Novel Sheep Model to Assess Critical-Sized Bone Regeneration with Periosteum for In Vivo Bioreactors.

Considerable research is being undertaken to develop novel biomaterials-based approaches for surgical reconstruction of bone defects. This extends to three-dimensional (3D) printed materials that provide stable, structural, and functional support in vivo. However, few preclinical models can simulate in vivo human biological conditions for clinically relevant testing. In this study we describe a novel ovine model that allows evaluation of in vivo osteogenesis via contact with bone and/or periosteum interfaced with printed polymer bioreactors loaded with biomaterial bone substitutes. The infraspinous scapular region of 14 Dorset cross sheep was exposed. Vascularized periosteum was elevated either attached to the infraspinatus muscle or separately. In both cases, the periosteum was supplied by the periosteal branch of the circumflex scapular vessels. In eight sheep, a 3D printed 4-chambered polyetheretherketone bioreactor was wrapped circumferentially in vascularized periosteum. In 6 sheep, 12 double-sided 3D printed 2-chambered polyetherketone bioreactors were secured to the underlying bone allowing direct contact with the bone on one side and periosteum on the other. Our model enabled simultaneous testing of up to 24 (12 double-sided) 10 × 10 × 5 mm bioreactors per scapula in the flat contact approach or a single 40 × 10 mm four-chambered bioreactor per scapula using the periosteal wrap. De novo bone growth was evaluated using histological and radiological analysis. Of importance, the experimental model was well tolerated by the animals and provides a versatile approach for comparing the osteogenic potential of cambium on the bone surface and elevated with periosteum. Furthermore, the periosteal flaps were sufficiently large for encasing bioreactors containing biomaterial bone substitutes for applications such as segmental mandibular reconstruction.

When should patients with T1N0 oral squamous cell carcinoma be considered for elective neck dissection?

AIMS: To identify adverse pathological features (APF) predicting nodal failure in clinically node negative T1 oral squamous cell carcinoma (OSCC). METHODOLOGY: This study evaluated patients with T1N0 (≤5 mm depth of invasion (DOI) and ≤2 cm diameter) oral cancers from a prospectively maintained database between 1988 and 2020. All patients underwent surgical excision of the primary lesion without neck dissection. Patients underwent three monthly clinical surveillance and salvage neck dissection was performed if nodal relapse was diagnosed. RESULTS: Overall, 141 patients were included. Nodal relapse was reported in 16/141 (11.3%) patients. Factors impacting regional recurrence-free survival were DOI ≥3 mm (HR: 2.4, P < 0.001), maximum tumour diameter ≥12 mm (HR: 1.1, P = 0.009), perineural invasion (PNI) (HR 7.5, P = 0.002) and poor differentiation (HR 5.3, P = 0.01). Rates of nodal relapse increased from 2% amongst patients with no APFs to 100% for those with four APFs. Patients with two or more APFs had significantly poorer 5-year regional recurrence-free survival (94.8% vs. 56.3%, P < 0.001). CONCLUSION: Patients with T1N0 OSCC with two or more APFs (DOI ≥3 mm, diameter ≥12 mm, PNI or poor differentiations) should be considered for elective neck dissection.

Prognostic and predictive biomarkers in head and neck cancer: something old, something new, something borrowed, something blue and a sixpence in your shoe.

A biomarker is a measurable indicator of biological or pathological processes or the response to an exposure or intervention and is used to guide management decisions. In head and neck pathology, biomarkers are assessed by histological criteria and immunohistochemical and molecular studies. Surgical resection remains the mainstay of management of many head and neck malignancies. Adjuvant radiotherapy and/or systemic therapy may be administered depending on the presence of adverse prognostic factors identified on histopathological or immunohistochemical examination. In this review, we outline the clinically relevant prognostic and predictive factors in head and neck malignancies including conventionally recognised factors such as tumour size, depth of invasion, lymphovascular and perineural invasion and margin status as well as novel evolving factors such as recurrent genetic rearrangements and assessment of immune checkpoints. Practical issues are discussed to assist with recognising and reporting of these factors. A summary of useful tools such as structured pathology report formats is also included to assist with comprehensive reporting of all clinically relevant parameters, minimise risk and improve workflow efficiencies.

Ex vivo tissue modelling informs drug selection for rare cancers.

The identification and therapeutic targeting of actionable gene mutations across many cancer types has resulted in improved response rates in a minority of patients. The identification of actionable mutations is usually not sufficient to ensure complete nor durable responses, and in rare cancers, where no therapeutic standard of care exists, precision medicine indications are often based on pan-cancer data. The inclusion of functional data, however, can provide evidence of oncogene dependence and guide treatment selection based on tumour genetic data. We applied an ex vivo cancer explant modelling approach, that can be embedded in routine clinical care and allows for pathological review within 10 days of tissue collection. We now report that ex vivo tissue modelling provided accurate longitudinal response data in a patient with BRAFV600E -mutant papillary thyroid tumour with squamous differentiation. The ex vivo model guided treatment selection for this patient and confirmed treatment resistance when the patient's disease progressed after 8 months of treatment.

How age affects health-related-quality-of-life outcomes in maxillomandibular reconstructive surgery.

INTRODUCTION: Maxillomandibular reconstruction has various functional, aesthetic, and psychosocial effects that can decrease patients' health-related quality of life (HRQOL). The aim of this study was to compare HRQOL outcomes in older and younger patients undergoing maxillomandibular reconstruction. METHODS: A cross-sectional study of patients undergoing maxillomandibular reconstruction surgery between November 2008 and January 2021 was conducted. Participants completed the FACE-Q Head and Neck Cancer Module, M.D. Anderson Dysphagia Inventory (MDADI), and Speech Handicap Index (SHI). Results from these instruments were used to compare HRQOL outcomes in old (≥70 years) and young (<70 years) patients. RESULTS: Ninety-nine patients who underwent maxillomandibular reconstruction completed the instruments (response rate 50%), of which 33 (33%) were aged ≥70 years. Older age was associated with improved FACE-Q speaking (+11.3, P = 0.045), FACE-Q cancer worry (-9.97, P = 0.050), and SHI score (-16.6, P = 0.013). After adjusting for the effect of radiotherapy, age was associated with improved FACE-Q speaking (+16.8, P = 0.012), FACE-Q smiling distress (+12.6, P = 0.040), FACE-Q worry (-11.0, P = 0.032), and SHI scores (-18.4, P = 0.004). Older age was associated with an increased likelihood of postoperative complications (odds ratio (OR) = 2.9, P = 0.02) and medical complications (OR = 4.6, P = 0.012). CONCLUSION: In patients undergoing maxillomandibular reconstruction, older age (≥70 years) was associated with better HRQOL outcomes in domains relating to speech and cancer worry. In all other HRQOL outcomes, the two age groups performed similarly.

A Comparison of In Vivo Bone Tissue Generation Using Calcium Phosphate Bone Substitutes in a Novel 3D Printed Four-Chamber Periosteal Bioreactor.

Autologous bone replacement remains the preferred treatment for segmental defects of the mandible; however, it cannot replicate complex facial geometry and causes donor site morbidity. Bone tissue engineering has the potential to overcome these limitations. Various commercially available calcium phosphate-based bone substitutes (Novabone®, BioOss®, and Zengro®) are commonly used in dentistry for small bone defects around teeth and implants. However, their role in ectopic bone formation, which can later be applied as vascularized graft in a bone defect, is yet to be explored. Here, we compare the above-mentioned bone substitutes with autologous bone with the aim of selecting one for future studies of segmental mandibular repair. Six female sheep, aged 7-8 years, were implanted with 40 mm long four-chambered polyether ether ketone (PEEK) bioreactors prepared using additive manufacturing followed by plasma immersion ion implantation (PIII) to improve hydrophilicity and bioactivity. Each bioreactor was wrapped with vascularized scapular periosteum and the chambers were filled with autologous bone graft, Novabone®, BioOss®, and Zengro®, respectively. The bioreactors were implanted within a subscapular muscle pocket for either 8 weeks (two sheep), 10 weeks (two sheep), or 12 weeks (two sheep), after which they were removed and assessed by microCT and routine histology. Moderate bone formation was observed in autologous bone grafts, while low bone formation was observed in the BioOss® and Zengro® chambers. No bone formation was observed in the Novabone® chambers. Although the BioOss® and Zengro® chambers contained relatively small amounts of bone, endochondral ossification and retained hydroxyapatite suggest their potential in new bone formation in an ectopic site if a consistent supply of progenitor cells and/or growth factors can be ensured over a longer duration.

From Free Tissue Transfer to Hydrogels: A Brief Review of the Application of the Periosteum in Bone Regeneration.

The periosteum is a thin layer of connective tissue covering bone. It is an essential component for bone development and fracture healing. There has been considerable research exploring the application of the periosteum in bone regeneration since the 19th century. An increasing number of studies are focusing on periosteal progenitor cells found within the periosteum and the use of hydrogels as scaffold materials for periosteum engineering and guided bone development. Here, we provide an overview of the research investigating the use of the periosteum for bone repair, with consideration given to the anatomy and function of the periosteum, the importance of the cambium layer, the culture of periosteal progenitor cells, periosteum-induced ossification, periosteal perfusion, periosteum engineering, scaffold vascularization, and hydrogel-based synthetic periostea.

Persisting facial nerve palsy or trigeminal neuralgia - red flags for perineural spread of head and neck cutaneous squamous cell carcinoma (HNcSCC).

BACKGROUND: Perineural spread (PNS) of head and neck cutaneous squamous cell carcinoma (HNcSCC) is a unique diagnostic challenge, presenting with insidious trigeminal (CN V) or facial nerve (CN VII) neuropathies without clinically discernible primary masses. These patients are often sub-optimally investigated and misdiagnosed as Bell's palsy or trigeminal neuralgia. This case series highlights the red flags in history and pitfalls that lead to delays to diagnosis and treatment. METHODS: A retrospective case series of 19 consecutive patients with complete clinical histories with HNcSCC PNS without an obvious cutaneous primary lesion at time of presentation to a quaternary head and neck centre in Australia were identified and included for analysis. RESULTS: Fifteen had CN VII PNS, 17 had CN V PNS, and 13 had both. The overall median symptom-to-diagnosis time was 12-months (IQR-15 months). Eight patients had CN VII PNS and described progressive segmental facial nerve palsy with a median symptom-to-diagnosis time of 9-months (IQR-11.75 months). Eleven patients had primary CN V PNS and described well localized parathesia, formication or neuralgia with a median symptom-to-diagnosis time of 19-months (IQR 27.5 months). CONCLUSION: PNS is often mistaken for benign cranial nerve dysfunction with delays in diagnosis worsening prognosis. Red flags such as progressive CN VII palsy or persistent CN V paraesthesia, numbness, formication or pain, particularly in the presence of immuno-compromise and/or a history of facial actinopathy should raise suspicion for PNS. Gadolinium-enhanced MR Neurography should be obtained expediently in patients with persistent/progressive CN V/CN VII palsies in patients with red flags, with low threshold for referral to a Head and Neck Surgeon.

Comparing Genomic Landscapes of Oral and Cutaneous Squamous Cell Carcinoma of the Head and Neck: Quest for Novel Diagnostic Markers.

Squamous cell carcinoma is the most common head and neck malignancy arising from the oral mucosa and the skin. The histologic and immunohistochemical features of oral squamous cell carcinoma (OSCC) and head and neck cutaneous squamous cell carcinoma (HNcSCC) are similar, making it difficult to identify the primary site in cases of metastases. With the advent of immunotherapy, reliable distinction of OSCC and HNcSCC at metastatic sites has important treatment and prognostic implications. Here, we investigate and compare the genomic landscape of OSCC and HNcSCC to identify diagnostically useful biomarkers. Whole-genome sequencing data from 57 OSCC and 41 HNcSCC patients were obtained for tumor and matched normal samples. Tumor mutation burden (TMB), Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, frequent chromosomal alterations, somatic single nucleotide, and copy number variations were analyzed. The median TMB of 3.75 in primary OSCC was significantly lower (P < .001) than that of 147.51 mutations/Mb in primary HNcSCC. The COSMIC mutation signatures were significantly different (P < .001) between OSCC and HNcSCC. OSCC showed COSMIC single-base substitution (SBS) mutation signature 1 and AID/APOBEC activity-associated signature 2 and/or 13. All except 1 HNcSCC from hair-bearing scalp showed UV damage-associated COSMIC SBS mutation signature 7. Both OSCC and HNcSCC demonstrated a predominance of tumor suppressor gene mutations, predominantly TP53. The most frequently mutated oncogenes were PIK3CA and MUC4 in OSCC and HNcSCC, respectively. The metastases of OSCC and HNcSCC demonstrated TMB and COSMIC SBS mutation signatures similar to their primary counterparts. The combination of high TMB and UV signature in a metastatic keratinizing squamous cell carcinoma suggests HNcSCC as the primary site and may also facilitate decisions regarding immunotherapy. HNcSCC and OSCC show distinct genomic profiles despite histologic and immunohistochemical similarities. Their genomic characteristics may underlie differences in behavior and guide treatment decisions in recurrent and metastatic settings.

Outcomes of immediate dental implants in vascularised bone flaps for mandibular reconstruction.

BACKGROUND: The aim of this study is to assess the outcomes of immediate implant placement for dental rehabilitation following mandibular reconstruction with vascularised bone flaps in a single Australian tertiary cancer centre. METHODS: A retrospective analysis of patients who underwent immediate dental implant or delayed placement in vascularised bone flaps was performed. Primary outcome measures assessed included the number of implants placed, operative time, complication rates, time to radiotherapy initiation, dental rehabilitation rates and time to dental rehabilitation. RESULTS: In total, 187 dental implants were placed in 52 patients, of which 34 patients underwent immediate implant placement and 18 had delayed implant placement. There were no significant differences in the postoperative complication rate (32% immediate vs. 33% delayed, P = 0.89) or time to postoperative radiotherapy (median 42 days immediate vs. 47 days delayed, P = 0.24). Dental rehabilitation was achieved in 62% of the immediate cohort versus 78% of the delayed cohort. The time to be fitted with a dental prosthesis was significantly shorter in the immediate cohort (median 150 days immediate vs. 843 days delayed, P = 0.002). CONCLUSIONS: The placement of immediate dental implants at the time of primary reconstruction of the mandible is a safe procedure and facilitates timely dental rehabilitation.

Comparative analysis of pre-operative ultrasound and histopathology in small papillary thyroid carcinoma in the era of active surveillance.

BACKGROUND: Contemporary management of small papillary thyroid carcinomas (PTC) includes active surveillance (AS) as a number of these tumours are indolent. Overseas studies have reported AS in tumours up to 15 mm. This study aims to look at an Australian cohort of patients who have had surgery for non-incidental PTCs and analyse their pre-operative ultrasound and histopathology data to investigate potential issues that might arise in the era of AS. METHODS: Retrospective review of 82 patients who had surgical removal of PTCs ≤15 mm in diameter. Pre-operative ultrasound imaging was reviewed by an experienced sonologist and histopathology data was obtained from medical records. The AS risk stratification framework by Brito et al. was used to determine those who were feasible for AS based on ultrasound findings. RESULTS: Review of pre-operative ultrasounds demonstrated there were 68 (82.9%) patients who were shown to be either appropriate or ideal for AS. On review of histopathology, 49 (69%) patients had at least one adverse pathological risk factor. This is more than half of the patients that were originally identified as candidates for AS. CONCLUSION: Our study has revealed a large proportion were suitable for AS but when compared with histopathological guidelines there was a high incidence of adverse pathological features found. This discrepancy indicates that although the guidelines are important, there are unknown pathological variables that need to be considered in patients selected for AS.

Anterolateral thigh, radial forearm and superficial circumflex iliac perforator flaps in oral reconstruction: a comparative analysis.

BACKGROUND: Anterolateral thigh (ALT) and Radial forearm free flaps (RFFF) are historically the most common methods of oral reconstruction. The Superficial circumflex iliac artery perforator flap (SCIP) is an alternative providing a donor site that can be readily closed primarily with improved cosmesis in younger patients, due to its concealability. METHODS: We reviewed 135 patients who received ALT, RFFF or SCIP flaps for oral reconstruction in our institution. Our aim was to compare operative and perioperative outcomes between each cohort. ANOVA and χ2 test were used for statistical analysis. RESULTS: There were 37 ALT, 64 RFFF and 35 SCIP reconstructions. Patients reconstructed with SCIP flaps had smaller resection volumes (P < 0.001) and earlier T and N classifications (P = 0.001, P = 0.008), and consequently reduced tracheostomy rates (P < 0.001), reduced need for enteral feeding at discharge (P < 0.001) and shorter length of stay and perioperative times (P < 0.001). SCIP flaps were more common in younger patients (P < 0.01). ALT flaps were used for more advanced disease (P = 0.001) and had larger resection volumes (P < 0.001) and increased need for assisted enteral feeding (P < 0.001). There were no significant differences in flap or donor site outcomes. There were two flap failures, both RFFF. CONCLUSION: Each flap plays an important role in the reconstruction of oral defects, with larger defects preferentially reconstructed with ALT flaps. SCIP appears to be a reliable alternative in small defects with excellent perioperative and postoperative outcomes.

Effect of operative time on complications associated with free flap reconstruction of the head and neck.

OBJECTIVE: To evaluate whether prolonged operative time is negatively associated with post-operative complications and length of stay in patients undergoing microvascular free flap reconstruction for complex head and neck defects. METHODS: 342 consecutive patients undergoing microvascular reconstruction for head and neck defects between 2017-2019 at a single institution were evaluated. Operative outcomes and operative time were compared whilst controlling for patient and treatment related factors. RESULTS: Mean operative time was 551 min and length of stay was 16.2 days. An 11% increase in the risk of a post-operative complication was observed for every additional hour of operative time (OR 1.11, 95% CI 1.03-1.21, p = 0.011) after adjusting for patient and treatment factors. A cut-off of 9 h yielded a 92% increase in complications on either side of this (OR 1.92, 95% CI 1.18-3.13, p = 0.009). Increased operative time was also associated with increased length of stay and return to theatres, but not medical complications. CONCLUSION: Prolonged operative time is significantly associated with increased surgical complications, length of stay and return to theatres when performing microvascular reconstructive surgery for head and neck defects.

A Rare Case of Small Bowel Obstruction in a Patient with Endosalpingiosis, Fitz-Hugh-Curtis Syndrome, and Chlamydia trachomatis Pelvic Inflammatory Disease.

A 19-year-old female has multiple presentations to emergency department with recurrent abdominal pain. During her third presentation, the radiological features were suggestive of high-grade small bowel obstruction in a virgin abdomen. A diagnostic laparoscopy has been performed. The intraoperative findings include a band adhesion between omentum and small bowel mesentery, and perihepatic adhesions consistent with Fitz-Hugh-Curtis syndrome. The histopathology from a biopsy of the macular lesions of the abdominal wall showed endosalpingiosis. The postoperative high vaginal swab was positive for Chlamydia trachomatis. The underlying cause of her small bowel obstruction could be due to pelvic inflammatory disease, Fitz-Hugh-Curtis syndrome, or endosalpingiosis. We aimed to create awareness amongst readers that small bowel obstruction in young female patients with no prior abdominal surgery is possible and often difficult to diagnose immediately.

Viral Integration Plays a Minor Role in the Development and Prognostication of Oral Squamous Cell Carcinoma.

Viruses are well known drivers of several human malignancies. A causative factor for oral cavity squamous cell carcinoma (OSCC) in patients with limited exposure to traditional risk factors, including tobacco use, is yet to be identified. Our study aimed to comprehensively evaluate the role of viral drivers in OSCC patients with low cumulative exposure to traditional risk factors. Patients under 50 years of age with OSCC, defined using strict anatomic criteria were selected for WGS. The WGS data was interrogated using viral detection tools (Kraken 2 and BLASTN), together examining >700,000 viruses. The findings were further verified using tissue microarrays of OSCC samples using both immunohistochemistry and RNA in situ hybridisation (ISH). 28 patients underwent WGS and comprehensive viral profiling. One 49-year-old male patient with OSCC of the hard palate demonstrated HPV35 integration. 657 cases of OSCC were then evaluated for the presence of HPV integration through immunohistochemistry for p16 and HPV RNA ISH. HPV integration was seen in 8 (1.2%) patients, all middle-aged men with predominant floor of mouth involvement. In summary, a wide-ranging interrogation of >700,000 viruses using OSCC WGS data showed HPV integration in a minority of male OSCC patients and did not carry any prognostic significance.

Effect of Radiotherapy on Functional and Health-Related Quality of Life Outcomes after Jaw Reconstruction.

Long-term health-related quality of life (HRQOL) and functional outcomes following mandibular and maxillary reconstruction are lacking. To determine these outcomes, a cross-sectional study of patients with a history of cancer who underwent jaw reconstruction was undertaken. Participants were identified from a database of jaw reconstruction procedures at the Chris O'Brien Lifehouse (Sydney, Australia). Eligible patients had at least one month follow-up, were aged ≥18 years at surgery, and had history of malignancy. HRQOL was measured using the FACE-Q Head and Neck Cancer Module (FACE-Q H&N). Functional outcomes were measured using the FACE-Q H&N, MD Anderson Dysphagia Inventory (MDADI) and Speech Handicap Index (SHI). Ninety-seven questionnaires were completed (62% response rate). Mean age of respondents was 63.7 years, 61% were male, and 64% underwent radiotherapy. Treatment with radiotherapy was associated with worse outcomes across 10/14 FACE-Q H&N scales, three MDADI subscales and one composite score, and the SHI. Mean differences in scores between irradiated and non-irradiated patients exceeded clinically meaningful differences for the MDADI and SHI. Issues with oral competence, saliva, speaking, and swallowing worsened with increasing time since surgery. Younger patients reported greater concerns with appearance, smiling, speaking, and cancer worry. Women reported greater concerns regarding appearance and associated distress. History of radiotherapy substantially impacts HRQOL and function after jaw reconstruction. Age at surgery and gender were also predictors of outcomes and associated distress. Pre-treatment counselling of patients requiring jaw reconstruction may lead to improved survivorship for patients with head and neck cancer.

Survival outcomes of perineural spread in head and neck cutaneous squamous cell carcinoma.

AIM: To present an institution's experience and survival outcomes for patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) and perineural spread (PNS). METHOD: Retrospective study of patients with HNcSCC and PNS treated between January 2010 and August 2020 from the Sydney Head and Neck Cancer Institute database, Sydney, Australia; a high-volume, tertiary, academic head and neck centre. Patient demographics, primary site, involved cranial nerves, treatment modality, loco-regional failure and survival data were obtained. RESULTS: Forty-five patients were identified, of which 32 patients were male (71%). Mean age at diagnosis was 68.7 years (range 43-90). Median follow-up was 16.1 months (range 1-107). The trigeminal nerve was most frequently involved (n = 30, 66.6%) followed by facial nerve (n = 13, 28.9%). Most patients underwent surgery followed by radiotherapy (n = 33, 73%) and eight received definitive radiotherapy. The median overall survival (OS) was 4.5 years (95% CI 3.71-5.38), median disease-specific survival 5.1 years (95% CI 4.21-5.97) and median disease-free survival (DFS) was 1.7 years (95% CI 1.11-2.22). The estimated 5-year OS and DFS were 45% and 25%, respectively. Patients treated with surgery and adjuvant radiotherapy with a clear proximal nerve margin had favourable DFS (P = 0.035) and trended towards better OS (P = 0.134) compared with patients with an involved nerve margin. Patients treated surgically with involved proximal nerve margins had similar outcomes compared with patients with treated definitive radiotherapy (HR 0.80, 95% CI 0.29-2.22, P = 0.664). CONCLUSION: The likelihood of achieving a clear proximal nerve margin should be a strong consideration in the selection of appropriate patients for primary surgery.

Sporadic medullary thyroid cancer: a systematic review and meta-analysis of clinico-pathological and mutational characteristics predicting recurrence.

INTRODUCTION: Sporadic medullary thyroid cancer accounts for 75% of all medullary thyroid cancers and presents at a more advanced disease stage than its hereditary counterparts. Yet there is little evidence to support risk stratification of patients according to risk of recurrence. METHODS: A systematic review and meta-analysis was performed investigating clinical and pathological factors that are associated with recurrent disease in patients with medullary thyroid cancer. RESULTS: 10 studies totalling 458 patients were included in the meta-analyses. T3 and T4 disease (OR 9.33 (95% CI 2.5 - 34.82) p = 0.0009.), AJCC stage III and IV disease (OR 13.34 (95% CI 2.9 - 60.3) p = 0.0008) and the presence of nodal disease (OR 7.28 (95% CI 7.2-43.3) p = 0.03) were all associated with recurrent disease. RET mutations (OR 0.08 (95% CI -0.03-0.19) p = 0.17) and RET 918 T mutations (OR 1.77 (95% CI 0.804.0) P = 0.17) were not associated with disease recurrence. It was not possible to pool data with respect to extrathyroidal extension, extracapsular extension, peri-neural and lymphovascular invasion and RAS mutations. CONCLUSION: T3 and T4 disease, AJCC stage III and IV disease and the presence of nodal disease are associated with recurrent disease. The heterogeneous reporting of recurrence and the lack of individual patient data precludes larger scale meta-analyses. Future research in this area should involve collaboration to establish standardised definitions of disease recurrence.