Multigene assays in early breast cancer: Insights from recent phase 3 studies.

Multigene assays (MGAs) guide treatment in early-stage breast cancer (ESBC) enabling selective and effective use of adjuvant chemotherapy (CT). Support for all MGAs had previously been derived from retrospectively-analyzed, prospective studies. Only 2 ESBC MGAs, the 70-gene signature (MammaPrint®) and the 21-gene Recurrence Score (RS) assay (Oncotype DX®), are now supported by entirely prospective randomized phase 3 trials. These studies varied in their primary objectives, design, and eligibility. The MINDACT study provided the first level 1 evidence for the 70-gene signature, identifying a prognostic capability irrespective of lymph node (LN) or hormone receptor (HR) status. However, the study did not support predictive value for the assay regarding adjuvant CT utility. The second prospective study, WSG-PlanB, confirmed the prognostic value of the 21-gene RS assay in HR-positive tumors with RS ≤ 11. A 5-year disease free survival (DFS) of 94% was identified in this group when treated with endocrine therapy (ET) alone regardless of N0 or N1 nodal status. The final new prospective study, TAILORx, confirmed the prognostic value of the 21-gene assay in N0 HR-positive disease, demonstrating a lack of CT benefit in patients with midrange RS. The information from these phase 3 studies confirms that MGAs are not interchangeable and that each provides different information for differing patient populations. Prognosis-only is supported for the 70-gene signature while both prognosis and the predictive value of CT are provided by the 21-gene assay. This review assesses and contrasts these phase 3 studies in the context of target populations and clinical utility.

Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?

BACKGROUND: Frontal fibrosing alopecia (FFA) is traditionally regarded as a variant of lichen planopilaris (LPP) based on histological features. Distinct clinical presentation, demographics and epidemiology suggest that differing pathogenic factors determine the final phenotype. OBJECTIVES: To map the hair follicle immune system in LPP and FFA by systematically comparing key inflammatory markers in defined hair follicle compartments. METHODS: Lesional scalp biopsies from LPP and FFA and healthy controls were stained with the following immunohistochemical markers: CD1a and CD209, CD4, CD8, CD56, CD68, CD123, CXCR3, forkhead box (FOX)P3, mast cell tryptase and cKit. Macrophage polarization was explored using CD206, CD163, CD86, receptor for advanced glycation end products (RAGE), interleukin (IL)-4 and IL-13 on paired lesional and nonlesional LPP and FFA samples. RESULTS: Increased numbers of CD8+ , CXCR3+ and FOXP3+ T cells and CD68+ macrophages were identified in the distal hair follicle epithelium and perifollicular mesenchyme in both LPP and FFA compared with controls. In both LPP and FFA, total and degranulated mast cells and CD123+ plasmacytoid dendritic cells were increased in the perifollicular mesenchyme adjacent to the bulge and infundibulum, whereas numbers of CD1a+ and CD209+ dendritic cells were significantly reduced in the infundibulum connective tissue sheath. However, only with CD68 staining was a significant difference between LPP and FFA identified, with greater numbers of CD68+ cells in LPP samples. Furthermore, the identified macrophage polarization markers downregulated CD86 and upregulated CD163 and IL-4 expression in lesional LPP compared with FFA samples. CONCLUSIONS: This comparative immunopathological analysis is the first to profile systematically the hair follicle immune system in LPP and FFA. Our analysis highlights a potential role of macrophages in disease pathobiology and suggests that macrophage polarization may differ between LPP and FFA, allowing microscopic differentiation. Linked Comment: Kinoshita-Ise. Br J Dermatol 2020; 183:419-420.

Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial.

Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

An analysis of true- and false-positive results of vocal fold uptake in positron emission tomography-computed tomography imaging.

OBJECTIVES: Positron emission tomography-computed tomography with fluorine-18 fluorodeoxy-D-glucose has a major role in the investigation of head and neck cancers. Fluorine-18 fluorodeoxy-D-glucose is not a tumour-specific tracer and can also accumulate in benign pathology. Therefore, positron emission tomography-computed tomography scan interpretation difficulties are common in the head and neck, which can produce false-positive results. This study aimed to investigate patients detected as having abnormal vocal fold uptake on fluorine-18 fluorodeoxy-D-glucose positron emission tomography-computed tomography. METHODS: Positron emission tomography-computed tomography scans were identified over a 15-month period where reports contained evidence of unilateral vocal fold uptake or vocal fold pathology. Patients' notes and laryngoscopy results were analysed. RESULTS: Forty-six patients were identified as having abnormal vocal fold uptake on positron emission tomography-computed tomography. Twenty-three patients underwent positron emission tomography-computed tomography and flexible laryngoscopy: 61 per cent of patients had true-positive positron emission tomography-computed tomography scans and 39 per cent had false-positive scan results. CONCLUSION: Most patients referred to ENT for abnormal findings on positron emission tomography-computed tomography scans had true-positive findings. Asymmetrical fluorine-18 fluorodeoxy-D-glucose uptake should raise suspicion of vocal fold pathology, accepting a false-positive rate of approximately 40 per cent.

Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa: best clinical practice guidelines.

This article summarizes recommendations reached following a systematic literature review and expert consensus on the diagnosis and management of cutaneous squamous cell carcinomas in people with epidermolysis bullosa. The guidelines are intended to help inform decision making by clinicians dealing with this complex complication of a devastating disease.

Adjuvant taxanes and the development of breast cancer-related arm lymphoedema.

BACKGROUND: Despite affecting approximately one-quarter of all patients undergoing axillary lymph node dissection, the pathophysiology of breast cancer-related lymphoedema (BCRL) remains poorly understood. More extensive locoregional treatment and higher body mass index have long been identified as major risk factors. This study aimed to identify risk factors for BCRL with a specific focus on the potential impact of chemotherapy on the risk of BCRL. METHODS: This was a retrospective analysis of a cohort of consecutive patients with breast cancer treated at a major London regional teaching hospital between 1 January 2010 and 31 December 2012. All patients had node-positive disease and underwent axillary lymph node dissection. Data regarding tumour-, patient- and treatment-related characteristics were collected prospectively. The diagnosis of BCRL was based on both subjective and objective criteria. Multivariable Cox proportional hazards regression was used to assess the association between treatment and risk of BCRL. RESULTS: Some 27.1 per cent of all patients (74 of 273) developed BCRL over the study period. Administration of taxanes showed a strong association with the development of BCRL, as 52 (33.5 per cent) of 155 patients who received taxanes developed BCRL. Multivariable Cox regression analysis demonstrated that patients who received taxanes were nearly three times more likely to develop BCRL than patients who had no chemotherapy (hazard ratio 2.82, 95 per cent c.i. 1.31 to 6.06). No such increase was observed when taxanes were administered in the neoadjuvant setting. CONCLUSION: The present findings suggest that adjuvant taxanes play a key role in the development of BCRL after surgery. This may support the use of taxanes in a neoadjuvant rather than adjuvant setting.

Incidence of bone metastases and survival after a diagnosis of bone metastases in breast cancer patients.

BACKGROUND: Bone is the most common metastatic site associated with breast cancer. Using a database of women with breast cancer treated at Guy's Hospital, London 1976-2006 and followed until end 2010, we determined incidence of and survival after bone metastases. METHODS: We calculated cumulative incidence of bone metastases considering death without prior bone metastases as a competing risk. Risk of bone metastases was modelled through Cox-regression. Survival after bone metastases diagnosis was calculated using Kaplan-Meier methodology. RESULTS: Of the 7064 women, 589 (22%) developed bone metastases during 8.4 years (mean). Incidence of bone metastases was significantly higher in younger women, tumour size >5 cm, higher tumour grade, lobular carcinoma and ≥ four positive nodes, but was not affected by hormone receptor status. Median survival after bone metastases diagnosis was 2.3 years in women with bone-only metastases compared with <1 year in women with visceral and bone metastases. There was a trend for decreased survival for patients who developed visceral metastases early, and proportionately fewer patients in this group. INTERPRETATION: Incidence of bone metastases has decreased but bone metastases remain a highly relevant clinical problem due to the large number of patients being diagnosed with breast cancer.

A validation study on the use of intra-operative video recording as an objective assessment tool for core ENT surgery.

OBJECTIVES: To investigate the reliability and validity of remote scoring a video assessment of a core ENT surgical procedure (myringotomy and grommet insertion) and its suitability as an objective tool for assessing the technical skills of ENT surgeons. DESIGN: Single-blinded (raters) video assessment. SETTING: Tertiary Care University Hospital. PARTICIPANTS: Consultant and trainee [Specialty Registrar (StR) and Core Trainee (CT)] ENT surgeons performing a total of 30 consecutive index procedures. MAIN OUTCOME MEASURES: To determine the construct validity and the reliability of video assessment scoring of myringotomy and grommet insertion by two raters at ENT Consultant level with a subspecialty interest in Otology. To measure the performance (by rating) of participants compared to operative time. RESULTS: A strong correlation between scores by the two blinded raters was demonstrated (ρ = 0.748; P < 0.001). Median scores (/45) for each group were as follows: CT 25.5 (IQR 21.13-31.25), StR 33 (IQR 24.88-35) and Consultant 40 (IQR 35.38-42.63). Kruskal-Wallis test analysis showed statistically significant mean rank scores between the three different levels of experience (H = 12.77, P = 0.002). Multiple group comparisons indicated a significant difference between CT and Consultant groups (P < 0.001) and StR and Consultant groups (P = 0.007). Analysis of the time taken between the experience groups demonstrated a difference (H = 8.689, P = 0.013) although individual intergroup comparisons indicated this was only significant between CT and Consultant groups (P = 0.004). There was a significant negative correlation (ρ = -0.842; P < 0.001) between time taken for procedure and score achieved. CONCLUSIONS: Video assessment of myringotomy and ventilation tube insertion may represent a valid, feasible tool for use in summative and formative assessments of trainee ENT surgeons. Remote scoring of assessment procedures minimises bias and enables blinding of raters. ENT is well positioned to benefit from video assessment due to the high number of surgical procedures within the specialty that are performed utilising digital technology.

Age at diagnosis and distant metastasis in breast cancer--a surprising inverse relationship.

INTRODUCTION: Predictors for site of distant metastasis and impact on survival in breast cancer are incompletely understood. METHODS: Clinico-pathological risk factors for site of distant metastasis and survival were analysed in patients with invasive breast cancer treated between 1986 and 2006. RESULTS: Of 3553 patients, with median follow-up 6.32years, 825 (23%) developed distant metastasis. The site of metastasis was bone in 196/825 (24%), viscera in 540/825 (65%) and unknown in 89 (11%). Larger primary invasive tumour size, higher tumour grade and axillary nodal positivity increased risk of metastasis to all sites. Lobular carcinoma was more likely to first metastasise to bone compared to invasive ductal carcinoma (NST). Oestrogen receptor (ER) negative, progesterone receptor (PgR) negative and/or Human epidermal growth factor (HER2) positive tumours were more likely to metastasise to viscera. A striking relationship between increasing age at diagnosis and a reduction in risk of distant metastasis to bone and viscera was observed. Median time to death from onset of metastatic disease was 1.52 (Interquartile range (IQR) 0.7-2.9)years for patients with bone metastasis and 0.7 (IQR 0.2-1.5)years for visceral metastasis. On multivariate analysis, despite the decrease in risk of distant metastasis with increasing age, there was an elevated hazard for death in patients >50years at diagnosis of metastasis if they developed bone metastasis, with a similar trend observed in the >70years age group if they developed visceral metastasis. CONCLUSION: These findings indicate that there are biological mechanisms underlying the impact of age on the development of distant metastasis and subsequent death. This may have important implications in the treatment of breast cancer.

Treatment modality: a predictor of continued tobacco use after treatment in patients with laryngeal cancer.

BACKGROUND: Laryngeal cancer patients who continue to smoke after treatment are at an elevated risk of mortality and morbidity. This study aimed to identify factors associated with continued tobacco use following treatment in patients with laryngeal cancer. METHODS: A smoking behaviour questionnaire, a self-report measure, was sent to 112 patients who were diagnosed with laryngeal cancer during 2006-2011 at the Brighton and Sussex University Hospitals, Brighton, UK. Patient demographics, tumour and treatment-related variables, comorbidity and socio-economic status were obtained from the medical records. RESULTS: Eighty-one per cent of patients responded to the survey; 22 per cent of these reported continued tobacco use after treatment. Treatment modality was found to be a predictor of post-therapeutic smoking (odds ratio: 4.9, p = 0.01); patients who received less invasive therapy (transoral laser microsurgery) were more likely to smoke after treatment. CONCLUSIONS: The findings of this preliminary study suggest that treatment modality influences smoking behaviour in patients with laryngeal cancer, which may have important implications for the design of anti-smoking interventions.

Treatment patterns, outcomes, and resource utilization of patients with metastatic melanoma in the U.K.: the MELODY study.

BACKGROUND: Advanced melanoma is an aggressive disease with a poor prognosis. Approved therapy is limited in the U.K. and, until recently, no treatment had improved survival over best supportive care. A deeper understanding of current clinical practice will help new agents find a place in future treatment pathways. OBJECTIVES: To document U.K. clinical practice for the treatment of patients with unresectable stage III/IV (advanced) melanoma. METHODS: MELODY (melanoma treatment patterns and outcomes among patients with unresectable stage III/IV disease: a retrospective longitudinal survey) compiled registries of consecutive patients with malignant melanoma (any stage) between 1 July 2005 and 30 June 2006 from France, Italy and the U.K. Patients with advanced melanoma and ≥ 2 months of follow-up were eligible for analysis. RESULTS: There were 220 eligible patients identified in the U.K., of whom 117 (53.2%) received systemic therapy outside of clinical trials. Over half of these patients received dacarbazine as first- or second-line therapy. Healthcare-resource utilization was extensive and patients had short survival times: 1- and 2-year survival rates after first-line systemic treatment were 45.5% [95% confidence interval (CI) 37.1-53.6] and 24.7% (95% CI 17.7-32.3), respectively. CONCLUSIONS: Systemic and palliative treatments used to manage advanced melanoma in the U.K. are associated with considerable healthcare resource utilization and poor short-term survival.

Foodborne hepatitis A outbreak associated with bakery products in northern Germany, 2012.

In October 2012, a hepatitis A (HA) outbreak with 83 laboratory-confirmed cases occurred in Lower Saxony. We defined primary outbreak cases as people with laboratory-confirmed HA and symptom onset between 8 October and 12 November 2012, residing in or visiting the affected districts. Secondary outbreak cases were persons with symptom onset after 12 November 2012 and close contact with primary cases. We identified 77 primary and six secondary cases. We enrolled 50 primary cases and 52 controls matched for age and sex, and found that 82% of cases and 60% of controls had consumed products from a particular bakery (OR=3.09; 95% CI: 1.15­8.68). Cases were more likely to have eaten sweet pastries (OR=5.74; 95% CI: 1.46­22.42). Viral isolates from five selected cases and three positively tested surfaces in the bakery had identical nucleotide sequences. One additional identical isolate derived from a salesperson of the bakery suffering from a chronic disease that required immunosuppressive treatment. Epidemiological and laboratory findings suggested that the salesperson contaminated products while packing and selling. Future risk assessment should determine whether food handlers with chronic diseases under immunosuppressive treatment could be more at risk of contaminating food and might benefit from HAV immunisation.

Training tomorrow's laryngologists - head and neck training alone is not sufficient.

BACKGROUND: Diagnostic ability is essential in laryngology. The UK Higher Surgical Training syllabus includes competencies specific to laryngology. This study aimed to identify the factors in training that lead to a consultant level of laryngology-related diagnostic ability. METHOD: An online test of training experience was constructed using laryngoscopy videos obtained from a specialist UK voice clinic. Participation was aimed at both trainees and trainers via invitation through national ENT forums. RESULTS: There were 51 complete responses. Trainees with six months of laryngology experience scored significantly higher than those without this experience (p < 0.001). There was no improvement in score demonstrated for those with head and neck specialty experience without laryngology experience. Trainees who had completed 12 months of laryngology, or 6 months of laryngology coupled with 12 months of head and neck training, scored similarly to their consultant trainers. CONCLUSION: It is recommended that all trainees have at least six months of experience in a specialist voice or laryngology placement prior to gaining the Certificate of Completion of Training.

The effect of alcohol on surgical skills.

INTRODUCTION: The General Medical Council states 'a surgeon must not work when their health state is adversely influenced by fatigue, disease, drugs or alcohol'. However, there are no defined criteria for acceptable blood alcohol levels when operating. The aim of this study was to measure the effect of varying amounts of alcohol on surgical dexterity, cognitive abilities and the social interactions required to ensure patient safety during a routine ear, nose and throat (ENT) operation. METHODS: ENT surgeons were asked to perform a microlaryngoscopy with excision of a predetermined glottic lesion on a validated laryngeal model. The procedure was repeated four times over a period of four hours with varying doses of alcohol (no alcohol control, one glass, three glasses and six glasses of wine). The parameters recorded included theatre etiquette, surgical time, operative skills and patient safety. Scores were adjudicated by two independent observers. RESULTS: The more glasses of wine consumed, the more detrimental the effect was on the surgical performance of all participants. There was a global reduction in ability of 7.25% after three glasses and 19.25% after six glasses of alcohol. No domain showed an improvement following sequential increase in blood alcohol concentration. CONCLUSIONS: This study suggests that there are no deleterious effects on surgical performance following the consumption of one glass of wine 45 minutes prior to microlaryngoscopy among ENT surgeons of varying experience. However, there is clear evidence that with three or more glasses of wine there is an adverse effect on performance, with decreased surgical dexterity, cognition functions and professionalism.