A report on the state of bullying & harassment within plastic surgery in the United Kingdom.

Many surgical and medical groups in the UK and around the world have investigated the existing cultures within their own workplaces. The Australian college of surgeons, in 2015, conducted a survey that identified that bullying, harassment, sexual harassment and discrimination were endemic. Unsurprisingly this culture persists, and not only produces a workforce which underperforms but leads to continuous poor behaviour and substandard clinical outcomes for patients. PLASTA, in collaboration with BAPRAS, adopted the Royal College of Australian Surgeons survey (RACS) to sample our own plastic surgery community, at all grades. We present the results here and our suggestions for addressing these issues in the following editorial.

Less than full time training in plastic surgery: A qualitative survey-based study and practical suggestions for improvement.

The General Medical Council (GMC) has voiced its support of less-than-full-time (LTFT) training, which has been shown to have a positive impact on workforce well-being, burnout and attrition and patient safety. However, barriers to LTFT exist within plastic surgery. This study aims to understand plastic surgery trainees' perceptions of LTFT and provide practical suggestions for improvement. Two surveys were disseminated by the UK Plastic Surgery Trainees' Association (PLASTA). Survey 1 formed part of the PLASTA National Training Survey (NTS) 2021, and all plastic surgery trainees with a National Training Number (NTN) were eligible. Survey 2 looked specifically at the lived experience of LTFT trainees in plastic surgery. A total of 177 trainees responded to the NTS. Seven per cent of respondents currently work LTFT, and 50% would consider it in future. Reported barriers to applying for LTFT included concerns about reduction in pay, extension of training time, and concerns about trainers' negative perceptions of LTFT. Twenty LTFT NTN trainees responded to the LTFT-specific survey. The majority of respondents reported an overall positive impact on their training and personal lives, although many still encountered negative attitudes from trainers and peers. Based on the results of this study, we provide practical suggestions to make LTFT more accessible to and acceptable for all trainees regardless of reason for applying or gender. Promoting the uptake of LTFT and improving the experience of LTFT in plastic surgery will support a healthy work-life balance in our workforce, prevent attrition and support gender equality.

Acquired resistance to EGFR tyrosine kinase inhibitors alters the metabolism of human head and neck squamous carcinoma cells and xenograft tumours.

BACKGROUND: Acquired resistance to molecularly targeted therapeutics is a key challenge in personalised cancer medicine, highlighting the need for identifying the underlying mechanisms and early biomarkers of relapse, in order to guide subsequent patient management. METHODS: Here we use human head and neck squamous cell carcinoma (HNSCC) models and nuclear magnetic resonance (NMR) spectroscopy to assess the metabolic changes that follow acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), and which could serve as potential metabolic biomarkers of drug resistance. RESULTS: Comparison of NMR metabolite profiles obtained from control (CAL(S)) and EGFR TKI-resistant (CAL(R)) cells grown as 2D monolayers, 3D spheroids or xenograft tumours in athymic mice revealed a number of differences between the sensitive and drug-resistant models. In particular, we observed elevated levels of glycerophosphocholine (GPC) in CAL(R) relative to CAL(S) monolayers, spheroids and tumours, independent of the growth rate or environment. In addition, there was an increase in alanine, aspartate and creatine+phosphocreatine in resistant spheroids and xenografts, and increased levels of lactate, branched-chain amino acids and a fall in phosphoethanolamine only in xenografts. The xenograft lactate build-up was associated with an increased expression of the glucose transporter GLUT-1, whereas the rise in GPC was attributed to inhibition of GPC phosphodiesterase. Reduced glycerophosphocholine (GPC) and phosphocholine were observed in a second HNSCC model probably indicative of a different drug resistance mechanism. CONCLUSIONS: Our studies reveal metabolic signatures associated not only with acquired EGFR TKI resistance but also growth pattern, microenvironment and contributing mechanisms in HNSCC models. These findings warrant further investigation as metabolic biomarkers of disease relapse in the clinic.

Risk factors for alloimmunisation in the general patient population.

For hospitals providing services to regional populations, difficulties are associated with transferred patients with poorly communicated medical history and a risk of alloimmunisation. Identification of patients at risk would assist in treatment planning. A retrospective study of alloimmunised patients was undertaken, comparing the demographics and diagnoses of this population with a control patient population. A preponderance of diagnoses of Sepsis, Haematological Malignancy, GIT Bleeds and Renal Failure was demonstrated in the alloimmunised population. Consistent with prior studies, RhD negative patients and female patients were over-represented in the study group, which was also on average significantly older.

Facing the World: audit of activity 2002-2010.

BACKGROUND: Craniofacial anomalies, although uncommon, can have considerable effects on the individual, their family and society.(1-4) They carry with them a large morbidity and require a highly specialized, multidisciplinary approach to treatment.(5) Facing the World (FTW), was founded in 2002, to offer facial reconstructive surgery to children with complex, craniofacial anomalies with no prospect of local treatment, from developing countries anywhere in the world. METHODS: We present an 8-year audit of the cases treated by FTW, where children are brought from their own countries to the UK for treatment. Patient selection takes place prior to their arrival in the UK by a multidisciplinary team. Specifically the condition has to be correctable to a degree that justifies the risks involved with the surgery, and the disruption to the child and their family. RESULTS: Since inception, FTW has evaluated more than 300 cases and provided treatment in the UK for over 24 cases from 18 different countries. We present our range of cases and complications. We discuss our complication rate of 28% and mortality rate of 4% (1 case). CONCLUSIONS: Key to the sustainability of FTW is the development of local healthcare infrastructure within the developing countries to facilitate eventual local management of the more straightforward cases and follow up of these patients by well-trained medical staff. By establishing these programs, FTW aims to not only change these children's lives but to raise awareness, and help to expand the global craniofacial network whereby in the future, satellite partners will be present to help manage these conditions locally. LEVEL OF EVIDENCE: III.

Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns.

Acquired resistance to selective FLT3 inhibitors is an emerging clinical problem in the treatment of FLT3-ITD(+) acute myeloid leukaemia (AML). The paucity of valid pre-clinical models has restricted investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. We generated selective FLT3 inhibitor-resistant cells by treating the FLT3-ITD(+) human AML cell line MOLM-13 in vitro with the FLT3-selective inhibitor MLN518, and validated the resistant phenotype in vivo and in vitro. The resistant cells, MOLM-13-RES, harboured a new D835Y tyrosine kinase domain (TKD) mutation on the FLT3-ITD(+) allele. Acquired TKD mutations, including D835Y, have recently been identified in FLT3-ITD(+) patients relapsing after treatment with the novel FLT3 inhibitor, AC220. Consistent with this clinical pattern of resistance, MOLM-13-RES cells displayed high relative resistance to AC220 and Sorafenib. Furthermore, treatment of MOLM-13-RES cells with AC220 lead to loss of the FLT3 wild-type allele and the duplication of the FLT3-ITD-D835Y allele. Our FLT3-Aurora kinase inhibitor, CCT137690, successfully inhibited growth of FLT3-ITD-D835Y cells in vitro and in vivo, suggesting that dual FLT3-Aurora inhibition may overcome selective FLT3 inhibitor resistance, in part due to inhibition of Aurora kinase, and may benefit patients with FLT3-mutated AML.

Immunohistochemical discrimination of wild-type EGFR from EGFRvIII in fixed tumour specimens using anti-EGFR mAbs ICR9 and ICR10.

BACKGROUND: The human epidermal growth factor receptor (EGFR) is an important therapeutic target in oncology, and three different types of EGFR inhibitors have been approved for the treatment of cancer patients. However, there has been no clear association between the expression levels of EGFR protein in the tumours determined by the FDA-approved EGFR PharmDx kit (Dako) or other standard anti-EGFR antibodies and the response to the EGFR inhibitors. METHOD: In this study, we investigated the potential of our anti-EGFR monoclonal antibodies (mAbs; ICR9, ICR10, ICR16) for immunohistochemical diagnosis of wild-type EGFR and/or the type-III deletion mutant form of EGFR (EGFRvIII) in formalin-fixed, paraffin-embedded human tumour specimens. RESULTS: We found that the anti-EGFR mAb in the EGFR PharmDx kit stained both wild-type and EGFRvIII-expressing cells in formalin-fixed, paraffin-embedded sections. This pattern of EGFR immunostaining was also found with our anti-EGFR mAb ICR16. In contrast, mAbs ICR10 and ICR9 were specific for the wild-type EGFR. CONCLUSION: We conclude that mAbs ICR9 and ICR10 are ideal tools for investigating the expression patterns of wild-type EGFR protein in tumour specimens using immunohistochemistry, and to determine their prognostic significance, as well as predictive value for response to therapy with EGFR antibodies.

Isolated groin recurrence in vulval squamous cell cancer (VSCC). The importance of node count.

OBJECTIVE: To determine whether there is a node count which can define an adequate inguinofemoral lymphadenectomy (IFL) in primary VSCC. METHODS: A retrospective and prospective review of patients with node negative VSCC who had a full staging IFL. Detection of isolated groin recurrences (IGR) would allow groins with higher risk of groin recurrence to be identified. RESULTS: The median node count of 228 IFLs in 139 patients was eight (0-24). There were six IGR (4.3%). Increased rate of IGR was present in patients with increased age, tumour diameter and depth of invasion, lymphovascular space invasion, unilateral IFL, and moderate/poor tumour grade. In the 138 groins with node counts of eight or greater there were no IGRs compared to six in the patients with either undissected groins or groin node counts less than eight (p = 0.030) Interval to IGR was significantly shorter than other sites of recurrence. Both disease-specific and overall survival were significantly reduced in IGR. CONCLUSIONS: An inadequate IFL is a nodal count of less than eight per groin; both these groins and undissected groins are at increased risk of IGR and should have close surveillance.

Guidelines for the welfare and use of animals in cancer research.

Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.

Cross-platform Q-TOF validation of global exo-metabolomic analysis: application to human glioblastoma cells treated with the standard PI 3-Kinase inhibitor LY294002.

The reproducibility of a metabolomics method has been assessed to identify changes in tumour cell metabolites. Tissue culture media extracts were analyzed by reverse phase chromatography on a Waters Acquity T3 column with a 13 min 0.1% formic acid: acetonitrile gradient on Agilent and Waters LC-Q-TOF instruments. Features (m/z, RT) were extracted by MarkerLynx (Waters) and Molecular Feature Extractor (Agilent) in positive and negative ionization modes. The number of features were similar on both instruments and the reproducibility of ten replicates was <35% signal variability for approximately 50% and 40% of all ions detected in positive and negative ionization modes, respectively. External standards spiked to the matrix showed CVs <25% in peak areas within and between days. U87MG glioblastoma cells exposed to the PI 3-Kinase inhibitor LY294002 showed significant alterations of several confirmed features. These included glycerophosphocholine, already shown by NMR to be modulated by LY294002, highlighting the power of this technology for biomarker discovery.

Phospholipase C gamma 1 regulates the Rap GEF1-Rap1 signalling axis in the control of human prostate carcinoma cell adhesion.

Phospholipase Cgamma1 (PLCgamma1) is activated downstream of a variety of extracellular stimuli and has previously been implicated in the regulation of motility responses central to tumour cell invasion. In this study, we used a novel RNAi vector system to achieve conditional PLCgamma1 knockdown in PC3LN3 human prostate carcinoma cells for further evaluation of PLCgamma1 in tumour cell biology. Using this approach, we revealed a role for PLCgamma1 in the regulation of PC3LN3 cell adhesion that appears to be independent of its effects on tumour cell chemotactic migration and spreading in response to extracellular matrix. Subsequent microarray analysis of PLCgamma1-knockdown cells revealed Rap GEF1 mRNA to be decreased in response to PLCgamma1 loss. This translated into a decrease in Rap GEF1 protein levels and a significant loss of Rap1 activity in PLCgamma1-knockdown cells. Transient knockdown of Rap GEF1 caused a reduction in PC3LN3 adhesion while overexpression of Rap GEF1 rescued the PLCgamma1 knockdown-induced adhesion defect. These data highlight control of the Rap GEF1-Rap1 molecular switch as a specific requirement for PLCgamma1-mediated tumour cell adhesion.

Expression of CC chemokine receptor 7 in tonsillar cancer predicts cervical nodal metastasis, systemic relapse and survival.

The aim of this study was to evaluate the expression of CC chemokine receptor 7 (CCR7) in squamous cell cancer of the tonsil with respect to patterns of spread, relapse-free, overall and disease-specific survival. Eighty-four patients with squamous cell cancer of the tonsil were identified. There was a male predominance of 3 : 1 and the median age at diagnosis was 53 (range 35-86) years. The median duration of follow-up was 33 (range 2-124) months. There was a significant association between CCR7 immunopositivity and synchronous cervical nodal metastasis in patients with tonsillar cancer (Spearman's correlation coefficient 0.564; P<0.001). Relapse-free (P=0.0175), overall (P=0.0136) and disease-specific (P=0.0062) survival rates were significantly lower in patients whose tumours expressed high levels of CCR7. On multivariate analysis, high-level CCR7 staining predicted relapse-free (hazard ratio 3.0, 95% confidence intervals 1.1-8.0, P=0.026) and disease-specific (hazard ratio 10.2, 95% confidence intervals 2.1-48.6, P=0.004) survival. Fifteen percent of patients with the highest level of tumour CCR7 immunopositivity relapsed with systemic metastases. These data demonstrated that CCR7 expression was associated with cervical nodal and systemic metastases from tonsillar cancers. High levels of CCR7 expression predicted a poor prognosis.

Gefitinib (ZD1839, Iressa) as palliative treatment in recurrent or metastatic head and neck cancer.

To assess the level of activity and toxicity of gefitinib (ZD1839, Iressatrade mark) in a population of patients with locally recurrent and/or metastatic head and neck cancer. Patients were recruited into an expanded access programme through the multidisciplinary head and neck clinics at the Royal Marsden and St George's Hospitals. Patients were required to have received at least one course of standard systemic chemotherapy or radiation therapy, or be medically unfit for chemotherapy. Patients were commenced on single-agent gefitinib at a dose of 500 mg day(-1). Clinical, symptomatic and radiological response, time to progression (TTP), survival and toxicity were recorded. A total of 47 patients were enrolled (35 male and 12 female) with a median age of 62 years (range 18-93 years). The observed clinical response rate was 8% with a disease control rate (complete response, partial response, stable disease) of 36%. In all, 34% of patients experienced an improvement in their symptoms. The median TTP and survival were 2.6 and 4.3 months, respectively. Acneiform folliculitis was the most frequent toxicity observed (76%) but the majority of cases were grade 1 or 2. Only four patients experienced grade 3 toxicity of any type (all cases of folliculitis). Gefitinib was well tolerated and yielded symptomatic improvement in one-third of patients. However, this agent appeared to possess limited antitumour activity in this group of patients with head and neck cancer in whom the objective response rate, median TTP and survival were all lower than has been reported in a previous study.

Granisetron attenuates exercise-induced conditioned taste aversion in the rat.

A conditioned taste aversion (CTA) paradigm was used in the present study to investigate whether CTA produced by exercise could be attenuated by the 5-HT(3) receptor antagonist granisetron. Male Sprague-Dawley rats were randomly allocated to one of four groups (Ns=6) and were exposed to salty (0.128 M sodium chloride) or sour (0.00138M citric acid) solutions. Subjects were injected with either saline solution (1.0 ml, 0.9%) or granisetron (0.5mg/kg, IP) and were exposed to 30 min of forced wheel running exercise (70 revolutions/30min) 10 min after injection. Exercise induced CTA to both the salty (3.7 ml intake) and sour-flaroured (3.1ml intake) solutions as compared with no exercise (intake 14.0 and 13.7 ml), and administration of granisetron significantly attenuated the exercise-induced CTA to the salty- and sour-flavoured solutions.

Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer.

Squamous cell carcinoma (SCC) of the oral tongue is characterized by a high propensity for cervical nodal metastasis, which affects the probability of regional control and survival. Until now, elective treatment of the clinically negative neck in early lesions (T(1-2)) of the oral tongue cancer remains controversial. This study attempted to identify predictive factor(s) for cervical nodal metastasis and treatment outcomes in patients with early stage SCC of the oral tongue treated primarily by surgery. Fifty patients with previously untreated Stage I/II primary tongue carcinomas with available archival specimens treated at the Royal Marsden Hospital between 1981 and 1998 were reviewed. Clinico-pathological features including age, gender, alcohol and tobacco consumption, tumour location, histological grade, tumour-stromal border, growth pattern, tumour thickness, and clinical stage were evaluated and the correlations with cervical metastases and outcome analysis were determined. The overall occult nodal metastatic rate was 40% (20/50). Tumour thickness exceeding 5 mm was statistically significantly correlated with cervical metastases (P = 0.003; relative risk = 2.429). No statistical correlation was observed between other clinico-pathological parameters and nodal metastasis. With a median follow-up of 98 months, 5-year actuarial overall, disease-specific (DSS), and relapse-free survival were 65.71, 67.77, and 68.18%, respectively. Univariate analysis for DSS showed poorer outcomes for patients with age > 60 years (P = 0.0423) and tumour thickness > 5 mm (P = 0.0067). The effect of tumour thickness was maintained (P = 0.005) on multivariate analysis. The present study indicates that the thickness of primary tumour has a strong predictive value for occult cervical metastasis and poor outcomes in patients with Stage I/II oral tongue SCC. Thus, elective neck treatment (surgery or irradiation) is indicated for tumours exceeding 5 mm thickness.

C-erbB receptors in squamous cell carcinomas of the head and neck: clinical significance and correlation with matrix metalloproteinases and vascular endothelial growth factors.

We studied the profile of four c-erbB receptors in head and neck squamous cell carcinomas (HNSCC) and to determine whether their expression was associated with clinicopathological features and key molecules involved in angiogenesis and metastasis. We also assessed the impact of expression on survival. This study included 54 cases of primary HNSCC, of which 27 cases showed lymph node metastasis. The expression of c-erbB receptors, matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) family members was analysed in the same tissue homogenates by semi-quantitative RT-PCR. HNSCC frequently co-expressed multiple c-erbB receptors and showed significant correlations amongst their levels. High expression of epidermal growth factor receptor (EGFR), c-erbB-2 or c-erbB-3 was associated with an infiltrating mode of invasion, nodal metastases and advanced pathological stages. EGFR and c-erbB-2 levels were strongly correlated (P=0.0004-0.029) with the expression of MMP-2, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, VEGF-A and VEGF-C whereas the levels of c-erbB-3 and B-4 showed a weaker correlation (P=0.049-0.01) with some MMPs and VEGF-C. Only nodal metastasis and EGFR levels were significantly associated with poor outcome in uni- and multi-variate analysis. We conclude that co-operative signalling of all four c-erbB receptors may play a significant role in the pathogenesis of HNSCC. Amongst these, EGFR appears to be the dominant component controlling the invasive and angio-/lymphangiogenic phenotype in HNSCC via upregulation of multiple MMPs and VEGFs.

Plasma basic fibroblast growth factor levels in colorectal cancer: a clinically useful assay?

Angiogenic cytokines in the plasma and serum of cancer patients may serve as 'surrogate' markers of tumour neoangiogenesis. Serum VEGF correlates with disease stage in colorectal cancer (CRC), but the role of bFGF in CRC is uncertain. This study aimed to assess plasma bFGF levels in CRC patients before treatment, during chemoradiotherapy and at one-year follow-up. Plasma samples were taken from 124 CRC patients, 26 polyp patients and 55 controls, and bFGF levels were measured by ELISA. 19 patients underwent pre-operative chemoradiotherapy. One-year follow-up samples were available from 48 disease-free patients and 18 patients with progressive disease. There were no detectable differences between plasma bFGF levels in polyp, Dukes' A or B patients (4.55, 5.77, 4.25 pg/ml, respectively), but there was a significant increase in metastatic CRC patients [Dukes' C and D (7.42 and 6.6 pg/ml; P = 0.004 and 0.048, respectively)], relative to median control levels of 4.14 pg/ml. At follow-up, there was a significant fall in plasma bFGF levels in disease-free patients (pre-op 6.09 and follow-up 3.45 pg/ml, P = 0.0004), but a non-significant rise in 18 patients with progressive disease (pre-treatment 5.90 and follow-up 9.99 pg/ml, P = 0.33). Pre-treatment plasma bFGF in patients receiving chemo-radiotherapy was similar in those with responsive and non-responsive tumours. There were no detectable changes in plasma bFGF through the adenoma-carcinoma sequence or patient groups with non-metastatic cancers. Elevated plasma bFGF was, however, associated with metastatic spread. The significant fall in bFGF in disease-free patients following therapy suggests that bFGF may be useful in clinical practice.

Non-invasive methods of assessing angiogenesis and their value in predicting response to treatment in colorectal cancer.

BACKGROUND: Tumour neoangiogenesis can be assessed non-invasively by measuring angiogenic cytokine concentrations in peripheral circulation and by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The aim of this study was to assess whether these methods can predict and monitor response to treatment in patients with rectal cancer treated with preoperative chemoradiotherapy. METHODS: Serum and plasma vascular endothelial growth factor levels were measured in 31 patients with T3/T4 rectal cancers before quantitating tumour permeability (ln Ktrans) by DCE-MRI. Sixteen patients receiving preoperative chemoradiotherapy had serial vascular endothelial growth factor (VEGF) and DCE-MRI measurements. Response to treatment was assessed using World Health Organization criteria. RESULTS: Serum VEGF and ln Ktrans correlated before treatment (r = 0.48, P = 0.01). Responsive tumours (n = 8) had higher pretreatment permeability values than non-responsive tumours (n = 8) (mean ln Ktrans - 0.46 and - 0.72 respectively; P = 0.03). Compared with pretreatment values, responsive tumours showed a marked reduction in permeability at the end of treatment (mean ln Ktrans - 0.46 and - 0.86 respectively; P = 0.04). Pretreatment serum VEGF levels were not statistically different between the two groups. CONCLUSION: Rectal tumours with higher permeability at presentation appear to respond better to chemoradiotherapy than those of lower permeability. This may allow preselection of appropriate tumours for these regimens, with patients with low-permeability tumours being considered for alternative therapies.