of the face and scalp over the last 10 years. We investigated risk factors for disease progression and assessed the utility of pre-operative imaging to predict bone, dura, and brain infiltration.

Results: Out of all factors analyzed, brain invasion, surgical margin involvement, and dural margin involvement were found to significantly reduce survival. CT and MRI correctly predicted bone infiltration in 88% and 89% of cases. MRI correctly predicted dura invasion in 89% but grossly underestimated the amount of dural invasion in 23% of reports.

Conclusions: Our data indicate that the resection of bone is a reasonable surgical option in the treatment of patients with advanced cutaneous malignancies of the face and scalp. Brain invasion and positive margins reduced the probability of survival.
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http://dx.doi.org/10.1002/jso.24693DOI Listing
September 2017

Laparoscopic harvest of the gastro-omental free flap for reconstruction after total pharyngolaryngectomy: Operative technique.

Head Neck 2017 08 5;39(8):1696-1698. Epub 2017 Jun 5.

Department of Surgery, Wollongong Hospital, New South Wales, Australia.

Circumferential defects following salvage pharyngolaryngectomy present significant challenges in reconstructive surgery. The gastro-omental free flap has been shown to reduce the incidence of major fistula and catastrophic complications. The current technique for harvest of the flap requires laparotomy, which is potentially associated with significant post-operative complications. Laparoscopic harvest of the gastro-omental free flap can negate some of the risks associated with open surgery. We describe here the operative technique for laparoscopic gastro-omental free flap harvest for use in reconstruction following total pharyngolaryngectomy. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1696-1698, 2017.
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http://dx.doi.org/10.1002/hed.24698DOI Listing
August 2017

Reviewing the genetic alterations in high-risk cutaneous squamous cell carcinoma: A search for prognostic markers and therapeutic targets.

Head Neck 2017 07 3;39(7):1462-1469. Epub 2017 Apr 3.

Illawarra Health and Medical Research Institute (IHMRI), Northfields Avenue, Wollongong, New South Wales, 2522, Australia.

Cutaneous squamous cell carcinoma (SCC) is second only in incidence to basal cell carcinoma (BCC), effecting up to 500 000 people in the United States annually. Metastasis to regional lymph nodes occurs in approximately 5% of cases and imparts significant morbidity. Standard treatment in this group involves a combination of surgery and adjuvant radiation. Currently, there are no clinically useful biomarkers of metastatic potential in primary cutaneous SCC and histological predictors can be unreliable. The high level of mutational burden in normal UV-exposed skin has hampered the search for novel drivers of invasive disease, and indeed metastatic potential. This review outlines the clinical problems in high-risk and metastatic cutaneous SCCs, reviews the known genetic events and molecular mechanisms in high-risk primary cutaneous SCC and metastasis, and identifies avenues for further investigation and potential therapy.
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http://dx.doi.org/10.1002/hed.24765DOI Listing
July 2017

Education and support needs in patients with head and neck cancer: A multi-institutional survey.

Cancer 2017 06 12;123(11):1949-1957. Epub 2017 Jan 12.

Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia.

Background: Head and neck cancer (HNC) encompasses a diverse group of tumors, and thus providing appropriate and tailored information to patients before, during, and after treatment is a challenge. The objective of the current study was to characterize the experience and unmet needs of patients with HNC with regard to information and support provision.

Methods: A 28-question, cross-sectional survey was completed by patients treated for HNC at 1 of 4 institutions in New South Wales, Australia (Chris O'Brien Lifehouse and Liverpool, Westmead, and Wollongong hospitals). It consisted of the adapted Kessler Psychological Distress Scale and questions assessing information quality, quantity, and format.

Results: A total of 597 patients responded. The mean age of the patients was 58 years (range, 21-94 years) with 284 men and 313 women (1:1.1). The majority of patients reported information concerning the disease process (76%), prognosis (67%), and treatment (77%) was sufficient, and approximately 50% reporting having received little or no information regarding coping with stress and anxiety. A substantial percentage of patients reported receiving minimal information concerning psychosexual health (56%) or the availability of patient support groups (56%). The majority of patients preferred access to multiple modes of information delivery (72%), with the preferred modality being one-on-one meetings with a health educator (37%) followed by internet-based written information (19%).

Conclusions: Patients with HNC are a diverse group, with complex educational and support needs. Patients appear to be given information regarding survivorship topics such as psychological well-being, patient support groups, and psychosexual health less frequently than information concerning disease and treatment. Verbal communication needs to be reinforced by accessible, well-constructed, written and multimedia resources appropriate to the patient's educational level. Cancer 2017;123:1949-1957. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30535DOI Listing
June 2017

Single innervated segmented vastus lateralis for midfacial reanimation during radical parotidectomy.

Head Neck 2017 03 9;39(3):602-604. Epub 2017 Jan 9.

Department of Head and Neck Surgery, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia.

Background: Innervated free muscle transfer using the gracilis muscle or temporalis myoplasty has been successfully utilized for facial reanimation in chronic facial palsy. These techniques are less suited to immediate facial reconstruction in the setting of radical parotidectomy, in which the complexity of the defect, patient age, postoperative radiotherapy, and limited life expectancy pose particular challenges.

Methods: We present a novel description of the use of a chimeric anterolateral thigh (ALT) flap and innervated vastus lateralis to achieve midface static suspension and dynamic reanimation in the setting of radical parotidectomy.

Results: The technique is described in detail along with a video demonstrating the early and medium-term results in an example case.

Conclusion: Although outcomes using the vastus lateralis free flap for midface reanimation need to be objectively determined, the flap adds the potential of dynamic midface movement in patients undergoing radical parotidectomy who would otherwise not be afforded this opportunity. © 2017 Wiley Periodicals, Inc. Head Neck 39: 602-604, 2017.
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http://dx.doi.org/10.1002/hed.24668DOI Listing
March 2017

Circulating tumour cells in regionally metastatic cutaneous squamous cell carcinoma: A pilot study.

Oncotarget 2016 07;7(30):47111-47115

Centre for Oncology Education and Research Translation (CONCERT), Liverpool, NSW 2170, Australia.

Background: Circulating tumour cells (CTCs) are increasingly being used in the surveillance of cancer, allowing for potential early detection and real-time monitoring of disease progression. The presence of CTCs in patients with metastatic cutaneous head and neck squamous cell carcinoma (cHNSCC) has not been evaluated.

Results: CTCs were detected in eight of ten patients with regional metastatic cHNSCC (80%; range 1-44 cells/9 mL blood). CTMs were detected in three of ten patients (30%, range 1-4 cells/9 mL blood).

Methods: Preoperative blood samples from ten patients with nodal metastases from cutaneous squamous cell carcinomas (cSCC) were analyzed using the IsoFluxTM System for the detection and enumeration of CTCs and circulating tumour microemboli (CTMs).

Conclusions: For the first time CTCs have been detected in patients with nodal metastases from cHNSCC. Further work is required to understand their prognostic significance and potential to directly influence clinical practice.
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http://dx.doi.org/10.18632/oncotarget.9946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216927PMC
July 2016

Oropharyngeal cancer and human papilloma virus: evolving diagnostic and management paradigms.

ANZ J Surg 2016 Jun 21;86(6):442-7. Epub 2015 Dec 21.

Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia.

The significant increase in human papilloma virus (HPV)-associated oropharyngeal carcinoma (OPC) over recent years has lead to a surge in research and an improved understanding of the disease. Most patients with HPV-associated OPC present with cystic nodal metastases with a small primary tumour, and respond well to all treatment modalities including primary surgery and primary chemoradiotherapy. Current research is evaluating treatment de-escalation to reduce long-term treatment-associated morbidities. Transoral robotic surgery (TORS) is particularly relevant as the transoral approach allows small primary tumours to be removed with lower morbidity than traditional surgical approaches. The current American Joint Committee on Cancer staging system for oropharyngeal cancer does not appropriately stratify HPV-associated OPC; hence, alternative risk stratification and staging classifications are being proposed.
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http://dx.doi.org/10.1111/ans.13417DOI Listing
June 2016

Contralateral neck failure in lateralized oral squamous cell carcinoma.

ANZ J Surg 2016 Mar 3;86(3):188-92. Epub 2015 Jul 3.

Department of Head and Neck Surgery, Liverpool Hospital, Sydney, New South Wales, Australia.

Background: Elective treatment of the contralateral clinically node-negative (cN0) neck is not routinely recommended for lateralized oral cavity squamous cell carcinoma (SCC). We sought to determine the failure rate in the untreated contralateral neck in patients with lateralized oral SCC undergoing treatment of the primary and ipsilateral neck and to identify any features placing patients at sufficient risk of contralateral regional failure to justify elective treatment.

Methods: We identified 688 patients with oral SCC undergoing curative surgery ± adjuvant therapy between 1985 and 2012 from a prospectively collected database. Patients with midline primaries and those undergoing bilateral neck treatment were excluded. The primary endpoint was isolated contralateral neck failure.

Results: Of 481 patients, 14 (2.9%) developed isolated contralateral neck recurrence, with median time to recurrence of 8 months. Patients with poorly differentiated tumours or pathologically proven ipsilateral nodal metastases were at significantly higher risk of contralateral failure (hazard ratio (HR) 3.6, 95% confidence interval (CI) 1.1-11.9, P = 0.037 and HR 4.6, 95% CI 1.5-13.8, P = 0.006 respectively). Presence of both of these factors conferred a 10% risk of contralateral failure.

Conclusion: Patients with lateralized oral SCC undergoing treatment of the primary tumour and ipsilateral neck have a low rate of isolated contralateral neck failure. Although poorly differentiated primaries and ipsilateral nodal metastases were predictors of contralateral recurrence, the risk remains relatively modest in this subset of patients suggesting close observation may be more appropriate than elective treatment. Our results support current recommendations for observation of the cN0 contralateral neck in lateralized oral SCC.
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http://dx.doi.org/10.1111/ans.13206DOI Listing
March 2016

Prospective study of sentinel node biopsy for high-risk cutaneous squamous cell carcinoma of the head and neck.

Head Neck 2016 04 15;38 Suppl 1:E884-9. Epub 2015 Jul 15.

Sydney Head and Neck Cancer Institute, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

Background: Nodal metastasis from cutaneous squamous cell carcinoma (SCC) is poorly predicted clinically and is associated with a high mortality rate.

Methods: From 2010 to 2013, patients with high-risk cutaneous SCC were assessed with sentinel node biopsy (SNB) either at the time of primary cutaneous tumor resection or at secondary wide local excision.

Results: Of 57 patients, 8 (14%) had nodal metastasis. Significant predictors of metastasis are the number of high-risk factors (p = .008), perineural invasion (PNI; p = .05), and lymphovascular invasion (LVI; p = .05). During a mean of 19.4 months, 9 patients developed recurrence and 6 died of cutaneous SCC, indicating that over 1300 patients would be required for a randomized controlled trial with 80% power to detect a significant difference in disease-free survival.

Conclusion: Lymph node metastasis occurs in 14% of patients with high-risk cutaneous SCC. Larger studies will be required to identify which "high-risk" factors should be considered as an indication for surgical assessment of the nodal basin. © 2015 Wiley Periodicals, Inc. Head Neck 38: E884-E889, 2016.
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http://dx.doi.org/10.1002/hed.24120DOI Listing
April 2016
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