Immunohistochemical analysis of the mechanistic target of rapamycin and hypoxia signalling pathways in basal cell carcinoma and trichoepithelioma

Background: Basal cell carcinoma (BCC) is the most common cancer in Caucasians. Trichoepithelioma (TE) is a benign neoplasm that strongly resembles BCC. Both are hair follicle (HF) tumours. HFs are hypoxic microenvironments, therefore we hypothesized that hypoxia-induced signalling pathways could be involved in BCC and TE as they are in other human malignancies. Hypoxia-inducible factor 1 (HIF1) and mechanistic/mammalian target of rapamycin (mTOR) are key players in these pathways. Objectives: To determine whether HIF1/mTOR signalling is involved in BCC and TE. Methods: We used immunohistochemical staining of formalin-fixed paraffin-embedded BCC (n = 45) and TE (n = 35) samples to assess activity of HIF1, mTORC1 and their most important target genes. The percentage positive tumour cells was assessed manually in a semi-quantitative manner and categorized (0%, 80%). Results: Among 45 BCC and 35 TE examined, expression levels were respectively 81% and 57% (BNIP3), 73% and 75% (CAIX), 79% and 86% (GLUT1), 50% and 19% (HIF1 alpha), 89% and 88% (pAKT), 55% and 61% (pS6), 15% and 25% (pMTOR), 44% and 63% (PHD2) and 44% and 49% (VEGF-A). CAIX, Glut1 and PHD2 expression levels were significantly higher in TE when only samples with at least 80% expression were included. Conclusions: HIF and mTORC1 signalling seems active in both BCC and TE. There are no appreciable differences between the two with respect to pathway activity. At this moment immunohistochemical analyses of HIF, mTORC1 and their target genes does not provide a reliable diagnostic tool for the discrimination of BCC and TE

Basal cell carcinoma: epigenetics and new treatment modalities, Out of the box

In the Netherlands, one in five people will develop basal cell carcinoma, the most common type of (skin)cancer. Surgical removal is the standard treatment for all variants of basal cell carcinoma. Although non-invasive treatments are available for superficial basal cell carcinomas, these are less effective compared to surgery. By analysing the whole genome, this dissertation demonstrates for the first time that in addition to genetic changes in basal cell carcinomas which were already known, epigenetic changes seem to play an important role as well. Epigenetic changes found in basal cell carcinomas lead to the activation of the immune system. These findings were supported by a study conducted in 124 patients. Treatment with diclofenac 3% gel (a well-known anti-inflammatory drug and painkiller) was shown to be effective by specifically inhibiting signalling pathways active in basal cell carcinomas, among other things. After applying diclofenac 3% gel for eight weeks, more than two-thirds of patients with superficial basal cell carcinoma were tumour-free. This is a first step towards more effective and specific non-invasive treatments. As a result of the involvement of several signalling pathways in basal cell carcinomas, the future lies in combination therapies

Impact of ankylosing spondylitis on sick leave, presenteeism and unpaid productivity, and estimation of the societal cost

To describe the influence of ankylosing apondylitis (AS) on sick leave, presenteeism and unpaid work restrictions and to estimate related productivity costs. 142 consecutive and unselected patients with AS under the care of rheumatologists participated in a longitudinal observational study and completed the Health and Labour Questionnaire (HLQ) assessing disease-related sick leave, presenteeism and restrictions in unpaid work over the previous 2 weeks. Logistic regressions explored which explanatory variables were associated with work outcome. Productivity loss was valued in monetary terms. Among 72 patients in paid employment, 12% had sick leave over a period of 2 weeks and 53% experienced an adverse influence of AS on work productivity while at work. Over this period they reported on average of 5.8 h sick leave and 2.4 inefficient working hours, for which they estimated an extra 1.9 h were needed to complete unfinished work. Among all patients (n=137), 71% had experienced restrictions in unpaid work during the previous 2 weeks with 42% needing help for these tasks for an average of 8 h. The annual production costs for the total group were euro1451 (95% CI 425 to 2742) per patient for sick leave, euro967 (95% CI 503 to 1496) to compensate for hours worked inefficiently while at work and euro1930 (95% CI 1404 to 2471) to substitute loss of unpaid work production. Patients with AS not only have substantial sick leave but also experience restrictions while being at work and when performing unpaid tasks. Limitations in physical functioning are strongly associated with work restrictions. Societal costs of formal and informal care are comparable with the costs of sick leave and presenteeism combine

Corporate governance and management earnings forecast behaviour:Evidence from a low private litigation environment

Purpose The purpose of our study is to examine the influence of three external corporate governance mechanisms (continuous disclosure regulatory reform, analyst following and ownership concentration) and one internal corporate governance mechanism (board structure) on the likelihood, frequency, horizon, precision and accuracy of management earnings forecasts in the low private litigation environment of New Zealand. Design/methodology/approach The authors use a sample of 1,082 management earnings forecasts issued by 125 firms listed on the New Zealand Exchange during the 1998-2007 financial reporting periods. The authors effectively control the self-selection bias problem inherent in management earnings forecasts. Findings The findings provide strong evidence that corporate governance significantly influences management earnings forecast behaviour. Firms with effective corporate governance tend to forecast earnings and provide these earnings forecasts more frequently and precisely. Earnings forecasts issued by firms with more non-executive directors on the board are less optimistically biased. A possible interpretation of the findings is that effective corporate governance mechanisms are able to substitute for a private enforcement alternative. Originality/value The findings have value in informing governance choices in the absence of external disciplinary mechanisms such as private litigation

Optical coherence tomography versus punch biopsy for diagnosis of basal cell carcinoma: a multicentre, randomised, non-inferiority trial

BACKGROUND: Punch biopsy is the gold standard for diagnosis and subtyping of basal cell carcinoma. The aim of this study was to assess whether use of optical coherence tomography (OCT), a non-invasive imaging tool, might avoid the need for biopsy. METHODS: In a multicentre, randomised, non-inferiority trial, patients (aged ≥18 years) with an indication for biopsy of a suspected basal cell carcinoma outside the H-zone (high-risk zone) of the face were randomly assigned (1:1) to receive either OCT or punch biopsy (regular care) via a web-based randomisation system. Patients were enrolled from three participating centres in the Netherlands: Maastricht University Medical Centre+, Catharina Hospital Eindhoven, and Zuyderland Medical Centre Heerlen. Stratification factors for randomisation were participating centre and the grade of clinical basal cell carcinoma suspicion (high vs low). The primary endpoint was the proportion of patients free from a recurrent or residual lesion (malignant or premalignant) 12 months after treatment. Modified intention-to-treat and per-protocol analyses were conducted, with a predefined non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov number, NCT03848078, and is complete. FINDINGS: Between Feb 25, 2019, and Sept 2, 2020, 598 patients were enrolled and randomly assigned to either the regular care group (n=299) or the OCT group (n=299). Data on the primary endpoint were available in 553 patients (n=268 in the regular care group, n=285 in the OCT group). After median follow-up of 12·7 months (IQR 11·2-14·1) in the OCT group and 12·6 months (10·8-14·3) in the regular care group, 253 (94%) of 268 patients in the OCT group and 266 (93%) of 285 patients in the regular care group were free from recurrent or residual lesions (malignant or pre-malignant) 12 months after treatment. According to our modified intention-to-treat analysis, the absolute difference (OCT vs regular care) was 1·07% (95% CI -2·93 to 5·06; one-sided p=0·30), with the lower limit of the 95% CI not exceeding the predefined non-inferiority margin of -10%. Per-protocol analyses led to proportions free from a residual or recurrent lesion (premalignant or malignant) of 95% (250 of 263) in the OCT group and 94% (262 of 278) in the regular care group, and an absolute difference of 0·81% (95% CI -2·98 to 4·60; one-sided p=0·34). INTERPRETATION: OCT-guided diagnosis and treatment of basal cell carcinoma is non-inferior to regular care punch biopsy. Implementation of OCT for diagnosis of basal cell carcinoma could reduce the number of consultations and invasive procedures. FUNDING: The Netherlands Organization for Health Research and Development and Maurits en Anna de Kock Stichting