Two by Two Factorial Design using Metformin and Curcumin for Second Primary Head and Neck Cancer Prevention Trial.

OBJECTIVE: The 2x2 factorial design is an effective method that allows for multiple comparisons, especially in the context of interactions between different interventions, without substantially increasing the required sample size. In view of the considerable preclinical evidence for Curcumin and Metformin in preventing the development and progression of head and neck squamous cell carcinoma (HNSCC), this study describes the protocol of the clinical trial towards applying the drug combination in prevention of second primary tumors. METHODS: We have applied the trial design to a large phase IIB/III double-blind, multi-centric, placebo-controlled, randomized clinical trial to determine the safety and efficacy of Metformin and Curcumin in the prevention of second primary tumours (SPT) of the aerodigestive tract following treatment of HNSCC (n=1,500) [Clinical Registry of India, CTRI/2018/03/012274]. Patients recruited in this trial will receive Metformin (with placebo), Curcumin (with placebo), Metformin, and Curcumin or placebo alone for a period of 36 months. The primary endpoint of this trial is the development of SPT, while the secondary endpoints are toxicities associated with the agents, incidence of recurrence, and identifying potential biomarkers. In this article, we discuss the 2x2 factorial design and how it applies to the head and neck cancer chemoprevention trial. CONCLUSION: 2x2 factorial design is an effective trial design for chemoprevention clinical trials where the effectiveness of multiple interventions needs to be tested parallelly.

Early Detection of Oral Potentially Malignant Disorders: A Review on Prospective Screening Methods with Regard to Global Challenges.

Oral cancer is a cancer type that is widely prevalent in low-and middle-income countries with a high mortality rate, and poor quality of life for patients after treatment. Early treatment of cancer increases patient survival, improves quality of life and results in less morbidity and a better prognosis. To reach this goal, early detection of malignancies using technologies that can be used in remote and low resource areas is desirable. Such technologies should be affordable, accurate, and easy to use and interpret. This review surveys different technologies that have the potentials of implementation in primary health and general dental practice, considering global perspectives and with a focus on the population in India, where oral cancer is highly prevalent. The technologies reviewed include both sample-based methods, such as saliva and blood analysis and brush biopsy, and more direct screening of the oral cavity including fluorescence, Raman techniques, and optical coherence tomography. Digitalisation, followed by automated artificial intelligence based analysis, are key elements in facilitating wide access to these technologies, to non-specialist personnel and in rural areas, increasing quality and objectivity of the analysis while simultaneously reducing the labour and need for highly trained specialists.

Contrasting clinical outcomes and socio-economic impact of young versus elderly-onset oral squamous cell carcinoma, a novel health economic analysis.

OBJECTIVES: The incidence of young-onset oral squamous cell carcinoma (OSCC) is growing, even among non-smokers/drinkers. The effects of adverse histopathological features on long-term oncologic outcomes between the young and old are controversial and confounded by significant heterogeneity. Few studies have evaluated the socio-economic impact of premature mortality from OSCC. Our study seeks to quantify these differences and their economic impact on society. MATERIALS AND METHODS: Four hundred and seventy-eight young (<45 years) and 1660 old patients (≥45 years) with OSCC were studied. Logistic regression determined predictors of recurrence and death. Survival analysis was calculated via the Kaplan-Meier method. A separate health economic analysis was conducted for India and Singapore. Years of Potential Productive Life Lost (YPPLL) were estimated with the Human Capital Approach, and premature mortality cost was derived using population-level data. RESULTS: Adverse histopathological features were seen more frequently in young OSCC: PNI (42.9% vs. 35%, p = 0.002), LVI (22.4% vs. 17.3%, p = 0.013) and ENE (36% vs. 24.5%, p < 0.001). Although 5-year OS/DSS were similar, the young cohort had received more intensive adjuvant therapy (CCRT 26.9% vs. 16.6%, p < 0.001). Among Singaporean males, the premature mortality cost per death was US $396,528, and per YPPLL was US $45,486. This was US $397,402 and US $38,458 for females. Among Indian males, the premature mortality cost per death was US $30,641, and per YPPLL was US $595. This was US $ 21,038 and US $305 for females. CONCLUSION: Young-onset OSCC is an aggressive disease, mitigated by the ability to receive intensive adjuvant treatment. From our loss of productivity analysis, the socio-economic costs from premature mortality are substantial. Early cancer screening and educational outreach campaigns should be tailored to this cohort. Alongside, more funding should be diverted to genetic research, developing novel biomarkers and improving the efficacy of adjuvant treatment in OSCC.

Improving accuracy in nodal staging of oral cancer: Proposal of a new system.

BACKGROUND: Despite introduction of extranodal extension (ENE) into the AJCC 8th edition of oral cancer staging, previous criticisms persist, such as limited discrimination between sub-stages and doubtful prognostic value of contralateral nodal disease. The purpose of this study was to compare our novel nodal staging system, based on the number of positive nodes and ENE, to the AJCC staging system in surgically treated patients. METHODS: Retrospective analysis of 4710 patients with oral squamous cell carcinoma (OSCC) treated with surgery±adjuvant therapy in 8 institutions in Australia, North America and Asia. With overall survival (OS) and disease specific survival (DSS) as endpoint, the prognostic performance of AJCC 8th and 7th editions were compared using hazard consistency, hazard discrimination, likelihood difference and balance. RESULTS: Our new nodal staging system (PN) a progressive and linear increase in hazard ratio (HR) from pN0 to pN3, with good separation of Kaplan Meier curves. Using the predetermined criteria for evaluation of a staging system, our proposed staging model outperformed AJCC 8th and 7th editions in prediction of OS and DSS. CONCLUSION: PN was the lymph node staging system that provided the most accurate prediction of OS and DSS for patients in our cohort of OSCC. Additionally, it can be easily adopted, addresses the shortcomings of the existing systems and should be considered for future editions of the TNM staging system.

Tobacco use and its impact on survival in young patients with oral cancer.

Background: Tobacco is a major risk factor associaetd with developing oral factor. Recent studies have shown that the age of onset, especially in Asia, is reducing. This study was to determine if tobacco exposure correlated with prognosis in oral squamous cell carcinoms (OSCC) based on age at diagnosis. Methods: Six hundred and forty three patients of OSCC treated in our institution were divided into four groups, younger patients (≤45 years) with or without tobacco exposure and older patients (>45 years) with or without tobacco exposure, and compared with respect to prognostically relevant variables, disease-free survival (DFS) and overall survival (OS). Survival analysis was performed. Results: The percentage of those with tobacco exposure was comparable in both age groups. Tobacco correlated with known pathological determinants in OSCC; however, perineural invasion, lymphovascular invasion, and extranodal extension were significantly more common in the young. On survival analysis, tobacco exposure impacted OS (P = 0.04) and DFS (P = 0.03) in patients ≤45 years, and not in older patients >45 years. On multivariate analysis, tobacco exposure in the young was significantly associated with recurrence (P = 0.03, hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.07-2.94) but not survival. Conclusion: Younger patients with a history of tobacco use have a significantly higher risk of recurrence and mortality due to OSCC, but this difference could not be attributed to any of the known prognostic determinants in OSCC. Younger patients also had more adverse pathological features. Whether this occurs because of altered disease biology or pathways of carcinogenesis in the young with tobacco exposure is unknown. Younger tobacco users with oral cancer are more likely to have a poor prognosis.

Primary Tumor Staging for Oral Cancer and a Proposed Modification Incorporating Perineural Invasion: An International Multicenter Study.

The objective of this study is to determine if the incorporation of perineural invasion (PNI) into the T-classification would improve the prognostic performance of TNM-8. An international, multicenter study of 1049 patients with oral cavity squamous cell carcinoma that were treated from 1994 to 2018 is performed. Various classification models are developed within each T-category and evaluated using the Harrel-concordance index (C-index), Akaike-information criterion (AIC), and visual inspection. Stratification into distinct prognostic categories, with internal validation, is performed using bootstrapping analysis (SPSS and R-software). Through multivariate analysis, PNI is significantly associated with disease-specific survival (p < 0.001). PNI integration into the staging system results in a significantly improved model compared with the current T category alone (lower AIC, p < 0.001). The PNI-integrated model is superior in predicting differential outcomes between T3 and T4 patients. A new model for T-classification of oral cavity squamous cell carcinoma is proposed, which is based on incorporating PNI into the staging system. These data can be used for future evaluations of the TNM staging system.

Simplified Virtual Surgical Planning Method for Reconstruction of Secondary Maxilla and Mandibular Defects Using Free Bone Flap.

Objective: Free fibula flap is the commonly used microvascular free tissue transfer for maxillary and mandibular reconstruction to restore form and function after ablative procedures. Bony reconstruction is an important aspect of reconstruction. This paper describes our technique in using virtual surgical planning for secondary reconstruction of the maxilla and mandible using only stereolithographic models. Discussion: In the recent past, virtual surgical planning has become a game changer in planning complex reconstruction of maxilla and mandible. This becomes even more important in the cases of secondary reconstruction. Virtual surgical planning requires close interaction between the surgeon and the design and manufacturing team. The latter is often done remotely making the process cumbersome and less user friendly. We have been using a simplified version of the virtual surgical planning at a low cost set up with effective outcomes. This report consists of 22 cases in which secondary reconstruction using osteo-cutaneous free fibula flap was carried out using virtual surgical planning. Mock surgery was performed on stereolithographic (STL) models (face and fibula), pre-bending of plates and fabrication of occlusal splints helped in precise translation of the treatment plan to the operating room which in turn helped in reducing the surgical time and attaining more predictable results. Conclusion: Secondary reconstruction of maxilla and mandible is complex and requires meticulous planning to achieve optimal and predictable results which directly improves the quality of life of the patients.

Early Combination of an Obturator with a Free Flap to Prevent Palatal Dehiscence Following Oral Cancer Surgery: Technique and Indications.

Introduction: In the Indian subcontinent where tobacco chewing is rampant, composite 'bite' defects are common after oral cancer ablation, which comprise buccal mucosa, maxilla and mandible with or without skin. These are often reconstructed with soft tissue flaps like anterolateral thigh flaps, which provide ample soft tissue replacement. A common problem is palatal dehiscence where these flaps are inset, due to the dynamics of speaking and chewing, as well as the gravitational pull on the flap. Materials and Methods: We describe our technique of combining an early custom obturator for these patients in the post operative period, which helps support the palatal inset and prevent dehiscence. We describe in detail the indications and workflow for this technique, mechanism of action and outcomes. Results: We show the successful result of use in a single patient with an early dehiscence and how it can be incorporated into standard workflow in selected patients at risk of dehiscence. Conclusions: This is a useful technique to prevent dehiscence in patients undergoing extensive buccal resections involving the maxilla. It allows for early oral intake and function while preventing dehiscence and dealyed wound healing, which is often costly.

Oncological outcomes of compartmental surgery and wide local excision in oral tongue and floor of the mouth cancer.

OBJECTIVES: Oral tongue carcinomas represent more than half of the tumors arising in the oral cavity, a site with a high cancer specific mortality and impact on quality of life. Current guidelines are lacking for a standardized surgical approach of these tumors. The aim of this study is to compare two currently adopted surgical strategies, compartmental surgery (CTS) and wide local excision (WLE), with loco-regional control as the main oncological endpoint. MATERIALS AND METHODS: An observational retrospective multicentric study was carried out enrolling a cohort of patients affected by oral tongue or floor of the mouth squamous cell carcinoma and surgically treated in 4 international tertiary referral centers. Survival analysis was performed by propensity-score matching approach and multivariable Cox regression analysis. RESULTS: A cohort of 933 patients was enrolled. CTS was applied in 113 patients (12.1%) and WLE in 820 (87.9%). Analyzing a propensity-score matched cohort (98 CTS vs. 172 WLE) and applying a survival multivariable modeling strategy on the whole cohort, both confirmed that CTS and WLE are comparable and oncologically safe. Parameters such as number of positive lymph nodes, depth of invasion, and lymphovascular invasion still represent the key prognosticators. CONCLUSION: The main goals for surgical resection of oral cancer remain its three-dimensional circumferential clearance with adequate margins and en-bloc removal of the tumor-lymph node tract, independently of the technique adopted (CTS or WLE). Further prospective studies including quality of life evaluation are needed to better understand if one of these approaches can provide superior functional outcomes.

Risk Stratification in Oral Cancer: A Novel Approach.

Background: Oral squamous cell carcinoma (OSCC) is a common head and neck cancer with high morbidity and mortality. Currently, treatment decisions are guided by TNM staging, which omits important negative prognosticators such as lymphovascular invasion, perineural invasion (PNI), and histologic differentiation. We proposed nomogram models based on adverse pathological features to identify candidates suitable for treatment escalation within each risk group according to the National Comprehensive Cancer Network (NCCN) guidelines. Methods: Anonymized clinicopathologic data of OSCC patients from 5 tertiary healthcare institutions in Asia were divided into 3 risk groups according to the NCCN guidelines. Within each risk group, nomograms were built to predict overall survival based on histologic differentiation, histologic margin involvement, depth of invasion (DOI), extranodal extension, PNI, lymphovascular, and bone invasion. Nomograms were internally validated with precision-recall analysis and the Kaplan-Meier survival analysis. Results: Low-risk patients with positive pathological nodal involvement and/or positive PNI should be considered for adjuvant radiotherapy. Intermediate-risk patients with gross bone invasion may benefit from concurrent chemotherapy. High-risk patients with positive margins, high DOI, and a high composite score of histologic differentiation, PNI, and the American Joint Committee on Cancer (AJCC) 8th edition T staging should be considered for treatment escalation to experimental therapies in clinical trials. Conclusion: Nomograms built based on prognostic adverse pathological features can be used within each NCCN risk group to fine-tune treatment decisions for OSCC patients.

Thyroglobulin Levels in Patients who have Undergone Hemithyroidectomy for Differentiated Thyroid Cancer. An Assessment of Levels and Trends at a Tertiary Referral Centre.

Subramanian Kannan Serum thyroglobulin (Tg) and thyroglobulin antibody (TgAb) levels are used to monitor patients with differentiated thyroid cancer (DTC) after total thyroidectomy with or without radioiodine (RAI) ablation. However, they are also measured in patients who are treated with thyroid lobectomy (TL)/hemithyroidectomy (HT). Data on the levels of Tg and its trend in those undergoing TL/HT is sparse in India. We reviewed retrospective data of DTC patients who underwent TL/HT and were followed-up with postoperative Tg levels between 2015 and 2020. Out of 247 patients, 17 had undergone either TL or HT, which included papillary thyroid cancer ( n = 12), follicular thyroid cancer ( n = 4), and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in 1 patient. All patients with DTC had tumor size < 4 cm (T1/2, clinical N0, Mx). The median follow-up was 15 months (range, 1-125) and the median Tg level was 7.5 ng/mL (interquartile range [IQR]; 3.6, 7.5) and ranged from 0.9 to 36.7 ng/mL. The median thyroid-stimulating hormone (TSH) level was 2.03 IU/L (IQR; 1.21, 3.59) and it ranged from 0.05 to 8.54 IU/L. As of last follow-up, none of them underwent completion thyroidectomy; however, eight patients had a decline in Tg ranging from 8 to 64%, four patients had increase in Tg ranging from 14 to 145%, three patients had stable Tg, and one of them had an increase in TgAb titers. As per American Thyroid Association (ATA) response-to-treatment category, six patients had indeterminate response, five patients had biochemical incomplete response, four patients had excellent response, and two did not have follow-up Tg and TgAb levels. While absolute values of Tg were well below 30 ng/mL in almost all patients with HT/TL, the Tg trends were difficult to predict, and only 23% of patients were able to satisfy the criteria for "excellent response" on follow-up. We suggest keeping this factor in mind in follow-up and while counselling for HT in patients with low-risk DTC.

Development of a Low-cost NGS Test for the Evaluation of Thyroid Nodules.

Ultrasound-guided fine needle aspiration cytology (FNAC) is the preferred method of identifying malignancy in palpable thyroid nodules using the Bethesda reporting system. However, in around 30-40% of FNACs (Bethesda categories III, IV, and V), the results are indeterminate and surgery is required to confirm malignancy. Out of those who undergo surgery, only 10-40% of patients in these categories are found to have malignancies, thus proving surgery to be unnecessary for some patients or to be incomplete in others. While molecular testing on thyroid FNAC material is part of the American Thyroid Association (ATA) guidelines in evaluating thyroid nodules, it is currently unavailable in India due to cost constraints. In this study, we prospectively collected FNAC samples from sixty-nine patients who presented with palpable thyroid nodules. We designed a cost-effective next-generation sequencing (NGS) test to query multiple variants in the DNA and RNA isolated from the fine needle aspirate. The identification of oncogenic variants was considered to be indicative of malignancy, and confirmed by surgical histopathology. The panel showed an overall sensitivity of 81.25% and a specificity of 100%, while in the case of Bethesda categories III, IV, and V, the sensitivity was higher (87.5%) and the specificity was established at 100%. The panel could thereby serve as a rule-in test for the diagnosis of thyroid cancer and therefore help identify patients who require surgery, especially in the indeterminate Bethesda categories III, IV, and V.

Remote Access Thyroid Surgery: A Review of Literature.

Since the first description of endoscopic thyroid lobectomy in 1997, a variety of techniques have been developed to avoid the visible cervical scar conventionally been associated with thyroidectomy. These "remote access" approaches, which typically use either endoscopic or robotic instrumentation, have successfully avoided the anterior neck scar, which has a measurable impact on the patient's quality of life (Graves and Suh Surgery 168(5):845-850, 2020; Sakorafas World J Surg 34(8):1793-1804, 2010). The main advantage of these techniques is better cosmesis compared to conventional transcervical approaches (Graves and Suh Surgery 168(5):845-850, 2020) However, these techniques have failed to gain widespread acceptance in the surgical community because of the technical challenges, scepticism about oncological safety and cost factors. This review presents an overview of the various methods of remote access thyroid surgery (RATS) and also evaluates the selection criteria, oncological efficacy, training requirements and key advantages of this technique.

Incorporation of adverse features in advanced oral cancer improves precision in staging and patient prognostication.

BACKGROUND: Despite revised staging criteria, stratification of patients with advanced oral squamous cell carcinoma (OSCC) remains difficult. Well-established features like perineural invasion (PNI), differentiation, and lymphovascular-invasion (LVI) are controversial, and hence omitted from staging. We endeavor to better stratify this cohort by identifying predictors of survival in advanced OSCC (T3-4). METHODS: Seven hundred and forty-two patients with T3-4 OSCC underwent surgery from 2006 to 2013. Cox regression was performed to determine predictors of overall survival (OS). RESULTS: OS was adversely impacted by PNI (p = 0.046), LVI (p = 0.038), moderate/poor differentiation (p = 0.001), close/involved surgical margins (p = 0.002), pT (p = 0.034), and pN (p < 0.001). The cumulative number of adverse histopathological features predicted poorer OS; HR 2.64 (CI 1.42-4.90) for one adverse feature and HR 4.23 (CI 2.34-7.67) for ≥2. CONCLUSION: In advanced OSCC, stratification with histopathologic risk factors can predict survival even in maximally treated patients; adjuvant therapies are unable to entirely mitigate this risk. Incorporation of adverse features into future editions of TNM can improve precision in staging and identify candidates for treatment escalation.

Low PDL1 Expression in Tumour Infiltrating Lymphocytes Predicts Local Recurrence in Oral Squamous Cell Carcinoma.

In oral squamous cell carcinoma (OSCC), expression of PDL1 is controversial with expressions showing a positive and negative correlation with survival in previous studies. Additionally, it is unclear whether expression on the tumour or tumour infiltrating lymphocytes (TIL) is a better predictor of survival. We performed this study on a cohort of Indian patients with OSCC to determine impact of PDL1 expression on survival. Retrospective analysis of 64 patients of OSCC treated with curative intent surgery with or without adjuvant therapy was performed. Stored tissue blocks were extracted and quantitative immunohistochemistry was performed for PDL1 expression separately on the tumour and the TIL using commercially available Dako kits. Correlation of clinical and pathological variables with PDL1 expression was performed using chi-square test. Survival analysis was performed using Kaplan-Meier method and Cox proportional hazards ratio. In our cohort, PDL1 expression was low, both in tumour (92% had <1% expression) and TIL (56% had <1% expression). Tumour low PDL1 expression (<1%) was associated with a higher risk of lymphovascular invasion (p = 0.044) and bone invasion (p = 0.01) but did not impact survival. Low TIL PDL1 expression (<1%) was more common in younger patients (<45 years) (p = 0.023) significantly predicting local recurrence (p = 0.02). PDL1 expression in OSCC was low. Low TIL PDL1 was common in younger patients and predicted local recurrence. Further study is required to better understand the relationship between age, tumour microenvironment and local recurrence.

Selective Neck Dissection in Oral Cavity Cancer Is Not Without Morbidity.

The objective of this study is to analyze the morbidity of selective neck dissection (SND) in oral cavity squamous cell carcinoma (OCSCC). This is a cross-sectional study of 106 consecutive patients with T1 and T2 (AJCC seventh edition) stage cancers. Morbidity in terms of scar characteristics, cervical lymphedema, sensation, shoulder dysfunction, and smile asymmetry were analyzed. Scar outcomes were inferior in terms of poor complexion in 15 patients (14.2%), poor texture in 25 patients (23.6%), limited skin movement in 9 patients (8.5%), soft tissue deficit in 13 patients (12.3%), and lymphedema in 14 patients (13.2%). Smile asymmetry was seen in 29.2%. Shoulder dysfunction was seen in 7.5%. Patients who received adjuvant treatment had significant scar issues (p = 0.001), lymphedema (p < 0.001), and sensory issues (p = 0.003). SND in OCSCC is not without morbidity. Smile asymmetry was the commonest problem. Patients who got adjuvant treatment had significantly more morbidity.

Metrics of pN-staging in oral squamous cell carcinoma: An analysis of 1,905 patients.

BACKGROUND: We aimed to compare the predictive performance of pN-categories in oral squamous cell carcinoma (OSCC) encompassing the most recent 8th edition (TNM8), its predecessor (TNM7), and a newly proposed algorithm (pN-N+), which classifies patients according to the number of positive lymph nodes and extranodal extension. METHODS: Consecutive, primary OSCC patients from seven previously published cohorts were included and classified according to the three pN-classifications: TNM7, TNM8 and pN-N+. Overall survival probabilities were summarised with the Kaplan-Meier method. We added each of the three metrics to a Cox regression adjusted for pT-category, lymph nodal yield, age, sex, radiotherapy and chemotherapy, and trained these models in one institution. We evaluated the predictive performance in the remaining six institutions and assessed the predicted 5-year risk of death using the area under the receiver operating characteristics curve (AUC) and Brier scores. RESULTS: All 1,905 included patients were classified according to TNM7 and pN-N+. A subset of 1,575 patients was additionally classified according to TNM8, leading to upstaging in 27.0%. The pN-N+ ranked overall best determined by the obtained AUC and Brier scores. In contrast to pN-N+, TNM7 and TNM8 both suffered from disproportionate patient distribution across pN-categories and poor pN-categorial discrimination on overall survival. CONCLUSIONS: The TNM8 pN-classification designates a larger subset to more advanced disease stages but failed to show improvement of its predictive performance compared to TNM7. The pN-categories of TNM7/8 are disproportionate and inconsistently discriminated. The pN-N+ conveyed the best measures of prognosis and should be considered in future TNM iterations.

Microvascular reconstruction of head and neck defects in the elderly.

BACKGROUND: Microvascular free-flap reconstruction of the head and neck is a common technique utilized across many ages. The purpose of this study was to identify if advanced age or comorbidity was associated with worse post-operative outcomes in patients undergoing free-flap reconstruction. METHODS: A retrospective analysis was performed on 344 consecutive patients undergoing free-flap surgery of the head and neck. Demographic, clinical and pathological factors were considered along with Charlson Comorbidity Index (CCI) scores and American Society of Anesthesiologists (ASA) status. Logistic regression analysis was used to investigate the association of age, CCI or ASA with post-operative complications. RESULTS: Elderly patients (≥75 years) had a higher overall complication rate (odds ratio (OR) 1.7, P = 0.04) that was restricted to medical complications (OR 2.1, P = 0.05) and not surgical complications (OR 1.4, P = 0.14). Reconstructions of defects from cutaneous malignancy predominated in the elderly cohort (48% versus 29%, P < 0.01), but there was no difference in complication rate when cutaneous or mucosal subgroups were separated by age. ASA IV status was weakly associated with surgical complications (OR 3.89, P = 0.053), but CCI and elderly age were not associated with any outcome. Median length of stay was similar between age groups. CONCLUSION: Free-flap reconstruction in older patients was associated with increased medical complications, and surgical complications were weakly associated with ASA status. Advanced age or comorbidity should not preclude microvascular reconstruction, but comorbid status should be optimized pre-operatively and factors predisposing to medical complications minimized where possible.