Vascularized free fibula flap oral rehabilitation using tissue engineered mucosa: Report of 3 cases.

The aim of this report is to introduce the use of the dermal substitute Integra® in the context of free fibula flap prelamination for mandibular reconstruction. Three cases of mandibular reconstruction with prefabricated and Integra-prelaminated vascularized fibula flaps are reported in this article. The patients reported in this case series presented with the following tumours: an extensive cemento-ossyfying fibroma, a multicystic ameloblastoma and an extensive calcifying epithelial odontogenic tumour. Virtual three-dimensional (3D) planning and 3D-printed cutting guides were used for the mandibulectomies, the flap harvest and the positioning of the implants. The dermal substitute Integra was used for prelamination instead of skin grafts. Treatment of all 3 patients was performed in two stages; the first consisted of the fibula prefabrication (dental implant insertion) and prelamination, and the second consisted of tumor resection and reconstruction with the vascularized implant-bearing fibula flap. Integra was shown to be able to generate complete mucosa-like tissue over the fibula flaps and in the peri-implant areas. The patients have been followed up for 1, 3 and 7 years, respectively, with satisfactory prosthetic, functional and aesthetic results. None of the patients developed peri-implant disease. It was observed that prelamination with the dermal substitute Integra leads to development of mucosal lining with clinical features similar to oral mucosa. In this report of three cases, use of Integra as part of the prelamination and prefabrication process, instead of skin grafts, appears able to clinically generate mucosal lining with avoidance of skin grafts.

Morbidity related to the lip-split mandibulotomy approach: a systematic and narrative review.

The lip-split mandibulotomy (LSMA) is an access procedure that has been used in head and neck (H&N) surgery as an aid to surgical resection of inaccessible tumours of the postertior oral cavity and oropharynx. Anecdotal evidence suggests that it has significant morbidity. Voices of concern within the H&N surgical community suggest that it has been abandoned in favour of technological advances such as robotic surgery. We report here the first (to our knowledge) registered systematic review of its kind, documenting the safety and efficiency of LSMA in H&N surgery. We performed a PRISMA-guided systematic review (PROSPERO-registered) and identified reports using a search algorithm in MEDLINE/EMBASE. LSMA-related surgical complications were recorded using the Clavien-Dindo classification. Secondary outcomes included swallowing dysfunction, facial cosmesis, and patient satisfaction recorded in health-related quality of life questionnaires (HRQoL). From 125 studies identified, 54 met the inclusion criteria (3872 patients). The LSMA mortality rate was 0%; we did not identify a single case of perioperative death. The median rate of osteoradionecrosis was 5.4%, whereas fistula formation was 5.7%. Malunion was noted in 4.9%. Other complications (surgical site infection, plate exposure) were around 5%. There was significant between-study variation with regards to swallowing assessment tools, but overall there was no significant difference in outcomes. This was also the case for the HRQoL questionairres. LSMA is a safe procedure with an acceptable rate of complications, and should definitely remain in the armamentarium of H&N surgery.

Internal jugular vein duplication: clinical significance for head and neck cancer ablative and reconstructive surgery.

We present the case of a 75-year-old patient with a T2N0Mo oral cancer, who underwent surgery for cancer ablation and reconstruction. Intraoperatively, a duplicate internal jugular vein (IJV) was identified. Both segments were preserved. The veins of the free radial forearm flap that was used to reconstruct the defect were anastomosed to tributaries of the anterior IJV segment. In this rare anatomical variation, the anterior segment of IJV lies medially/anteriorly to the sternocleidomastoid muscle which poses a risk of inadvertent injury during the early steps of the neck dissection (ND). The posterior segment is at risk of injury during developing levels II-III-IV of ND. It is important to preserve the anterior IJV segment as this receives all tributaries that can be used for end-to-end anastomosis for the free flap. Preoperative contrast computed tomography scan can aid in recognition of IJV duplication and help prepare the surgeon to adjust certain operative steps.

Management of the clinically N0 neck in early-stage oral squamous cell carcinoma (OSCC). An EACMFS position paper.

Metastasis of oral squamous cell carcinoma (OSCC) to the cervical lymph nodes has a significant impact on prognosis. Accurate staging of the neck is important in order to deliver appropriate treatment for locoregional control of the disease and for prognosis. The management of the neck in early, low volume disease (clinically T1/T2 oral cavity tumours) has long been debated. The risk of occult nodal involvement in cT1/T2 OSCC is estimated around 20-30%. We describe the natural evolutionary history of OSCC and its patterns of spread and metastasis to the local lymphatic basins. We discuss most published literature and studies on management of the clinically negative neck (cN0). Particular focus is given to prospective randomized trials comparing the outcomes of upfront elective neck dissection against the observational stance, and we summarize the results of the sentinel node biopsy studies. The paper discusses the significance of the primary tumour histological characteristics and specifically the tumour's depth of invasion (DOI) and its impact on predicting nodal metastasis. The DOI has been incorporated in the TNM staging highlighting its significance in aiding the treatment decision making and this is reflected in world-wide oncological guidelines. The critical analysis of all available literature amalgamates the existing evidence in early OSCC and provides recommendations in the management of the clinically N0 neck.

Surgical tracheostomies in COVID-19 patients: A multidisciplinary approach and lessons learned.

Surgical tracheostomies have a role in the weaning process of COVID-19 patients treated in intensive care units. A multidisciplinary team approach (MDT) is required for decision making. This process is augmented by specific standard operating practices implemented by senior clinicians. Here, we report on our early experience and outcomes with open tracheostomies in a cohort of COVID-19 patients. We outline the criteria that guide decision making and explore the challenges faced by our intensive care colleagues in the management of these patients. The cohort was 100% male with 90% of them having a raised Body Mass Index (BMI) and other comorbidities (hypertension and diabetes). 60% have been decannulated and have been stepped down the intensive care unit. We recorded no surgical complications or adverse events. The service to date has been shown to be effective, safe, largely reproducible and reflective.

Surgical tracheostomies in Covid-19 patients: important considerations and the "5Ts" of safety.

The coronavirus disease (covid19) pandemic (caused by the SARS-CoV-2 virus) is the greatest healthcare challenge in a generation. Clinicians are modifying the way they approach day-to-day procedures. Safety and reduction of transmission risk is paramount. Surgical tracheostomies in covid19 patients are aerosol generating procedures linked with a significant risk of viral contamination. Here, we describe our local approach for these procedures, introducing the "5Ts" of safe tracheostomy practice: Theatre set-up, Team Briefing, Transfer of patient, Tracheostomy Procedure, Team Doffing and De-brief. We identify the critical steps of the procedure and explain how we overcome the risks associated with breaking the transfer circuit to attach the patient to the theatre ventilator. We explain our technique to reduce secretion spillage when opening the trachea. We emphasise the importance of closed tracheal suctioning and mouth suctioning prior to patient transfer. We highlight the importance of maintaining a closed circuit throughout the procedure and describe tips on how to achieve this. We summarise the steps of our protocol in an "easy to reproduce" way. Finally, we emphasise the importance of communication in a constantly changing environment and challenging circumstances.

The Familial Rhino Tooth: Two Mesiodentes.

The authors herein report on 2 cases of patients who had supernumerary teeth. The 2 cases outline how 1 was managed sub-optimally and other managed efficiently. The patients were direct relatives with a very similar clinical problem. This case report explores the genetic relevance of mesiodentes. This case report aims to outline the importance in examination, diagnosis and surgical removal of supernumerary teeth. It also describes several lessons that all members of the dental and wider surgical team can learn from, with regards to supernumerary teeth and more specifically mesiodentes.

Head and neck sarcomas: A single institute series.

BACKGROUND: Sarcomas are tumours of mesenchymal origin, accounting for 1% of all malignancies. METHODS: This is a retrospective analysis of 107 head and neck sarcoma cases, treated over a period of thirteen years. RESULTS: Fifty-four patients had with craniofacial bone sarcomas (BSs) (male: 33; female: 21) with high grade osteosarcoma being the most predominant type. The soft tissue sarcomas (STS) (53 patients; male: 28, female: 25) were histologically diverse with rhabdomyosarcomas and myxofibrosarcomas being the predominant types. The majority of BSs were managed with neoadjuvant chemotherapy followed by surgery, whereas in STSs treatment included predominantly surgery followed by radiotherapy. Overall survival estimates were 79% at 2years and 64% at 5years (mean follow-up period was 48months). CONCLUSIONS: The mesenchymal origin of sarcomas, the pattern of disease spread and the different extent of cancellous bone infiltration in contrast to epithelial tumours, dictate distinct principles for surgical clearance.

Common maxillofacial terminology: do our patients understand what we say?

UNLABELLED: For a patient to make appropriate, informed decisions regarding their medical care, it is vital that the information given to them is complete and comprehensible. We have investigated patients' understanding of commonly used terms in an oral and maxillofacial clinic. To the authors' knowledge, this pertinent subject has not previously been explored for this specialty. METHOD: Patients were recruited for this questionnaire-based study in the oral and maxillofacial department out-patient clinics. The questionnaire includes multiple choice questions and 'free text' answers. RESULTS: All patients were invited to participate and we have shown the results of the 100 consecutive patients who agreed to take part. The 100 patients recruited ranged between the ages of 16 and 75. English was the first language for 76 participants. The term 'mandible' was correctly defined by 37 respondents. Sixty per cent of patients' think that a fracture is a 'crack' and less severe than a broken bone. CONCLUSION: Common maxillofacial jargon can easily be misunderstood by patients. It is essential that all clinicians appropriately modify their language during consultations in order to deliver information in a comprehensive manner, to educate patients on their condition and to ensure sensible decision making by patients.

Patterns of cervicofacial infections: analysis of the use of computed tomography.

OBJECTIVE: The aim of this study was to determine which clinical, microbiological and radiological factors contribute to the need for repeated computed tomography (CT) imaging and surgical drainage. METHODS: In this retrospective study, medical records of all patients who underwent surgical drainage of cervicofacial infections between January 2006 and August 2010 at a London tertiary referral centre were analysed. Patients who underwent CT due to a clinical suspicion of deep cervicofacial infection were divided into two groups: (1) single CT only and (2) repeated CT imaging. These groups were then compared using Fisher's exact test. Patients requiring return to theatre for additional exploration and drainage of collection were also analysed. RESULTS: Four hundred and forty-five patients were admitted with cervicofacial infections, of whom 78 patients had a CT scan. The most frequent site of infection was the submandibular space, involving 54 % of patients. Among the patients who underwent repeated imaging compared to those who underwent a single CT scan, the parapharyngeal space was involved significantly more frequently (5/24 vs 2/54, p = 0.03), as was the presence of multiple-space infections (13/24 vs 15/54, p = 0.04) and osteomyelitis (4/24 vs 0/54, p = 0.007). Multiple-space infection was also more frequent in the group who required repeat visits to theatre as compared to those who had a single drainage (7/9 vs 23/69, p = 0.02). CONCLUSIONS: The majority of cervicofacial infections are managed without the need for CT scanning. Presence of infection in multiple cervicofacial spaces and in the parapharyngeal space and presence of osteomyelitis result in persistent sepsis necessitating repeat imaging and drainage.

Nevirapine induces growth arrest and premature senescence in human cervical carcinoma cells.

OBJECTIVE: The aim of this study was to assess the impact of nevirapine on a cervix carcinoma cell line. METHODS: HeLa cells were cultured in Dulbecco's modified Eagle medium supplemented with 20% fetal bovine serum at 37 degrees C and humidified 10% CO(2) in air. Nevirapine was purified from commercially available Viramune (Boehringer-Ingelheim), diluted in dimethyl sulfoxide (DMSO, Sigma-Aldrich) in 350 microMu final concentration and added to cell cultures 5 h after seeding. The same DMSO volume (0.2% final concentration) was added to controls. RESULTS: We found that nevirapine treatment induces reversible growth arrest and produces morphological changes in treated cells. In contrast with previous reports the observed effects of nevirapine did not correlate with promotion of differentiation, but with induction of premature senescence. Premature senescence as a response to anti-tumour treatment is a common effect of the most anti-cancer chemotherapeutics. Nevirapine treated cells strongly accumulated SA-b-Gal activity and also expressed increased levels of p53 and p21 when analyzed via RT-PCR. In order to further explore the potent mechanisms of premature senescence induction we performed pChk2-Thr68 immunofluorescence analysis and found that nevirapine treated cells exhibited increased number of nuclear foci, indicating activated DNA damage response. CONCLUSION: We propose that at least in HeLa cell line nevirapine treatment exerts an effect far from the differentiation process, by introducing the cells into premature senescence. Based on these data, the effects of RT inhibitors should be further investigated since they may represent an additional agent against human cancer.

Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.

Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions.

DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.

Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1.

Replication licensing ensures once per cell cycle replication and is essential for genome stability. Overexpression of two key licensing factors, Cdc6 and Cdt1, leads to overreplication and chromosomal instability (CIN) in lower eukaryotes and recently in human cell lines. In this report, we analyzed hCdt1, hCdc6, and hGeminin, the hCdt1 inhibitor expression, in a series of non-small-cell lung carcinomas, and investigated for putative relations with G(1)/S phase regulators, tumor kinetics, and ploidy. This is the first study of these fundamental licensing elements in primary human lung carcinomas. We herein demonstrate elevated levels (more than fourfold) of hCdt1 and hCdc6 in 43% and 50% of neoplasms, respectively, whereas aberrant expression of hGeminin was observed in 49% of cases (underexpression, 12%; overexpression, 37%). hCdt1 expression positively correlated with hCdc6 and E2F-1 levels (P = 0.001 and P = 0.048, respectively). Supportive of the observed link between E2F-1 and hCdt1, we provide evidence that E2F-1 up-regulates the hCdt1 promoter in cultured mammalian cells. Interestingly, hGeminin overexpression was statistically related to increased hCdt1 levels (P = 0.025). Regarding the kinetic and ploidy status of hCdt1- and/or hCdc6-overexpressing tumors, p53-mutant cases exhibited significantly increased tumor growth values (Growth Index; GI) and aneuploidy/CIN compared to those bearing intact p53 (P = 0.008 for GI, P = 0.001 for CIN). The significance of these results was underscored by the fact that the latter parameters were independent of p53 within the hCdt1-hCdc6 normally expressing cases. Cumulatively, the above suggest a synergistic effect between hCdt1-hCdc6 overexpression and mutant-p53 over tumor growth and CIN in non-small-cell lung carcinomas.

Distinct expression patterns of the transcription factor E2F-1 in relation to tumour growth parameters in common human carcinomas.

E2F-1 is a pivotal transcription factor that integrates signals from a variety of G1/S phase regulators and modulates diverse cellular functions, such as DNA synthesis, repair, mitosis, and apoptosis. Its role in cellular proliferation and apoptosis, as depicted from experimental models and limited reports in human malignancies, remains a matter of debate. Recently, in non-small cell lung cancer, it was observed that E2F-1 overexpression was associated with tumour growth, implying an 'oncogenic' effect. To clarify further the role of E2F-1 in carcinogenesis, the investigation was expanded in four of the most common human malignancies by examining its expression status and putative impact on tumour kinetics. These issues were addressed by immunohistochemical and molecular means in 52 breast carcinomas, 42 prostate adenocarcinomas, 58 colon adenocarcinomas, and 77 superficial bladder transitional cell carcinomas (TCCs). The following results were found: (i). in breast carcinomas, E2F-1 expression correlated with proliferation (p < 0.001) and growth index (p = 0.001); (ii). in prostate adenocarcinomas, absence of E2F-1 was noted, in contrast to its expression in normal and hyperplastic glands; (iii). in colon adenocarcinomas, E2F-1 expression was inversely related to growth index (p = 0.001), being expressed in lesions with increased apoptosis (p = 0.001) and low proliferation (p < 0.001); and (iv) in superficial TCCs, E2F-1 expression correlated with proliferation (p = 0.002). Taken together, these results suggest that E2F-1 has a growth-promoting effect in breast carcinomas and superficial TCC, whereas the opposite seems to be the case for colon and prostate cancer. To interpret the above findings, the status of the pRb and p53 tumour suppressor pathways, which are known to affect E2F-1 activity, was further investigated. The results suggest that the actions of E2F-1 are mainly dependent on the functionality of these pathways. Nevertheless, the data also imply that p53-independent pathways may play a nodal role in the function of E2F-1 in colon cancer.