High frequency and mortality of head and neck malignancy in organ transplant recipients in Ireland - A national cohort study.

BACKGROUND: Solid organ transplant recipients are recognized to carry a high burden of malignancy and frequently this cancer develops in the head and neck region. Furthermore, cancer of the head and neck post-transplant carries a significantly increased mortality. In this study, we aim to conduct a national retrospective cohort study to investigate the impact of head and neck cancer in terms of frequency and mortality in a large group of solid organ transplant recipients over a 20 year time span and compare the mortality in transplant patients to non-transplant patients with head and neck cancer. METHODS: Patients in the Republic of Ireland who underwent solid organ transplantation between 1994 and 2014 who developed post-transplant head and neck malignancy were identified from the records of two prospective, national databases (National Cancer Registry of Ireland (NCRI) and The Irish Transplant Cancer Group database) working in conjunction with each other. Incidence of head and neck malignancy post-transplant was compared with the general population by means of standardised incidence ratios (SIR). Cumulative incidence of all cause and cancer related mortality from head and neck keratinocytic was undertaken by a competing risks analysis. RESULTS: A total of 3346 solid organ transplant recipients were identified, 2382 (71.2 %) kidney, 562 (16.8 %) liver, 214 (6.4 %) cardiac and 188 (5.6 %) lung. During the period of follow up of 428 patients developed head and neck cancer, representing (12.8 %) of the population. 97 % of these patients developed keratinocytic cancers, specifically, of head and neck. The frequency of post-transplant head and neck cancer was related to the duration of immunosuppression with 14 % of patients developing cancer at 10 years and 20 % having developed at least one cancer by 15 years. 12 (3 %) patients developed non-cutaneous head and neck malignancy. 10 (0.3 %) patients died due to head and neck keratinocytic malignancy post-transplant. Competing risk analysis demonstrated that organ transplantation conferred a strong independent effect of death, compared to non-transplant patients with head and neck keratinocytes. This applied specifically for kidney (HR 4.4, 95 % CI 2.5-7.8) and heart transplants (HR 6.5, 95 % CI 2.1-19.9), and overall, across the four transplant categories (P < 0.001). The SIR of developing keratinocyte cancer varied based on primary tumor site, gender, and type of transplant organ. CONCLUSION: Transplant patients demonstrate a particularly high rate of head and neck keratinocyte cancer with a very high rate of associated mortality. Physicians should be cognizant of the increased rate of malignancy in this population and monitor for red flag signs/symptoms.

The impact of switching to mTOR inhibitor-based immunosuppression on long-term non-melanoma skin cancer incidence and renal function in kidney and liver transplant recipients.

Background: Solid organ transplantation is associated with increased risk of non-melanoma skin cancer. Studies with short follow up times have suggested a reduced occurrence of these cancers in recipients treated with mammalian target of rapamycin inhibitors as maintenance immunosuppression. We aimed to describe the occurrence of skin cancers in renal and liver transplant recipients switched from calcineurin inhibitor to sirolimus-based regimes.Methods: We performed a retrospective study of sirolimus conversion within the Irish national kidney and liver transplant programs. These data were linked with the National Cancer Registry Ireland to determine the incidence of NMSC among these recipients. The incidence rate ratio (IRR) for post versus pre-conversion NMSC rates are referred in this study as an effect size with [95% confidence interval].Results: Of 4,536 kidney transplants and 574 liver transplants functioning on the 1 January 1994 or transplanted between 1 January 1994 and 01 January 1994 and 01 January 2015, 85 kidney and 88 liver transplant recipients were transitioned to sirolimus-based immunosuppression. In renal transplants, the rate of NMSC was 131 per 1000 patient years pre-switch to sirolimus, and 68 per 1000 patient years post switch, with adjusted effect size of 0.48 [0.31 - 0.74] (p = .001) following the switch. For liver transplant recipients, the rate of NMSC was 64 per 1,000 patient years pre-switch and 30 per 1,000 patient years post switch, with an adjusted effect size of 0.49 [0.22 - 1.09] (p .081). Kidney transplant recipients were followed up for a median 3.4 years. Liver transplants were followed for a median 6.6 years.Conclusions: In this study, the conversion of maintenance immunosuppression from calcineurin inhibitors to mTOR inhibitors for clinical indications did appear to reduce the incidence of NMSC in kidney and liver transplant recipients.

Post-transplant malignancy in solid organ transplant recipients in Ireland, The Irish Transplant Cancer Group.

OBJECTIVE: Solid organ transplant recipients are at increased risk of cancer compared to the general population. To date, this risk in Ireland has not been investigated. We conducted a national registry study of cancer incidence following solid organ transplantation. METHODS: National centers for solid organ transplantation supplied their respective registry databases to cross-reference with episodes of malignancy from the National Cancer Registry Ireland (NCRI) between 1994 and 2014. Standardized incidence of cancer post-transplant was compared to the general population by means of standardized incidence ratios (SIRs), and between solid organ transplant types by incidence rate ratios. RESULTS: A total of 3346 solid organ transplant recipients were included in this study. Kidney transplant recipients constituted the majority of participants (71.2%), followed by liver (16.8%), heart (6.4%), and lung (5.6%) transplants. The most common cancers within the composite of all transplant recipients included the following (SIR [95% CI]): squamous and basal cell carcinoma (20.05 [17.97, 22.31] and 7.16 [6.43, 7.96], respectively), non-Hodgkin lymphoma (6.23 [4.26, 8.59]), and renal cell carcinoma (3.36 [1.96, 5.38]). CONCLUSIONS: This study reports the incidence of cancer following solid organ transplantation in Ireland. These results have significant national policy implications for surveillance, and early diagnosis in this patient group.

Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER).

BACKGROUND: The nuclear transcription factor c-Jun is preferentially expressed in basal-cell carcinoma. Dz13 is a deoxyribozyme that targets JUN messenger RNA and has inhibited the growth of a range of tumours in mice. We did a phase 1 study to assess safety and tolerability in human beings. METHODS: Adults with nodular basal-cell carcinoma were recruited from Royal Prince Alfred Hospital, Sydney, Australia, between September, 2010, and October, 2011. Patients were assigned to receive one intratumoral injected dose of 10, 30, or 100 µg Dz13, in a 50 µL volume of lipid carrier, and were assessed for adverse effects in the first 24 h then at 7, 14, and 28 days after injection. Treated tumours were surgically excised 14 days after injection and compared with the baseline biopsy samples for expression of c-Jun and tumorigenesis markers. FINDINGS: Nine patients were recruited, of whom three received each dose of Dz13. All patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected. c-Jun expression was reduced in the excised tumours of all nine (100%) patients, compared with baseline, and histological tumour depth had decreased in five (56%) of nine. Proportions of cells positive for caspases 3, 8, and 9 and P53 were increased, but those of cells positive for Bcl-2 and MMP-9 were decreased. Infiltration by inflammatory and immune cells was stimulated. INTERPRETATION: Dz13 was safe and well tolerated after single intratumoral injections at all doses. FUNDING: Cancer Institute NSW, Cancer Council Australia, and National Health and Medical Research Council.

Staphylococcus Scalded Skin Syndrome-Induced Thrombosis Leading to Free Flap Complications: A Case Report and Review.

Staphylococcal scalded skin syndrome (SSSS) is a clinical term used for a spectrum of blistering skin conditions induced by the epidermolytic toxins of the Staphylococcus aureus bacteria. The complications of SSSS include thrombosis; however, the pathophysiology of this is still poorly understood. We present a case of free anterolateral thigh (ALT) flap failure in a patient as a result of widespread flap thrombosis associated with staphylococcal scalded skin syndrome (SSSS). This is the first reported case of free flap failure associated with SSSS. Free flap failure due to acquired prothrombotic conditions, such as infection, is a rare and potentially under-reported phenomenon. This article aims to further explore the role of both thrombophilias and provoked thrombotic events in free flap failure. A review of the literature will also be presented, and cases of free flap failure in patients with infection-induced vascular complications will be summarised.

Comparison of humans versus mobile phone-powered artificial intelligence for the diagnosis and management of pigmented skin cancer in secondary care: a multicentre, prospective, diagnostic, clinical trial.

BACKGROUND: Diagnosis of skin cancer requires medical expertise, which is scarce. Mobile phone-powered artificial intelligence (AI) could aid diagnosis, but it is unclear how this technology performs in a clinical scenario. Our primary aim was to test in the clinic whether there was equivalence between AI algorithms and clinicians for the diagnosis and management of pigmented skin lesions. METHODS: In this multicentre, prospective, diagnostic, clinical trial, we included specialist and novice clinicians and patients from two tertiary referral centres in Australia and Austria. Specialists had a specialist medical qualification related to diagnosing and managing pigmented skin lesions, whereas novices were dermatology junior doctors or registrars in trainee positions who had experience in examining and managing these lesions. Eligible patients were aged 18-99 years and had a modified Fitzpatrick I-III skin type; those in the diagnostic trial were undergoing routine excision or biopsy of one or more suspicious pigmented skin lesions bigger than 3 mm in the longest diameter, and those in the management trial had baseline total-body photographs taken within 1-4 years. We used two mobile phone-powered AI instruments incorporating a simple optical attachment: a new 7-class AI algorithm and the International Skin Imaging Collaboration (ISIC) AI algorithm, which was previously tested in a large online reader study. The reference standard for excised lesions in the diagnostic trial was histopathological examination; in the management trial, the reference standard was a descending hierarchy based on histopathological examination, comparison of baseline total-body photographs, digital monitoring, and telediagnosis. The main outcome of this study was to compare the accuracy of expert and novice diagnostic and management decisions with the two AI instruments. Possible decisions in the management trial were dismissal, biopsy, or 3-month monitoring. Decisions to monitor were considered equivalent to dismissal (scenario A) or biopsy of malignant lesions (scenario B). The trial was registered at the Australian New Zealand Clinical Trials Registry ACTRN12620000695909 (Universal trial number U1111-1251-8995). FINDINGS: The diagnostic study included 172 suspicious pigmented lesions (84 malignant) from 124 patients and the management study included 5696 pigmented lesions (18 malignant) from the whole body of 66 high-risk patients. The diagnoses of the 7-class AI algorithm were equivalent to the specialists' diagnoses (absolute accuracy difference 1·2% [95% CI -6·9 to 9·2]) and significantly superior to the novices' ones (21·5% [13·1 to 30·0]). The diagnoses of the ISIC AI algorithm were significantly inferior to the specialists' diagnoses (-11·6% [-20·3 to -3·0]) but significantly superior to the novices' ones (8·7% [-0·5 to 18·0]). The best 7-class management AI was significantly inferior to specialists' management (absolute accuracy difference in correct management decision -0·5% [95% CI -0·7 to -0·2] in scenario A and -0·4% [-0·8 to -0·05] in scenario B). Compared with the novices' management, the 7-class management AI was significantly inferior (-0·4% [-0·6 to -0·2]) in scenario A but significantly superior (0·4% [0·0 to 0·9]) in scenario B. INTERPRETATION: The mobile phone-powered AI technology is simple, practical, and accurate for the diagnosis of suspicious pigmented skin cancer in patients presenting to a specialist setting, although its usage for management decisions requires more careful execution. An AI algorithm that was superior in experimental studies was significantly inferior to specialists in a real-world scenario, suggesting that caution is needed when extrapolating results of experimental studies to clinical practice. FUNDING: MetaOptima Technology.

Trigeminal trophic syndrome treated with thermoplastic occlusion.

A 72-year-old man with a history of thrombotic CVA causing lateral medullary infarction presented with non-healing ulcers of the right side of the face of 5 months' duration. After extensive investigations, a diagnosis of trigeminal trophic syndrome was made. The ulcers progressed relentlessly despite amitriptyline and gabapentin, and he was treated with a combination of carbamazepine and thermoplastic mask occlusion of the right side of his face. Over the next 10 weeks the shallower facial ulcers began to diminish in depth and diameter, and the deeper ulcers stopped progressing. Although the patient showed early signs of healing, he died because of complications from the CVA.

Mammalian target of rapamycin (mTOR) inhibitors and skin cancer risk in nonrenal solid organ transplant recipients: systematic review and meta-analysis.

BACKGROUND: Solid organ transplant recipients have an increased risk of malignancy compared with the general population. Mammalian target of rapamycin (mTOR) inhibitors have been used as immunosuppressants in transplant recipients. There remains a lack of evidence of this treatment in nonrenal solid organ transplantation. We aimed to perform a systematic review and meta-analysis to assess the effects of mTOR inhibitors on secondary nonmelanoma skin cancer (NMSC) malignancies in nonrenal transplant recipients. METHODS: A systematic review and meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies for the present systematic review and meta-analysis included those in which patient cohorts underwent heart, liver, lung, and pancreas (i.e. nonrenal solid organ) transplantation, with treatment group being those treated with an mTOR inhibitor such as sirolimus or everolimus, and control group being placebo, or alternative non-mTOR inhibitor treatment such as calcineurin inhibitors or as per standard treatment protocol. RESULTS: From the six included studies, we found no significant difference in the odds of either primary or secondary NMSC (OR 0.73, 95% CI 0.41-1.29, P = 0.28). Pooled analysis of patients with secondary NMSC demonstrated a trend toward significant benefit with mTOR inhibitor treatment (OR 0.61, 95% CI 0.37-1.02, P = 0.06) but no protective effect for primary NMSC (OR 0.53, 95% CI 0.03-9.96, P = 0.67). CONCLUSIONS: Our results suggest that in nonrenal transplant recipients, mTOR inhibitors may have a protective effect against secondary NMSC but not primary NMSC posttransplantation. Extrapolating the findings of reduced NMSC in renal transplant populations to nonrenal transplant cases should be cautioned.

Artificial Intelligence in Dermatology-Where We Are and the Way to the Future: A Review.

Although artificial intelligence has been available for some time, it has garnered significant interest recently and has been popularized by major companies with its applications in image identification, speech recognition and problem solving. Artificial intelligence is now being increasingly studied for its potential uses in medicine. A sound understanding of the concepts of this emerging field is essential for the dermatologist as dermatology has abundant medical data and images that can be used to train artificial intelligence for patient care. There are already a number of artificial intelligence studies focusing on skin disorders such as skin cancer, psoriasis, atopic dermatitis and onychomycosis. This article aims to present a basic introduction to the concepts of artificial intelligence as well as present an overview of the current research into artificial intelligence in dermatology, examining both its current applications and its future potential.

Variation in Nonmelanoma Skin Cancer Incidence by Treatment Modality Among Patients Receiving Multiple Kidney Transplants.

IMPORTANCE: Existing data suggest that nonmelanoma skin cancer (NMSC) is more common in renal transplant recipients than in maintenance dialysis patients. However, whether the risk of NMSC varies as the treatment modality for end-stage kidney disease (ESKD) changes between dialysis and transplantation is not well described. OBJECTIVE: To determine whether the incidence of NMSC is attenuated during periods of graft loss with a return to dialysis in those who receive multiple kidney transplants. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of data from recipients of kidney transplants from the Irish National Kidney Transplant Service database, linked with the Irish Cancer Registry, from 1994 to 2014. All analysis took place between January 10, 2018 and March 31, 2018. Standardized incidence ratios (SIRs) were calculated for NMSC incidence in comparison with the general population using Irish census data as the denominator. Incidence of NMSC was calculated with modality of treatment for ESKD varying over time; incidence rates and rate ratios associated with dialysis intervals were calculated using Poisson regression; and disease was defined according to International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for cancer diagnosis. EXPOSURES: Kidney transplantation. MAIN OUTCOMES AND MEASURES: Incidence rates per 1000 patient-years and incident rate ratios of NMSC after kidney transplant. RESULTS: Data from the records of 3821 deceased or living donor kidney transplant recipients were assessed; 2399 (62.8%) male and 1422 (37.2%) female recipients; mean (SD) age at time of first data recorded, 41.9 (16.0) years. A total of 3433 recipients were included who had a functioning transplant on January 1, 1994, or received a transplant after that date up to December 31, 2014: 3215 received 1 transplant, 522 a second kidney transplant, and 84 had 3 or more kidney transplants. Periods of treatment with a functioning transplant were associated with a higher incidence of NMSC diagnosis than periods of graft failure: adjusted incidence rate ratio (aIRR), 2.19 (95% CI, 1.56-3.07), P < .001. The aIRRs of NMSC fell from 41.7 (95% CI, 39.38-44.15) per 1000 patient-years in the first transplant to 19.29 (95% CI, 13.41-27.76) in the dialysis period following the first allograft failure. Incidence similarly rose and fell following each subsequent consecutive transplant. CONCLUSIONS AND RELEVANCE: In recipients of multiple kidney transplants, while the incidence of NMSC fell during periods defined by transplant failure, there was residual elevated risk. While ascertainment bias may have contributed to the observed trends, the stagnant incidence of invasive cancer overall highlights the need for continued cancer surveillance during graft failure.

Association of methylenetetrahydrofolate reductase polymorphism and the risk of squamous cell carcinoma in renal transplant patients.

The relative risk of developing cutaneous squamous cell carcinoma (SCC) is significantly increased after organ transplantation. We investigated the genetic association of SCC in two pathways associated with cancer risks, with the potential for modification by vitamin supplementation. A total of 367 renal transplant recipients (117 with SCC and 250 without any skin cancer) were genotyped for key polymorphisms in the folate pathway (methylene tetrahydrofolate reductase; MTHFR:C677T), and the vitamin D pathway (vitamin D receptor: Intron8G/T;). Individuals carrying the MTHFR 677T allele had a marked increase in risk of SCC (adjusted odds ratio=2.54, P=0.002, after adjustment for age, ender, skin type, sun exposure score, and immunosuppression duration; lower 95% confidence boundary odds ratio of 1.41). In contrast, vitamin D receptor polymorphisms were not significantly associated. Folate-sensitive pathways may play a critical role in the elevated rate of SCC in renal transplant recipients.

Sunscreen use before and after transplantation and assessment of risk factors associated with skin cancer development in renal transplant recipients.

OBJECTIVE: To determine the degree of compliance with sunscreen use among renal transplant recipients before and after transplantation and to determine risk factors associated with skin carcinogenesis. DESIGN: Single-observer study with structured interview using a standardized questionnaire. Medical records and histology reports were examined for details of prior skin cancer. Cox proportional hazards regression was used for analysis of risk factors for developing skin cancer after transplantation. SETTING: Patients attending Beaumont Hospital, the national renal transplantation center in Dublin, Ireland. PATIENTS: The study population comprised 270 patients (182 male and 88 female). MAIN OUTCOME MEASURES: Patients' use of sunscreens before and after transplantation relative to known skin cancer risk factors and subsequent skin carcinogenesis. RESULTS: Prior to transplantation, 68.5% of patients never applied sunscreen on a sunny day compared with 25.9% after transplantation. Patients 50 years or younger were more likely to always apply sunscreen both before and after transplantation (P = .01), as were female patients prior to transplantation (P = .02). Those patients who participated in an outdoor recreation were more likely to subsequently develop nonmelanoma skin cancer (P = .04), as were those older than 50 years (P<.001) and those with a history of 2 or more painful sunburns (P = .03). CONCLUSIONS: Transplant recipients are poorly compliant with the use of sunscreens both before and after transplantation. Compliance is poorest in those groups at higher risk of nonmelanoma skin cancer.

Sunscreens: safety, efficacy and appropriate use.

Promoting sunscreen use is an integral part of prevention programmes aimed at reducing ultraviolet (UV) radiation-induced skin damage and skin cancers. Protection against both UVB and UVA radiation is advocated. Most sunscreens combine chemical UV absorbing sunscreens and physical inorganic sunscreens, which reflect UV, to provide broad-spectrum protection. Newer triazole and camphor-derivative based sunscreens, also provide broad-spectrum protection and are more cosmetically acceptable than many traditional agents. Currently licensed sunscreen ingredients in common use rarely cause allergic or photoallergic reactions. Vitamin D levels are not significantly affected by regular use of a sunscreen. Sunscreen use reduces both the development of precancerous solar keratosis and the recurrence of squamous cell carcinomas. Sunscreen use early in life may be important in prevention of basal cell carcinomas. Increased melanoma risk is influenced by the behaviour patterns of regular sunscreen users, as opposed to any direct effect of sunscreens. Sun protection factor (SPF) is affected by application density, water resistance and other factors. An adequate SPF for an individual should be balanced to skin phenotype and exposure habits. The correct use of sunscreens should be combined with the avoidance of midday sun and the wearing of protective clothing and glasses, as part of an overall sun protection regimen.