Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Field Therapy in Solid Organ Transplant Recipients: Are We Initiating Early Enough?

Organ transplant recipients (OTRs) are at increased risk for more aggressive non-melanoma skin cancer (NMSC). Recent emphasis on field therapy has complimented the canonical surgical treatment paradigm. This retrospective analysis of survey responses by patients seen at Oregon Health and Science University from 2013-2018 offers insights into patient trends and practice gaps in caring for OTRs. All patients completed a 57-point questionnaire at their first clinic visit, which included questions regarding demographics, transplant history, dermatologic history, and use of field therapy. Of the 295 patients (mean age, 56 years; M/F: 193/102) who completed the questionnaire, field therapy was reported by 31 (11%) patients. Field therapy patients noted an overall higher AK and SCC burden, with a greater proportion of patients reporting >20 AKs and >10 SCCs. Field therapy use was sparse in the low AK/low SCC group (n=25) when compared to those reporting high AK/high SCC (n=11) burden (n=4 (16%) vs n=8 (73%), P<0.01). This data suggests that OTRs with several clinically evident AKs and/or a low number of SCCs are less likely to have been treated with field therapy modalities compared to OTRs who have developed >10 AKs or ≥6 SCCs. A delay in initiation of preventative measures or field therapy in this population, however, may be a missed opportunity for intervention. Early intervention with field therapy in particularly high-risk OTRs with a low skin cancer burden may mitigate future skin cancer development.J Drugs Dermatol. 2020;19(3): doi:10.36849/JDD.2020.4759.

Long-term follow-up of two randomized trials comparing laparoscopic Nissen 360° with anterior 90° partial fundoplication.

BACKGROUND: The side-effects of Nissen fundoplication have led to modifications, including partial fundoplications such as an anterior 90° wrap. Five-year follow-up of two randomized trials suggested fewer side-effects following anterior 90° partial fundoplication, but better reflux control after Nissen fundoplication. However, longer-term outcomes have not been reported. This study combined data from previous trials to determine 10-year outcomes. METHODS: From 1999 to 2003, 191 patients were enrolled in two randomized trials comparing anterior 90° partial versus Nissen fundoplication. Trial protocols were similar, and data were combined to determine long-term clinical outcomes. Patients completed annual questionnaires assessing dysphagia, heartburn, medications, satisfaction and other symptoms. Visual analogue scales (0-10), a composite dysphagia score (0-45) and yes/no responses were used. RESULTS: Of the 191 patients, 152 (79·6 per cent) were available for 10-year follow-up. After anterior 90° fundoplication, patients reported less dysphagia to solids (score 2·03 versus 3·18 for the Nissen procedure; P = 0·037). Heartburn scores were lower after Nissen fundoplication (1·90 versus 2·83 for anterior 90° fundoplication; P = 0·035) and fewer patients required proton pump inhibitors (PPIs) (22 versus 39 per cent respectively; P = 0·035). Satisfaction scores were similar for both anterior 90° and Nissen groups (7·45 versus 7·36 respectively; P = 0·566), and the majority considered their original decision for surgery to be correct (86 versus 84 per cent; P = 0·818). CONCLUSION: After 10 years, both procedures achieved similar success as measured by global satisfaction measures. Patients who had a Nissen fundoplication reported more dysphagia, whereas more heartburn and PPI consumption were reported after anterior 90° fundoplication. Registration numbers: ACTRN12607000298415 and ACTRN12607000304437 (http://www.anzctr.org.au/).

ANTECEDENTES: Para evitar los efectos secundarios de la fundoplicatura de Nissen se han propuesto modificaciones técnicas, incluyendo las fundoplicaturas parciales como la plicatura anterior de 90°. El seguimiento a 5 años de dos ensayos aleatorizados sugiere menos efectos secundarios tras la fundoplicatura anterior de 90°, pero mejor control del reflujo con la fundoplicatura de Nissen. Sin embargo, no se han descrito los resultados a largo plazo. Este estudio combinó datos de dos ensayos previos para determinar los resultados a 10 años. MÉTODOS: Entre 1999 y 2003, se reclutaron 191 pacientes en dos ensayos aleatorizados que comparaban la fundoplicatura parcial anterior 90° versus fundoplicatura de Nissen. Los protocolos de ambos ensayos fueron similares, y los datos se combinaron para determinar los resultados clínicos a largo plazo. Los pacientes completaron cuestionarios anuales que evaluaban disfagia, pirosis, medicaciones, satisfacción y otros síntomas. Se utilizaron escalas analógicas visuales (0-10), una variable compuesta para la puntuación de disfagia (0-45) y respuestas sí/no. RESULTADOS: De los 191 pacientes, 152 (79,6%) pudieron seguirse a los 10 años. Tras la fundoplicatura anterior de 90°, los pacientes refirieron menos disfagia a sólidos (2,03 versus 3,18, P = 0,037). Las puntuaciones de pirosis fueron inferiores tras fundoplicatura de Nissen (2,83 versus 1,90, P = 0,035) y menos pacientes tomaban inhibidores de la bomba de protones (proton pump inhibitors, PPIs; 22% versus 39%, P = 0,035). Las puntuaciones de satisfacción fueron similares para ambos grupos de fundoplicatura anterior 90° y Nissen (7,45 versus 7,36, P = 0,566), y la mayoría consideró su decisión original para la cirugía como correcta (86,1% versus. 83,8%, P = 0,818). Las tasas de reoperación fueron similares (10,0% versus 8,8%). CONCLUSIÓN: Después de 10 años, ambos procedimientos lograron un éxito similar medido con medidas de satisfacción global. Los pacientes con fundoplicatura de Nissen referían más disfagia mientras que los pacientes con fundoplicatura anterior 900 describieron más pirosis y consumo de PPIs.

Primary cutaneous Epstein-Barr virus-positive diffuse large B-cell lymphoma (DLBCL) in a patient taking fingolimod.

A 55-year-old man with relapsing-remitting multiple sclerosis on fingolimod presented to the dermatology clinic with skin lesions on the left temple and cheek. Histopathology showed a diffuse infiltrate of enlarged, atypical lymphocytes throughout the dermis with an overlying grenz zone and a subpopulation of scattered smaller lymphocytes and plasma cells. Epstein-Barr virus-encoded RNA in situ hybridization stain was positive. Based on the morphologic and immunophenotypic findings, a diagnosis of EBV-positive diffuse large B-cell lymphoma was made. This case aims to raise awareness for the dermatologist that patients on fingolimod may be at increased risk of lymphoproliferative disorders.

Airflow limitation and survival after surgery for non-small cell lung cancer: Results from a systematic review and lung cancer screening trial (NLST-ACRIN sub-study).

OBJECTIVE: Lung cancer remains the single greatest cause of cancer mortality where surgery for early stage non-small cell lung cancer achieves the greatest survival. While there is growing optimism for better outcomes with screening using annual computed tomography, the impact of co-existing airflow limitation on survival remains unknown. To compare survival in non-small cell lung cancer patients undergoing surgery stratified according to the presence or absence of pre-surgery airflow limitation. MATERIALS AND METHODS: We undertook a systematic literature search of non-screen lung cancer that encompassed studies reported between January 1946 and January 2017. Full-text articles were identified following eligibility scoring, with data extracted and analysed using a standardised analytical method (PRISMA). The results of this systematic review in non-screen lung cancers were compared to real-world results from a lung cancer screening cohort (N = 10,054), where outcomes following surgery could be compared after stratification according to pre-surgery airflow limitation. RESULTS: In the systematic review, 6899 subjects were included from 10 studies; 7 were retrospective, 3 were prospective. Overall survival was 950 (44%) in 2144 people with COPD and 2597 (55%) from 4755 controls (unadjusted P value <0.001). However, the overall meta-analysed random effects odds ratio for overall survival (N = 10) and 5-year survival (N = 4) comparing those with and without COPD was 0.91 (95% CI = 0.84-1.00) and 0.99 (95% CI = 0.79-1.24) respectively. There were no signs of significant heterogeneity (I2 = 19.1%, P = 0.27) nor publication bias as assessed by funnel plot and Egger's test (P = 0.19). In the lung cancer screening sub-study of 10,054 screening participants we found no difference in 5-year survival in those with and without airflow limitation (84% and 81% respectively, P = 0.64). CONCLUSION: Survival after surgery for non-small cell lung cancer is comparable between those with and without spirometry evidence of airflow limitation. This finding was replicated in lung cancer diagnosed during screening.

Low-intensity pulsed ultrasound for treatment of tibial fractures: an economic evaluation of the TRUST study.

AIMS: This 501-patient, multi-centre, randomised controlled trial sought to establish the effect of low-intensity, pulsed, ultrasound (LIPUS) on tibial shaft fractures managed with intramedullary nailing. We conducted an economic evaluation as part of this trial. PATIENTS AND METHODS: Data for patients' use of post-operative healthcare resources and time taken to return to work were collected and costed using publicly available sources. Health-related quality of life, assessed using the Health Utilities Index Mark-3 (HUI-3), was used to derive quality-adjusted life years (QALYs). Costs and QALYs were compared between LIPUS and control (a placebo device) from a payer and societal perspective using non-parametric bootstrapping. All costs are reported in 2015 Canadian dollars unless otherwise stated. RESULTS: With a cost per device of $3,995, the mean cost was significantly higher for patients treated with LIPUS versus placebo from a payer (mean increase = $3647, 95% confidence interval (CI) $3244 to $4070; p < 0.001) or a societal perspective (mean increase = $3425, 95% CI $1568 to $5283; p < 0.001). LIPUS did not provide a significant benefit in terms of QALYs gained (mean difference = 0.023 QALYs, 95% CI -0.035 to 0.069; p = 0.474). Incremental cost-effectiveness ratios of LIPUS compared with placebo were $155 433/QALY from a payer perspective and $146 006/QALY from a societal perspective. CONCLUSION: At the current price, LIPUS is not cost-effective for fresh tibial fractures managed with intramedullary nailing. Cite this article: Bone Joint J 2017;99-B:1526-32.

Incidence of and Risk Factors for Skin Cancer in Organ Transplant Recipients in the United States.

Importance: Skin cancer is the most common malignancy occurring after organ transplantation. Although previous research has reported an increased risk of skin cancer in solid organ transplant recipients (OTRs), no study has estimated the posttransplant population-based incidence in the United States. Objective: To determine the incidence and evaluate the risk factors for posttransplant skin cancer, including squamous cell carcinoma (SCC), melanoma (MM), and Merkel cell carcinoma (MCC) in a cohort of US OTRs receiving a primary organ transplant in 2003 or 2008. Design, Setting, and Participants: This multicenter retrospective cohort study examined 10 649 adult recipients of a primary transplant performed at 26 centers across the United States in the Transplant Skin Cancer Network during 1 of 2 calendar years (either 2003 or 2008) identified through the Organ Procurement and Transplantation Network (OPTN) database. Recipients of all organs except intestine were included, and the follow-up periods were 5 and 10 years. Main Outcomes and Measures: Incident skin cancer was determined through detailed medical record review. Data on predictors were obtained from the OPTN database. The incidence rates for posttransplant skin cancer overall and for SCC, MM, and MCC were calculated per 100 000 person-years. Potential risk factors for posttransplant skin cancer were tested using multivariate Cox regression analysis to yield adjusted hazard ratios (HR). Results: Overall, 10 649 organ transplant recipients (mean [SD] age, 51 [12] years; 3873 women [36%] and 6776 men [64%]) contributed 59 923 years of follow-up. The incidence rates for posttransplant skin cancer was 1437 per 100 000 person-years. Specific subtype rates for SCC, MM, and MCC were 812, 75, and 2 per 100 000 person-years, respectively. Statistically significant risk factors for posttransplant skin cancer included pretransplant skin cancer (HR, 4.69; 95% CI, 3.26-6.73), male sex (HR, 1.56; 95% CI, 1.34-1.81), white race (HR, 9.04; 95% CI, 6.20-13.18), age at transplant 50 years or older (HR, 2.77; 95% CI, 2.20-3.48), and being transplanted in 2008 vs 2003 (HR, 1.53; 95% CI, 1.22-1.94). Conclusions and Relevance: Posttransplant skin cancer is common, with elevated risk imparted by increased age, white race, male sex, and thoracic organ transplantation. A temporal cohort effect was present. Understanding the risk factors and trends in posttransplant skin cancer is fundamental to targeted screening and prevention in this population.

The current economic burden of illness of osteoporosis in Canada.

UNLABELLED: We estimate the current burden of illness of osteoporosis in Canada is double ($4.6 billion) our previous estimates ($2.3 billion) due to improved data capture of the multiple encounters and services that accompany a fracture: emergency room, admissions to acute and step-down non-acute institutions, rehabilitation, home-assisted or long-term residency support. INTRODUCTION: We previously estimated the economic burden of illness of osteoporosis-attributable fractures in Canada for the year 2008 to be $2.3 billion in the base case and as much as $3.9 billion. The aim of this study is to update the estimate of the economic burden of illness for osteoporosis-attributable fractures for Canada based on newly available home care and long-term care (LTC) data. METHODS: Multiple national databases were used for the fiscal-year ending March 31, 2011 (FY 2010/2011) for acute institutional care, emergency visits, day surgery, secondary admissions for rehabilitation, and complex continuing care, as well as national dispensing data for osteoporosis medications. Gaps in national data were supplemented by provincial and community survey data. Osteoporosis-attributable fractures for Canadians age 50+ were identified by ICD-10-CA codes. Costs were expressed in 2014 dollars. RESULTS: In FY 2010/2011, the number of osteoporosis-attributable fractures was 131,443 resulting in 64,884 acute care admissions and 983,074 acute hospital days. Acute care costs were $1.5 billion, an 18 % increase since 2008. The cost of LTC was 33.4 times the previous estimate ($31 million versus $1.03 billion) because of improved data capture. The cost for rehabilitation and secondary admissions increased 3.4 fold, while drug costs decreased 19 %. The overall cost of osteoporosis was over $4.6 billion, an increase of 83 % from the 2008 estimate. CONCLUSION: Since the 2008 estimate, new Canadian data on home care and LTC are available which provided a better estimate of the burden of osteoporosis in Canada. This suggests that our previous estimates were seriously underestimated.

Gene by Environment Interaction Linking the Chromosome 15q25 Locus With Cigarette Consumption and Lung Cancer Susceptibility--Are African American Affected Differently?

The majority of lung cancer cases result from complex interactions between smoking exposure, genetic susceptibility and a person's immune response to chronic inflammation or lung remodelling. Epidemiological studies confirm that susceptibility to developing chronic obstructive pulmonary disease (COPD), especially emphysema, is also closely linked to lung cancer susceptibility. Genetic epidemiology studies have consistently reported associations between the chromosome 15q25 locus with lung cancer and COPD. In addition, studies show this locus to be independently associated with cigarette consumption and nicotine addiction in a dose-response manner, primarily at lower levels of cigarette consumption. Studies that measure both cigarette consumption and lung function, together with extensive genotype analysis, will be needed to further unravel these complex relationships.

The efficacy and short-term effects of electronic cigarettes as a method for smoking cessation: a systematic review and a meta-analysis.

OBJECTIVES: E-cigarettes are increasingly popular as smoking cessation aids. This review assessed the efficacy of e-cigarettes for smoking cessation as well as desire to smoke, withdrawal symptoms, and adverse events in adult smokers. METHODS: A systematic review was conducted. Studies comparing e-cigarettes to other nicotine replacement therapies or placebo were included. Data were pooled using meta-analysis. RESULTS: Of 569 articles, 5 were eligible. Study participants were more likely to stop smoking when using nicotine e-cigarettes (43/489, 9 %) versus placebo e-cigarettes (8/173, 5 %); however, this difference was not statistically significant (RR 2.02; 95 % CI 0.97, 4.22). The pooled effect estimates for the desire to smoke (RR -0.22; 95 % CI -0.80, 0.36), irritability (RR -0.03; 95% CI -0.38, 0.31), restlessness (RR -0.03; 95 % CI -0.42, 0.35), poor concentration (RR -0.01; 95 % CI -0.35, 0.32), depression (RR -0.01; 95 % CI -0.22, 0.20), hunger (RR -0.01; 95 % CI -0.32, 0.30), and average number of non-serious adverse events (RR -0.09; 95 % CI -0.28, 0.46) were not statistically significantly different. Only one study reported serious adverse events with no apparent association with e-cigarette use. CONCLUSIONS: Limited low-quality evidence of a non-statistically significant trend toward smoking cessation in adults using nicotine e-cigarettes exists compared with other therapies or placebo. Larger, high-quality studies are needed to inform policy decisions.

Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer(®) peptides.

Cryptosporidiosis, a gastroenteric disease characterised mainly by diarrheal illnesses in humans and mammals is caused by infection with the protozoan parasite Cryptosporidium. Treatment options for cryptosporidiosis are limited, with the current therapeutic nitazoxanide, only partly efficacious in immunocompetent individuals. The parasite lacks de novo purine synthesis, and is exclusively dependant on purine salvage from its host. Inhibition of the inosine 5' monophosphate dehydrogenase (IMPDH), a purine salvage enzyme that is essential for DNA synthesis, thereby offers a potential drug target against this parasite. In the present study, a yeast-two-hybrid system was used to identify Phylomer peptides within a library constructed from the genomes of 25 phylogenetically diverse bacteria that targeted the IMPDH of Cryptosporidium parvum (IMPcp) and Cryptosporidium hominis (IMPch). We identified 38 unique interacting Phylomers, of which, 12 were synthesised and screened against C. parvum in vitro. Two Phylomers exhibited significant growth inhibition (81.2-83.8% inhibition; P < 0.05), one of which consistently exhibited positive interactions with IMPcp and IMPch during primary and recapitulation yeast two-hybrid screening and did not interact with either of the human IMPDH proteins. The present study highlightsthe potential of Phylomer peptides as target validation tools for Cryptosporidium and other organisms and diseases because of their ability to bind with high affinity to target proteins and disrupt function.

Putting the pieces together: necrolytic migratory erythema and the glucagonoma syndrome.

Glucagonomas are slow-growing, rare pancreatic neuroendocrine tumors. They may present with paraneoplastic phenomena known together as the "glucagonoma syndrome." A hallmark sign of this syndrome is a rash known as necrolytic migratory erythema (NME). In this paper, the authors describe a patient with NME and other features of the glucagonoma syndrome. The diagnosis of this rare tumor requires an elevated serum glucagon level and imaging confirming a pancreatic tumor. Surgical and medical treatment options are reviewed. When detected early, a glucagonoma is surgically curable. It is therefore imperative that clinicians recognize the glucagonoma syndrome in order to make an accurate diagnosis and refer for treatment.

Clinical applications of gene-based risk prediction for lung cancer and the central role of chronic obstructive pulmonary disease.

Lung cancer is the leading cause of cancer death worldwide and nearly 90% of cases are attributable to smoking. Quitting smoking and early diagnosis of lung cancer, through computed tomographic screening, are the only ways to reduce mortality from lung cancer. Recent epidemiological studies show that risk prediction for lung cancer is optimized by using multivariate risk models that include age, smoking exposure, history of chronic obstructive pulmonary disease (COPD), family history of lung cancer, and body mass index. It has also been shown that COPD predates lung cancer in 65-70% of cases, conferring a four- to sixfold greater risk of lung cancer compared to smokers with normal lung function. Genome-wide association studies of smokers have identified a number of genetic variants associated with COPD or lung cancer. In a case-control study, where smokers with normal lungs were compared to smokers who had spirometry-defined COPD or histology confirmed lung cancer, several of these variants were shown to overlap, conferring the same susceptibility or protective effects on both COPD and lung cancer (independent of COPD status). In this perspective article, we show how combining clinical data with genetic variants can help identify heavy smokers at the greatest risk of lung cancer. Using this approach, we found that gene-based risk testing helped engage smokers in risk mitigating activities like quitting smoking and undertaking lung cancer screening. We suggest that such an approach could facilitate the targeted selection of smokers for cost-effective life-saving interventions.

Neoplastic/paraneoplastic dermatitis, fasciitis, and panniculitis.

The skin changes outlined in this article can be important clues to an underlying malignancy. Paraneoplastic dermatoses are skin disorders associated with an underlying neoplasm and whose course parallels that of the neoplasm. Recognizing these skin presentations leads to early diagnosis and management of the underlying malignancy. Effective treatment of the associated neoplasm often leads to improvement of the cutaneous manifestations and should be the primary focus of each patient's management.