HER2-low expression in patients with advanced or metastatic solid tumors.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low is a newly defined category with HER2 1+ or 2+ expression by immunohistochemistry (IHC) and lack of HER2 gene amplification measured by in situ hybridization (ISH). Much remains unknown about the HER2-low status across tumor types and changes in HER2 status between primary and metastatic samples. PATIENTS AND METHODS: HER2 expression by IHC was evaluated in 4701 patients with solid tumors. We have evaluated the HER2 expression by IHC and amplification by ISH in paired breast and gastric/gastroesophageal (GEJ) primary and metastatic samples. HER2 expression was correlated with ERBB2 genomic alterations evaluated by next-generation sequencing (NGS) in non-breast, non-gastric/GEJ samples. RESULTS: HER2 expression (HER2 IHC 1-3+) was found in half (49.8%) of the cancers, with HER2-low (1 or 2+) found in many tumor types: 47.1% in breast, 34.6% in gastric/GEJ, 50.0% in salivary gland, 46.9% in lung, 46.5% in endometrial, 46% in urothelial, and 45.5% of gallbladder cancers. The concordance evaluation of HER2 expression between primary and metastatic breast cancer samples showed that HER2 3+ remained unchanged in 87.1% with a strong agreement between primary and metastatic samples, with a weighted kappa (Κ) of 0.85 (95% confidence interval 0.79-0.91). ERBB2 alterations were identified in 117 (7.5%) patients with non-breast, non-gastric/GEJ solid tumors who had NGS testing. Of 1436 patients without ERBB2 alterations, 512 (35.7%) showed any level HER2 expression by IHC. CONCLUSION: Our results show that HER2-low expression is frequently found across tumor types. These findings suggest that many patients with HER2-low solid tumors might benefit from HER2-targeted therapies.

Dosimetric feasibility of hippocampal avoidance whole brain radiotherapy with an MRI-guided linear accelerator.

PURPOSE/OBJECTIVE(S): Whole brain radiotherapy with hippocampal avoidance (HA-WBRT) is a technique utilized to treat metastatic brain disease while preserving memory and neurocognitive function. We hypothesized that the treatment planning and delivery of HA-WBRT plans is feasible with an MRI-guided linear accelerator (linac) and compared plan results with clinical non-MRI-guided C-Arm linac plans. MATERIALS/METHODS: Twelve HA-WBRT patients treated on a non-MRI-guided C-Arm linac were selected for retrospective analysis. Treatment plans were developed using a 0.35T MRI-guided linac system for comparison to clinical plans. Treatment planning goals were defined as provided in the Phase II Trial NRG CC001. MRI-guided radiotherapy (MRgRT) treatment plans were developed by a dosimetrist and compared with clinical plans. quality assurance (QA) plans were generated and delivered on the MRI-guided linac to a cylindrical diode detector array. Planning target volume (PTV) coverage was normalized to ∼95% to provide a control point for comparison of dose to the organs at risk. RESULTS: MRgRT plans were deliverable and met all clinical goals. Mean values demonstrated that the clinical plans were less heterogeneous than MRgRT plans with mean PTV V37.5 Gy of 0.00% and 0.03% (p = 0.013), respectively. Average hippocampi maximum doses were 14.19 ± 1.29 Gy and 15.00 ± 1.51 Gy, respectively. The gamma analysis comparing planned and measured doses resulted in a mean of 99.9% ± 0.12% of passing points (3%/2mm criteria). MRgRT plans had an average of 38.33 beams with average total delivery time and beam-on time of 13.7 (11.2-17.5) min and 4.1 (3.2-5.4) min, respectively. Clinical plan delivery times ranged from 3 to 7 min depending on the number of noncoplanar arcs. Planning time between the clinical and MRgRT plans was comparable. CONCLUSION: This study demonstrates that HA-WBRT can be treated using an MRI-guided linear accelerator with comparable treatment plan quality and delivery accuracy.

Mycobacterium bovis BCG Danish Strain 1331 isolated from a periarticular lesion in a domestic cat.

A 7-year-old male neutered domestic shorthair outdoor cat was referred for chronic left forelimb lameness, which had been treated with intra-articular injections of triamcinolone acetonide. A soft tissue swelling around the elbow joint, extending from the distal humerus to the proximal ulna, was surgically explored and biopsy samples obtained. Mycobacterium bovis was cultured from samples from the soft tissue and bone. The mycobacteria from the media were killed and the DNA extracted and tested on a multiplex real-time PCR for the absence of specific genes and the presence of mycobacterial genus markers. The PCR revealed bacillus Calmette-Guérin Danish Strain 1331; this was also isolated from the prescapular lymph node, muscle and bone, obtained at post mortem examination. Badgers had been vaccinated with the bacillus Calmette-Guérin vaccine SSI (Statens Serum Institute) in the area where the cat lived, in the spring and autumn of the previous year. To the authors' knowledge, this is the first report of infection with M. bovis bacillus Calmette-Guérin Danish Strain 1331 in a domestic cat, potentially associated with annual vaccination of badgers in the proximity of the cat's home.

MR-guided stereotactic body radiation therapy for intracardiac and pericardial metastases.

AIMS: To assess the safety and efficacy of MR-guided stereotactic body radiation therapy (MRgSBRT) for cardiac metastases. MATERIALS/METHODS: This single institution retrospective analysis evaluated our experience with MRgSBRT for cardiac metastases. Response rate was compared between pre-RT and post-RT imaging. Symptomatic changes were also tracked and documented. RESULTS: Between 4/2019 and 3/2020, five patients with cardiac metastases (4 intracardiac and 1 pericardial) were treated with MRgSBRT. Median age at treatment was 73 years (range 64-80) and two patients had pre-existing cardiac disease. Histologies included melanoma and breast adenocarcinoma. Median lesion diameter was 2 cm (range 1.96-5.8 cm). Three patients were symptomatic, one of whom had pulmonary hypertension and RV enlargement. Another patient had an asymptomatic arrythmia. Median PTV prescribed dose was 40 Gy (range 40-50 Gy) and delivered in five fractions on nonconsecutive days. Median PTV volume was 53.4 cc (range 8.7-116.6 cc) and median coverage was 95% (range 84.1-100%). A uniform 3 mm margin was used for real-time gating, allowing a median 7% (range 5-10%) pixel excursion tolerance. Median follow-up was 4.7 months (range 0.9-12.3). Two patients exhibited stable disease, two had a partial response and one exhibited a complete response. All symptomatic patients experienced some relief. There were no acute adverse events, however, one patient without prior cardiac disease developed atrial fibrillation 6 months after treatment. Two patients died of causes unrelated to cardiac MRgSBRT. CONCLUSION: In this largest known series of cardiac metastasis MRgSBRT, real-time image guidance enables safe treatment resulting in good response with improving presenting symptoms without acute adverse events.

Secukinumab for patients failing previous tumour necrosis factor-α inhibitor therapy: results of a randomized open-label study (SIGNATURE).

BACKGROUND: Efficacy data on therapies for patients with psoriasis who have failed tumour necrosis factor (TNF)-α inhibitor therapy is limited. OBJECTIVES: To determine the effectiveness and tolerability of secukinumab, an interleukin (IL)-17A inhibitor, in patients with moderate/severe chronic plaque psoriasis with documented efficacy failure of TNF-α inhibitor therapy (SIGNATURE study). METHODS: This was a randomized, open-label, noncomparator study in 53 dermatology centres in the U.K. and Republic of Ireland. Patients were randomized 1 : 1 to receive secukinumab 300 mg or 150 mg subcutaneously every week for 4 weeks, then 4-weekly thereafter. Patients were stratified by their prior efficacy failure with TNF-α inhibitors. Only patients who started and stayed on the same dose at each time point were included for efficacy assessments. RESULTS: In total, 233 patients were analysed. The primary end point was met, with a statistically significant improvement in response rates [75% reduction in Psoriasis Area and Severity Index (PASI 75)] from baseline to week 16 in both secukinumab 300 mg and 150 mg dose groups [77 of 118 patients (65·3%) and 51 of 115 patients (44·3%), respectively; P < 0·0001]. After 72 weeks, in patients starting and remaining on 300 mg, 77% (54 of 70) achieved PASI 75. Improvements in Dermatology Life Quality Index from baseline to week 16 occurred and were maintained up to 72 weeks. The safety profile was generally consistent with previous secukinumab studies, although a higher incidence of some adverse events (e.g. candida infections) was observed. CONCLUSIONS: This study provides evidence of efficacy and safety of secukinumab for treatment of patients with psoriasis who failed prior TNF-α inhibitor therapy. This study represents a 'real-world' population, providing reassurance that secukinumab is a treatment option in this difficult-to-treat population. What's already known about this topic? Conventional systemic nonbiological and tumour necrosis factor (TNF)-α inhibitor therapies for plaque psoriasis have not fully met patients' needs. There is a lack of data to support the treatment pathways for patients with psoriasis who have inadequate responses to TNF-α inhibitor therapy. Secukinumab, a recombinant high-affinity fully human monoclonal anti-human interleukin-17A antibody of the IgG1/κ-class, has shown excellent safety and efficacy in the treatment of moderate-to-severe psoriasis. What does this study add? This is the first study evaluating treatment with biologics after prior efficacy failure of TNF-α inhibitor therapy as defined by the U.K. National Institute for Health and Care Excellence criteria. Secukinumab is an effective treatment in this difficult-to-treat patient population. This study provides important practical information for clinicians managing psoriasis. Adverse events were consistent with the phase III programme for secukinumab, although some adverse events, e.g. candida, were increased.

Validation and psychometric evaluation of a brief screening questionnaire for psychological distress in patients with psoriasis.

BACKGROUND: Patients with psoriasis are at risk of a co-morbid diagnosis of depression and/or anxiety. It is therefore essential for dermatologists to have valid and effective instruments that can screen and monitor depression and anxiety symptoms in psoriasis patients. OBJECTIVE: The aim of this study was to validate the Mental Health Inventory (MHI-5) as a brief measure that can be used to evaluate psychological distress related to anxiety and depression in psoriasis patients. METHODS: The sample included 76 adult dermatological outpatients diagnosed with psoriasis. Participants completed the MHI-5, the Hospital Anxiety and Depression Scale (HADS) and six subscales of the Self-Compassion Scale (SCS). Confirmatory factor analysis (CFA) was applied to examine the factor structure of MHI-5. Convergent validity was examined by applying correlations among all measures. Discriminant validity was examined by applying hierarchical regression models. Reliability was examined by calculating Cronbach's alpha coefficient. RESULTS: Confirmatory factor analysis showed that the proposed one-factor model has a good fit to the data. The MHI-5 demonstrated satisfactory convergent validity by yielding significant moderate to strong correlations with the HADS and with the positive and negative subscales of the SCS. Discriminant validity was also evident with being at risk of anxiety predicting MHI-5 scores above and beyond the effect of gender and age. Hierarchical regressions were not performed because a very small number of participants (n = 3) were classified at risk of depression. The MHI-5 showed high internal consistency (α = 0.84). CONCLUSION: This investigation provided evidence that MHI-5 is a reliable and valid instrument that can be used to effectively capture psychological distress in psoriasis patients.

Investigation of the skin microbiome: swabs vs. biopsies.

BACKGROUND: Human skin is populated by diverse bacteria and there is increasing evidence that resident bacteria play a key role initiating immune responses in cutaneous diseases such as atopic dermatitis, psoriasis and hidradenitis suppurativa. Bacteria are present at all layers of the skin but many studies have relied on swabs to profile the skin microbiota. OBJECTIVES: As the pathogenesis of many skin conditions is dermal, we wanted to compare the microbiota obtained in swabs (surface) and biopsies (dermis). METHODS: Using 16S rRNA gene sequencing we established the microbial profiles of skin swabs and skin biopsies in 16 patients. RESULTS: We found differences in both diversity and taxonomic composition of the microbiome obtained from swabs and biopsies of the same individual. Several taxa were found to be more abundant in the swabs, which displayed significantly higher community richness, but Clostridiales and Bacteroidetes were significantly enriched in the biopsies. Most published research on cutaneous microbiota has been based on skin swabs, which represent the surface of the skin. CONCLUSIONS: Our study demonstrated a clear difference between the microbiome observed from skin swabs and skin biopsies. These findings may be highly relevant in disorders such as psoriasis where pathogenesis arises in the dermis. What's already known about this topic? 16S RNA gene sequencing has facilitated study of the skin microbiome. Several studies have sequenced the microbiome sampled by skin swabs. What does this study add? The microbiome data obtained using swabs and biopsies were different. Diseases that are predominantly dermal should be studied using both swabs and biopsies.

Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization - systematic review and recommendations from the HS ALLIANCE working group.

Hidradenitis suppurativa (HS)/acne inversa is a debilitating chronic disease that remains poorly understood and difficult to manage. Clinical practice is variable, and there is a need for international, evidence-based and easily applicable consensus on HS management. We report here the findings of a systematic literature review, which were subsequently used as a basis for the development of international consensus recommendations for the management of patients with HS. A systematic literature review was performed for each of nine clinical questions in HS (defined by an expert steering committee), covering comorbidity assessment, therapy (medical, surgical and combinations) and response to treatment. Included articles underwent data extraction and were graded according to the Oxford Centre for Evidence-based Medicine criteria. Evidence-based recommendations were then drafted, refined and voted upon, using a modified Delphi process. Overall, 5310 articles were screened, 171 articles were analysed, and 65 were used to derive recommendations. These articles included six randomized controlled trials plus cohort studies and case series. The highest level of evidence concerned dosing recommendations for topical clindamycin in mild disease (with systemic tetracyclines for more frequent/widespread lesions) and biologic therapy (especially adalimumab) as second-line agents (following conventional therapy failure). Good-quality evidence was available for the hidradenitis suppurativa clinical response (HiSCR) as a dichotomous outcome measure in inflammatory areas under treatment. Lower-level evidence supported recommendations for topical triclosan and oral zinc in mild-to-moderate HS, systemic clindamycin and rifampicin in moderate HS and intravenous ertapenem in selected patients with more severe disease. Intralesional or systemic steroids may also be considered. Local surgical excision is suggested for mild-to-moderate HS, with wide excision for more extensive disease. Despite a paucity of good-quality data on management decisions in HS, this systematic review has enabled the development of robust and easily applicable clinical recommendations for international physicians based on graded evidence.

Evaluation of factors associated with retained surgical sponges in veterinary patients: a survey of veterinary practitioners.

OBJECTIVES: To evaluate factors that could be associated with retained surgical sponges in veterinary patients. MATERIALS AND METHODS: A survey was distributed to 322 veterinarians attending a national veterinary conference in the UK. The survey included questions about the staff, scheduling, type of surgical procedure, surgical sponges, methods to track surgical sponges and details of clinical cases with retained surgical sponges. RESULTS: The response rate was 64 of 322 (19%). Lack of designated scheduled time for surgical procedures was reported by 30% of respondents and was variable for 31%. More than half of respondents (66%) had two people involved in each surgical procedure. The majority of respondents sterilised their own surgical sponges (91%) and used non-radiopaque surgical sponges (56%). Sponges were not counted by 27% of respondents and only occasionally by 20%. Sponge count was not recorded by 70% of respondents. The majority (66%) did not use or have a surgical checklist. Lack of awareness of gossypibomas was reported by 11% of respondents. In all, 27% of respondents were aware of at least one case of retained surgical sponge. Of the 17 cases reported, 14 were small animals. The abdomen was the most common anatomical location for retained surgical sponges and followed elective neutering. CLINICAL SIGNIFICANCE: Despite the low-response rate, our results suggest that methods of surveillance might reduce the incidence of retained surgical sponges. Lack of specifically scheduled time for surgery, few theatre staff and lack of sponge counting and documentation may have contributed to the 17 retained surgical sponge cases reported.

A cross-sectional epidemiological study of hidradenitis suppurativa in an Irish population (SHIP).

BACKGROUND: Hidradenitis suppurativa (HS), a chronic inflammatory disease that affects apocrine gland-bearing skin, has a significant impact on patients' quality of life. Estimates of the epidemiologic prevalence of HS are highly variable, and clinical data on disease characteristics and patient burden of disease remain limited. OBJECTIVE: The primary objective of this study was to determine the number of patients with HS attending dermatology clinics in a hospital setting in Ireland (within a 6-month time period). Secondary objectives included the assessment of disease characteristics and the collection of patient responses on disease burden and work productivity. METHODS: This was an epidemiologic, non-interventional, cross-sectional study across four dermatology clinics in Ireland over a 6-month time period. The disease prevalence was estimated by calculating the percentage of total patients with a diagnosis of HS (the primary population) across the selected sites. Secondary analyses were performed using the full analysis set, which consisted of eligible adults (≥18 years of age) from the primary population who provided informed consent. Data from these analyses are presented as descriptive summary statistics, with the use of an analysis of covariance for continuous endpoints. RESULTS: The prevalence of HS across the four selected sites was estimated at 1.4% (95% CI, 1.24-1.62). One hundred and fifty eligible patients comprised the full analysis set. The majority of participants were white (95.3%), female (70.0%), cigarette smokers (56.0%) and overweight or obese (body mass index ≥25 kg/m2 , 81.8%). Most patients for whom data were available presented with Hurley stage II (50.4%), and more than a third of the full analysis set had a relative with HS (34.7%). Questionnaire responses revealed a profound impact on quality of life, including diminished work productivity and various psychological comorbidities. CONCLUSION: This study offers insight into the clinical features and disease burden of hidradenitis suppurativa in an Irish population.

The relevance of serum vitamin D in psoriasis: a review.

Observational research has identified low serum levels of 25-hydroxyvitamin D (25[OH]D) in many non-skeletal diseases. Whether this is causal or due to underlying illness is unknown. Low serum 25[OH]D levels are also reported in the general population. Observational and experimental studies identify that vitamin D supplementation may be beneficial in reducing all-cause mortality in elderly women, as well as cancer mortality. Our aim was to review the literature to identify the relevance of serum 25[OH]D levels in psoriasis. Forty-five studies were included in our analysis. Most of these studies identified low serum 25[OH]D levels in psoriasis patients. Evidence of causality is lacking. Treatment with phototherapy leads to an increase in serum 25[OH]D. There is little evidence that the increase in 25[OH]D after phototherapy correlates with improved disease severity. Multiple studies report an improvement in psoriasis with vitamin D supplementation. These data are predominantly from small observational or non-randomised interventional studies. Randomised controlled trials to date have had small numbers and short follow-up periods. The optimal dose of supplementation is unknown and dosing is not standardised across different studies. The definition of vitamin D insufficiency varies across studies. Low serum 25[OH]D levels may be associated with comorbidities in psoriasis patients, including metabolic syndrome and cardiovascular risk. Evidence of causation is absent. Until further high-quality evidence is available, the relevance of low serum 25[OH]D levels in psoriasis patients is unknown, as is the benefit of supplementation on disease control. Supplementation in patients with low 25[OH]D is of benefit to those at risk of impaired bone health.

Identification of factors that may influence the selection of first-line biological therapy for people with psoriasis: a prospective, multicentre cohort study.

BACKGROUND: The Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium has a collective aim to develop a prescribing algorithm to help stratify eligible patients with psoriasis to the most appropriate biological treatment. To facilitate the adoption of a stratified approach, it is necessary to first understand the factors driving the choice of first-line biological therapy. OBJECTIVES: To identify and quantify factors that influence the selection of the first-line biological therapy for people with psoriasis. METHODS: Multinomial logistic regression was used to determine the factors that influenced the probability of treatment selection, using data from the British Association of Dermatologists Biologic Interventions Register from January 2012 to December 2015. Sensitivity analyses were performed to assess the robustness of the findings to key assumptions. RESULTS: The main analysis was based on a dataset comprising 3040 people with psoriasis. The identified factors affecting first-line biological selection within the available therapies were: presence of psoriatic arthritis; patient weight; employment status; country of registration; and baseline disease severity. Importantly, the analysis showed a general shift in prescribing behaviour over time. These results were robust to sensitivity analysis. CONCLUSIONS: This study offers important insights into the factors influencing current prescribing practice for first-line biological therapies for people with psoriasis. It provides baseline data to inform the evaluation of future potential changes that may affect prescribing behaviour, such as stratified medicine.

Renal dysfunction in patients taking fumaric acid esters - a retrospective cross-sectional study.

BACKGROUND: Fumaric acid esters (FAE) have been used for over 30 years in the management of psoriasis. There have been a number of case reports linking the use of FAE with nephrotoxicity, including acute renal injury and Fanconi syndrome. However, one large multicentre retrospective trial showed no evidence of renal dysfunction with FAE. OBJECTIVES/AIMS: The aim of this study was to determine the number of patients in our institution being treated with FAE who developed significant proteinuria or renal dysfunction. METHODS: This was a single-centre retrospective study assessing all patients on FAE who attended for follow-up during an 18-week period between February and June 2015. Demographics, comorbidities, duration and dose of treatment with FAE, proteinuria, renal function and other biochemical serum abnormalities were recorded. RESULTS: One hundred and twenty-seven patients were included in the study. Eighty-two patients had proteinuria detected at some stage during treatment with FAE, and 18 of these had persistent proteinuria (positive in at least three consecutive specimens, 12 weeks apart). Six patients (five female) developed proximal tubular dysfunction (PTD). The risk factors for the development of PTD appear to be lower bodyweight (P = 0.03), higher dose per weight (P = 0.03) and longer duration of treatment (P = 0.03). Renal dysfunction improved on discontinuation or dose reduction in FAE. CONCLUSION: Fumaric acid esters are frequently associated with transient or persistent proteinuria. Significant renal dysfunction is rare and usually reversible on dose reduction or discontinuation of FAE. This study highlights the importance of screening for proteinuria. Higher doses per weight of treatment and longer duration of FAE therapy are likely risk factors for PTD.