e13579 Background: Cutaneous squamous cell carcinoma (cSCC) are the most common form of metastasi... more e13579 Background: Cutaneous squamous cell carcinoma (cSCC) are the most common form of metastasising skin cancer. Whilst rates of metastatic cSCC are low, they account for a significant proportion of skin cancer related morbidity and mortality, particularly within elderly cohorts, which poses a significant burden to healthcare services. Established cSCC tumour staging systems perform poorly at predicting metastatic risk. Additionally, we lack clinically validated prognostic biomarkers – highlighting the unmet need for novel risk stratification tools to guide clinical practice and improve outcomes for patients with advanced disease. We aimed to train four recognised machine learning (ML) algorithms on a large clinic-pathological dataset of primary cSCC, with the objective of optimising an ML strategy and developing a reliable and clinically useful risk stratification tool capable of accurately predicting metastatic events following primary cSCC. Methods: A dataset of primary cSCC re...
Background Combined loss of the autophagy-regulatory protein AMBRA1 and the terminal differentiat... more Background Combined loss of the autophagy-regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoural epidermis of stage I melanomas can identify tumour subsets at low risk of metastasis. Objectives The aim of the present study was to validate the combined loss of peritumoural AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. Methods Automated Immunohistochemistry was used to analyse peritumoural AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of non-ulcerated AJCC stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. Results Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low risk group compared to 81.7% in the AMBLor at-risk group (multivariate log-...
Failure to properly form bone or integrate surgical implants can lead to morbidity and additional... more Failure to properly form bone or integrate surgical implants can lead to morbidity and additional surgical interventions in a significant proportion of orthopedic surgeries. While the role of skeletal stem cells (SSCs) in bone formation and repair is well-established, very little is known about the factors that regulate the downstream Bone, Cartilage, Stromal, Progenitors (BCSPs). BCSPs, as transit amplifying progenitor cells, undergo multiple mitotic divisions to expand the pool of lineage committed progenitors allowing stem cells to preserve their self-renewal and stemness. Del1 is a protein widely expressed in the skeletal system, but its deletion led to minimal phenotype changes in the uninjured mouse. In this paper, we demonstrate that Del1 is a key regulator of BCSP expansion following injury. In Del1 knockout mice, there is a significant reduction in the number of BCSPs which leads to a smaller callus and decreased bone formation compared with wildtype (WT) littermates. Del1 ...
Reconstruction of nasal lesions is complex due to the topography, mobile free margins and borders... more Reconstruction of nasal lesions is complex due to the topography, mobile free margins and borders of anatomical subunits. Reconstructive challenges can lead to multiple revisional surgeries to achieve the final aesthetic result. This study aimed to evaluate risk factors and predictors of revisional surgery in patients undergoing reconstruction after Mohs micrographic surgery for nasal tumours. This was a prospective cohort study from April 2, 2008 to February 26, 2019. The study population included all consecutive patients who underwent Mohs micrographic surgery for nasal skin cancer. Resection and reconstruction of nasal skin cancer was performed by the Mohs team. A total of 988 cases met our study inclusion criteria with 64 (6.5%) cases requiring unplanned surgical revision. Revision rates were highest in the ala (9.0%, p < 0.05) and complex anatomical subunits (16.7%, p < 0.0001). In contrast, revision rates for dorsum lesions were lowest (1.8%, p < 0.001). In terms of r...
BACKGROUND Basal cell carcinoma (BCC) is the most common human cancer. Facial BCCs most commonly ... more BACKGROUND Basal cell carcinoma (BCC) is the most common human cancer. Facial BCCs most commonly occur on the nose and the management of these lesions is particularly complex, given the functional and complex implications of treatment. Multidisciplinary team (MDT) meetings are routinely held to integrate expertise from dermatologists, surgeons, oncologists, radiologists, pathologists and allied health professionals. The aim of this research was to develop a supervised machine-learning algorithm to predict MDT recommendations for nasal BCC to potentially reduce MDT caseload, provide automatic decision support and permit data audit in a health service context. METHODS The study population included all consecutive patients who were discussed at skin cancer-specialised MDT (SSMDT) with a diagnosis of nasal BCC between January 1, 2015 and December 31, 2015. We conducted analyses for gender, age, anatomical location, histological subtype, tumour size, tumour recurrence, anticoagulation, pacemaker, immunosuppressants and therapeutic modalities (Mohs surgery, conventional excision or radiotherapy). We used S-statistic computing language to develop a supervised machine-learning algorithm. RESULTS We found that 37.5% of patients could be reliably predicted to be triaged to Mohs micrographic surgery (MMS), based on tumour location and age. Similarly, the choice of conventional treatment (surgical excision or radiotherapy) by the MDT could be reliably predicted based on the patient's age, tumour phenotype and lesion size. Accordingly, the algorithm reliably predicted the MDT decision outcome of 45.1% of nasal BCCs. CONCLUSIONS Our study suggests that the machine-learning approach is a potentially useful tool for predicting MDT decisions for MMS vs conventional surgery or radiotherapy for a significant group of patients. We suggest that utilising this algorithm gives the MDT more time to consider more complex patients, where multiple factors, including recurrence, financial costs and cosmetic outcome, contribute to the final decision, but cannot be reliably predicted to determine that outcome. This approach has the potential to reduce the burden and improve the efficiency of the specialist skin MDT and, in turn, improve patient care, reduce waiting times and reduce the financial burden. Such an algorithm would need to be updated regularly to take into account any changes in patient referral patterns, treatment options or local clinical expertise. CLINICAL TRIAL REGISTRATION lPLAS_20-21_A08.
Background: Randomized controlled trials (RCTs) are gold standard assessments for healthcare inte... more Background: Randomized controlled trials (RCTs) are gold standard assessments for healthcare interventions. The Consolidated Standards of Reporting Trials (CONSORT) statement was published to maximize RCT reporting transparency. The authors conducted a systematic review to assess current compliance of RCTs published within craniofacial surgery with the CONSORT statement. Methods: The Thomson Reuters Impact Factor Report 2016 was consulted to identify craniofacial surgery journals. PubMed was used to search for recent RCTs published within the 5 journals identified. Two independent researchers assessed each study for inclusion and performed data extraction. The primary outcome was compliance of each RCT with the CONSORT statement. Secondary outcomes were the pathology and interventions examined, impact factor, multi-versus-single center, number of authors, and publication date. Results: Eighty-six studies met the inclusion criteria, across which a median of 56% (range 33%–94%) applicable CONSORT items were reported. The 5 least reported items were: trial design (3a); registration number and name of trial registry (23); who generated random allocation sequences, enrolled participants, and assigned participants to interventions (10); sample size determination (7a); mentioning “randomized trial” in the title (1a). Conclusion: The compliance of craniofacial surgery RCTs with the CONSORT statement requires improvement. Areas in need are identified, and methods to improve reporting transparency, are discussed.
Orbital dysmorphology and midface retrusion are the hallmarks of Crouzon and Apert syndromes. The... more Orbital dysmorphology and midface retrusion are the hallmarks of Crouzon and Apert syndromes. The precise nature of this deficiency is not known. Untreated Crouzon and Apert syndrome patients and age- and sex-matched controls were included. Computed tomographic scans were digitized and reconstructed. Craniometric and volumetric data relating to the orbit were collected. Thirty-one scans were included (control, n = 12; Crouzon; n = 9; Apert, n = 10). The mean age of the Apert group was 5.31 ± 5 years; Crouzon, 5.77 ± 2.7 years; and control, 6.4 ± 3.6 years. The bony orbit length was 12 percent shorter in Apert (p = 0.004) and 17 percent shorter in the Crouzon group when compared to controls (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). The bony orbital volume was 21 percent smaller in the Apert children (p = 0.0006) and 23 percent smaller in Crouzon when compared to controls (p = 0.003). Globe volume was 15 percent larger in Apert (p = 0.008) and 36 percent larger in the Crouzon group when compared to controls (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Orbital soft-tissue volume was 19 percent less in the Apert group (p = 0.004) and 29 percent less in the Crouzon group (p = 0.001) when compared to controls. A shortened bony orbit, decreased orbital and orbital soft-tissue volumes, and an increased volume of the globe were found in both conditions. Despite normal volume of the overall orbital contents, the contents are altered, and the bony orbit is shorter and holds less volume.
American journal of medical genetics. Part A, 2018
To extend the knowledge base about possible prevalence declines of specific orofacial cleft pheno... more To extend the knowledge base about possible prevalence declines of specific orofacial cleft phenotypes, here we examine prevalence in a population base from California over a two-decade period among numerous race/ethnic groups. This population-based study used vital statistics and birth defects registry data. Its population involved all births (~1.5 million births) in central California counties from 1987 to 2010. Orofacial clefts were defined as cleft lip with or without cleft palate (CLP, n=1766), and cleft palate (CP, n=922) only. The slope of prevalence of each cleft phenotype over the period 1987-2010 was estimated using weighted least squares regression. Birth prevalence of CLP was 121/100,000 live births, and 63/100,000 live births for CP. The slope for CLP decreased by 1.2 (slope: -1.2; 95% CI: -1.9, -0.5), and for CP by 0.7 (slope: -0.7; 95% CI: -1.7, 0.2) for CP. Stratification by race/ethnicity or infant sex did not demonstrate a statistical difference in slopes. We obser...
e13579 Background: Cutaneous squamous cell carcinoma (cSCC) are the most common form of metastasi... more e13579 Background: Cutaneous squamous cell carcinoma (cSCC) are the most common form of metastasising skin cancer. Whilst rates of metastatic cSCC are low, they account for a significant proportion of skin cancer related morbidity and mortality, particularly within elderly cohorts, which poses a significant burden to healthcare services. Established cSCC tumour staging systems perform poorly at predicting metastatic risk. Additionally, we lack clinically validated prognostic biomarkers – highlighting the unmet need for novel risk stratification tools to guide clinical practice and improve outcomes for patients with advanced disease. We aimed to train four recognised machine learning (ML) algorithms on a large clinic-pathological dataset of primary cSCC, with the objective of optimising an ML strategy and developing a reliable and clinically useful risk stratification tool capable of accurately predicting metastatic events following primary cSCC. Methods: A dataset of primary cSCC re...
Background Combined loss of the autophagy-regulatory protein AMBRA1 and the terminal differentiat... more Background Combined loss of the autophagy-regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoural epidermis of stage I melanomas can identify tumour subsets at low risk of metastasis. Objectives The aim of the present study was to validate the combined loss of peritumoural AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. Methods Automated Immunohistochemistry was used to analyse peritumoural AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of non-ulcerated AJCC stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. Results Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low risk group compared to 81.7% in the AMBLor at-risk group (multivariate log-...
Failure to properly form bone or integrate surgical implants can lead to morbidity and additional... more Failure to properly form bone or integrate surgical implants can lead to morbidity and additional surgical interventions in a significant proportion of orthopedic surgeries. While the role of skeletal stem cells (SSCs) in bone formation and repair is well-established, very little is known about the factors that regulate the downstream Bone, Cartilage, Stromal, Progenitors (BCSPs). BCSPs, as transit amplifying progenitor cells, undergo multiple mitotic divisions to expand the pool of lineage committed progenitors allowing stem cells to preserve their self-renewal and stemness. Del1 is a protein widely expressed in the skeletal system, but its deletion led to minimal phenotype changes in the uninjured mouse. In this paper, we demonstrate that Del1 is a key regulator of BCSP expansion following injury. In Del1 knockout mice, there is a significant reduction in the number of BCSPs which leads to a smaller callus and decreased bone formation compared with wildtype (WT) littermates. Del1 ...
Reconstruction of nasal lesions is complex due to the topography, mobile free margins and borders... more Reconstruction of nasal lesions is complex due to the topography, mobile free margins and borders of anatomical subunits. Reconstructive challenges can lead to multiple revisional surgeries to achieve the final aesthetic result. This study aimed to evaluate risk factors and predictors of revisional surgery in patients undergoing reconstruction after Mohs micrographic surgery for nasal tumours. This was a prospective cohort study from April 2, 2008 to February 26, 2019. The study population included all consecutive patients who underwent Mohs micrographic surgery for nasal skin cancer. Resection and reconstruction of nasal skin cancer was performed by the Mohs team. A total of 988 cases met our study inclusion criteria with 64 (6.5%) cases requiring unplanned surgical revision. Revision rates were highest in the ala (9.0%, p < 0.05) and complex anatomical subunits (16.7%, p < 0.0001). In contrast, revision rates for dorsum lesions were lowest (1.8%, p < 0.001). In terms of r...
BACKGROUND Basal cell carcinoma (BCC) is the most common human cancer. Facial BCCs most commonly ... more BACKGROUND Basal cell carcinoma (BCC) is the most common human cancer. Facial BCCs most commonly occur on the nose and the management of these lesions is particularly complex, given the functional and complex implications of treatment. Multidisciplinary team (MDT) meetings are routinely held to integrate expertise from dermatologists, surgeons, oncologists, radiologists, pathologists and allied health professionals. The aim of this research was to develop a supervised machine-learning algorithm to predict MDT recommendations for nasal BCC to potentially reduce MDT caseload, provide automatic decision support and permit data audit in a health service context. METHODS The study population included all consecutive patients who were discussed at skin cancer-specialised MDT (SSMDT) with a diagnosis of nasal BCC between January 1, 2015 and December 31, 2015. We conducted analyses for gender, age, anatomical location, histological subtype, tumour size, tumour recurrence, anticoagulation, pacemaker, immunosuppressants and therapeutic modalities (Mohs surgery, conventional excision or radiotherapy). We used S-statistic computing language to develop a supervised machine-learning algorithm. RESULTS We found that 37.5% of patients could be reliably predicted to be triaged to Mohs micrographic surgery (MMS), based on tumour location and age. Similarly, the choice of conventional treatment (surgical excision or radiotherapy) by the MDT could be reliably predicted based on the patient's age, tumour phenotype and lesion size. Accordingly, the algorithm reliably predicted the MDT decision outcome of 45.1% of nasal BCCs. CONCLUSIONS Our study suggests that the machine-learning approach is a potentially useful tool for predicting MDT decisions for MMS vs conventional surgery or radiotherapy for a significant group of patients. We suggest that utilising this algorithm gives the MDT more time to consider more complex patients, where multiple factors, including recurrence, financial costs and cosmetic outcome, contribute to the final decision, but cannot be reliably predicted to determine that outcome. This approach has the potential to reduce the burden and improve the efficiency of the specialist skin MDT and, in turn, improve patient care, reduce waiting times and reduce the financial burden. Such an algorithm would need to be updated regularly to take into account any changes in patient referral patterns, treatment options or local clinical expertise. CLINICAL TRIAL REGISTRATION lPLAS_20-21_A08.
Background: Randomized controlled trials (RCTs) are gold standard assessments for healthcare inte... more Background: Randomized controlled trials (RCTs) are gold standard assessments for healthcare interventions. The Consolidated Standards of Reporting Trials (CONSORT) statement was published to maximize RCT reporting transparency. The authors conducted a systematic review to assess current compliance of RCTs published within craniofacial surgery with the CONSORT statement. Methods: The Thomson Reuters Impact Factor Report 2016 was consulted to identify craniofacial surgery journals. PubMed was used to search for recent RCTs published within the 5 journals identified. Two independent researchers assessed each study for inclusion and performed data extraction. The primary outcome was compliance of each RCT with the CONSORT statement. Secondary outcomes were the pathology and interventions examined, impact factor, multi-versus-single center, number of authors, and publication date. Results: Eighty-six studies met the inclusion criteria, across which a median of 56% (range 33%–94%) applicable CONSORT items were reported. The 5 least reported items were: trial design (3a); registration number and name of trial registry (23); who generated random allocation sequences, enrolled participants, and assigned participants to interventions (10); sample size determination (7a); mentioning “randomized trial” in the title (1a). Conclusion: The compliance of craniofacial surgery RCTs with the CONSORT statement requires improvement. Areas in need are identified, and methods to improve reporting transparency, are discussed.
Orbital dysmorphology and midface retrusion are the hallmarks of Crouzon and Apert syndromes. The... more Orbital dysmorphology and midface retrusion are the hallmarks of Crouzon and Apert syndromes. The precise nature of this deficiency is not known. Untreated Crouzon and Apert syndrome patients and age- and sex-matched controls were included. Computed tomographic scans were digitized and reconstructed. Craniometric and volumetric data relating to the orbit were collected. Thirty-one scans were included (control, n = 12; Crouzon; n = 9; Apert, n = 10). The mean age of the Apert group was 5.31 ± 5 years; Crouzon, 5.77 ± 2.7 years; and control, 6.4 ± 3.6 years. The bony orbit length was 12 percent shorter in Apert (p = 0.004) and 17 percent shorter in the Crouzon group when compared to controls (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). The bony orbital volume was 21 percent smaller in the Apert children (p = 0.0006) and 23 percent smaller in Crouzon when compared to controls (p = 0.003). Globe volume was 15 percent larger in Apert (p = 0.008) and 36 percent larger in the Crouzon group when compared to controls (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Orbital soft-tissue volume was 19 percent less in the Apert group (p = 0.004) and 29 percent less in the Crouzon group (p = 0.001) when compared to controls. A shortened bony orbit, decreased orbital and orbital soft-tissue volumes, and an increased volume of the globe were found in both conditions. Despite normal volume of the overall orbital contents, the contents are altered, and the bony orbit is shorter and holds less volume.
American journal of medical genetics. Part A, 2018
To extend the knowledge base about possible prevalence declines of specific orofacial cleft pheno... more To extend the knowledge base about possible prevalence declines of specific orofacial cleft phenotypes, here we examine prevalence in a population base from California over a two-decade period among numerous race/ethnic groups. This population-based study used vital statistics and birth defects registry data. Its population involved all births (~1.5 million births) in central California counties from 1987 to 2010. Orofacial clefts were defined as cleft lip with or without cleft palate (CLP, n=1766), and cleft palate (CP, n=922) only. The slope of prevalence of each cleft phenotype over the period 1987-2010 was estimated using weighted least squares regression. Birth prevalence of CLP was 121/100,000 live births, and 63/100,000 live births for CP. The slope for CLP decreased by 1.2 (slope: -1.2; 95% CI: -1.9, -0.5), and for CP by 0.7 (slope: -0.7; 95% CI: -1.7, 0.2) for CP. Stratification by race/ethnicity or infant sex did not demonstrate a statistical difference in slopes. We obser...
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