RATIONALE:Common and rare variants that are associated with the risk of developing idiopathic pulmonary fibrosis (IPF) have been identified predominantly in European ancestry populations. OBJECTIVES:To better understand the genetic variants that contribute to IPF in individuals with Asian ancestry, we conducted a genome-wide association study of IPF in East Asian populations. METHODS:We included 1026 patients with IPF and compared them to 1723 unaffected controls of Japanese and Korean ancestry. Genome-wide association analysis was conducted in the Japanese and Korean ancestry cohorts separately and combined using meta-analysis. Restricted maximum likelihood was used to estimate the SNP-based heritability and local ancestry of chromosome 11 was inferred for each subject. MEASUREMENTS AND MAIN RESULTS:We identified loci on chromosomes 4 (FAM13A; rs7690839), 5 (TERT; rs7734992), 6 (DSP; rs2076295), and 11 (MUC5B; rs35705950) that were significantly associated with risk of IPF. Importantly, the sentinel variants in each of these loci are the same as, or in strong linkage disequilibrium with, the risk variants that have been observed in studies of European ancestry populations. In aggregate, common variants (not including the MUC5B promoter variant) account for approximately 25% of the risk of developing IPF in these East Asian ancestry cohorts. Moreover, local ancestry analysis indicates that the presence of MUC5B promoter variant in the East Asian population is not a result of admixture with European ancestry populations. CONCLUSIONS:We conclude that the IPF risk loci in East Asian populations are shared with those of European ancestry populations, although their risk allele frequencies and effect sizes differ. These findings indicate shared genetic risk factors of IPF across ancestries.

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.

RATIONALE Idiopathic pulmonary fibrosis is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to non-genetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants genome-wide may contribute to the risk of IPF remains unknown. OBJECTIVES We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. METHODS As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ≤0.01) within genes or regions. We also identified individual variants that are influential within genes and estimated the heritability of IPF based on rare and common variants. MEASUREMENTS AND MAIN RESULTS Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP-heritability of IPF was estimated to be 32% (s.e. 3%). CONCLUSIONS Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

The importance of lung cancer as a complication of lung transplantation is increasingly recognised. It may become an important survival-limiting factor in lung transplant patients as management of other complications continues to improve and utilisation of extended criteria donors grows. Radiology can play a key role in tackling this issue at multiple stages in the transplantation pathway and follow-up process. Routine chest CT as part of pre-transplant recipient assessment (and donor assessment if available) can identify suspicious lung lesions with high sensitivity and detect chronic structural lung diseases such as pulmonary fibrosis associated with an increased risk of malignancy post-transplant. Pre-transplant CT also provides a comparison for later CT studies in the assessment of nodules or masses. The potential role of regular chest CT for lung cancer screening after transplantation is less certain due to limited available evidence on its efficacy. Radiologists should be cognisant of how the causes of pulmonary nodules in lung transplant patients may differ from the general population, vary with time since transplantation and require specific recommendations for further investigation/follow-up as general guidelines are not applicable. As part of the multidisciplinary team, radiology is involved in an aggressive diagnostic and therapeutic management approach for nodular lung lesions after transplant both through follow-up imaging and image-guided tissue sampling. This review provides a comprehensive overview of available clinical data and evidence on lung cancer in lung transplant recipients, and in particular an assessment of the current and potential roles of pre- and post-transplant imaging. KEY POINTS: • Lung cancer after lung transplantation may become an increasingly important survival-limiting factor as mortality from other complications declines. • There are a number of important roles for radiology in tackling the issue which include pre-transplant CT and supporting an aggressive multidisciplinary management strategy where lung nodules are detected in transplant patients. • The introduction of routine surveillance chest CT after transplant in addition to standard clinical follow-up as a means of lung cancer screening should be considered.

COVID 19 (SARS-COV-2) disease expression remains uncertain. Immunocompromised individuals may be at particular risk of increased mortality. Lung transplant recipients provide a unique phenotype because the allograft is a preferred host location for the SARS-COV-2. We conducted a single centre review of all lung transplant recipients SARS-COV-2 PCR positive between 17th March and June 2020. 7 of a total of 266 lung transplant recipients were SARS-COV-2 positive. 4 cases had a descriptive analysis of the immune microenvironment. There was no association between COVID 19 disease severity and time from transplant. The most prevalent comorbidities were chronic kidney disease (86%), hypertension (71%) and diabetes mellitus (42%). One case died and 6 recovered. Forty-two percent of cases had established chronic allograft dysfunction. Six patients were receiving Azithromycin 500mg, 3 times per week prior COVID 19. Immunosuppression was altered in the three severe cases with calcineurin inhibitor (CNI) reduction and antimetabolite withdrawal. The frequency of both CD4 and CD8 T cell subtypes were low in all 4 patients analysed. In the 2 severe cases CD8 subpopulations responsible for cellular antiviral response were profoundly diminished. The recipient requiring mechanical ventilation demonstrated an increased CD4/CD8 ratio of 5.9 and significantly reduced NK cells. NK cell reduction corresponded with disease severity. The indirect potential COVID 19 prophylaxis with Azithromycin may have mitigated disease expression and mortality. Decreased anti-viral immune surveillance associated with a reduction in CD8 positive cytotoxic lymphocytes and raised CD4/CD8 ratio was associated with disease severity and may be a tool to identify high risk cases.

Summary Phaeochromocytoma is a rare catecholamine-producing tumour. We present the case of phaeochromocytoma in a young man with a background history of a double-lung transplant for cystic fibrosis (CF). Clinical case: A 25-year-old man, with a background history of CF, CF-related diabetes (CFRD) and a double-lung transplant in 2012 was presented to the emergency department with crampy abdominal pain, nausea and vomiting. He was diagnosed with distal intestinal obstructions syndrome (DIOS). Contrast-enhanced CT imaging of the abdomen and pelvis showed a 3.4 cm right adrenal lesion. This was confirmed by a subsequent MRI of adrenal glands that demonstrated moderate FDG uptake, suggestive of a diagnosis of phaeochromocytoma. The patient was noted to be hypertensive with a blood pressure averaging 170/90 mm/Hg despite treatment with three different anti-hypertensive medications – amlodipine, telmisartan and doxazosin. He had hypertension for the last 3 years and had noted increasingly frequent sweating episodes recently, without palpitations or headache. Laboratory analysis showed elevated plasma normetanephrines (NMN) of 3167 pmol/L (182–867) as well as elevated metanephrines (MN) of 793 pmol/L (61–377) and a high 3-MT of 257 pmol/L (<185). Once cathecholamine excess was identified biochemically, we proceeded to functional imaging to further investigate. MIBG scan showed a mild increase in the uptake of tracer to the right adrenal gland compared to the left. The case was discussed at a multidisciplinary (MDT) meeting at which the diagnosis of phaeochromocytoma was made. Following a challenging period of 4 weeks to control the patient’s blood pressure with an alpha-blocker and beta-blocker, the patient had an elective right adrenalectomy, with normalisation of his blood pressure post-surgery. The histopathology of the excised adrenal gland was consistent with a 3 cm phaeochromocytoma with no adverse features associated with malignant potential. Learning points Five to ten per cent of patients have a secondary cause for hypertension. Phaeochromocytomas are rare tumours, originating in chromaffin cells and they represent 0.1–1.0% of all secondary hypertension cases. Secondary causes should be investigated in cases where: Patient is presenting <20 years of age or >50 years of age, There is refractory hypertension, or There is serious end-organ damage present. Patients may present with the triad of headache, sweating and palpitations or more vague, non-specific symptoms. Patients with suspected phaeochromocytoma should have 24-h urinary catecholamines measured and if available, plasma metanephrines measured. Those with abnormal biochemical tests should be further investigated with imaging to locate the tumour. Medical treatment involves alpha- and beta-blockade for at least 2 to 3 weeks before surgery as well as rehydration. There is a possibility of relapse so high-risk patients require life-long follow-up.

Purpose Antifungal prophylaxis in heart transplantation is not universally prescribed in our institution. We reviewed the incidence of invasive fungal diseases (IFD) in heart transplants, risk factors, and diagnostic yield of culture and nonculture-based testing for IFD. Methods A 5-year retrospective audit of heart transplant recipients in a national transplant centre from 2015 to 2019 was conducted. Proven and probable IFD were identified based on host factors, clinical features and mycological evidence outlined by the updated EORTC/MSGERC definitions. Results The incidence of proven or probable IFD was 14% (11/77) with 207 median days (IQR 54.5-306) post-transplant to diagnosis. 4 (36%) cases occurred 0.05). Of the 7 with rejection, median time from transplant to 1st rejection was 17 days (IQR11-51), and 1st rejection to IFD was 125 days (IQR 44-191). 45% (5/11) with IFD had required post-operative renal replacement therapy. 45% had neutrophils Conclusion Antifungal surgical prophylaxis could have prevented 1 IFD. A cohort of high-risk heart transplant recipients may benefit from antifungal prophylaxis.

To the Editor: Basal cell carcinomas (BCC) occur more frequently than cutaneous squamous cell carcinomas (cSCC) with a general population ratio of 2.5:1.1NCRI Cancer trends.https://www.ncri.ie/sites/ncri/files/pubs/Trends%20report%20skin%20cancer%20final180717.pdfDate accessed: February 23, 2021Google Scholar There is wide variation in this ratio likely due to differences in demographics, latitude, and immunosuppression. The ratio is reversed following solid organ transplantation.2Euvrard S. Kanitakis J. Pouteil-Noble C. et al.Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation.J Am Acad Dermatol. 1995; 33: 222-229Abstract Full Text PDF PubMed Scopus (212) Google Scholar The Irish National Cancer Registry records first cSCC and BCC, providing a robust dataset to explore patient and transplant-related factors unique to the development of cSCC compared to BCC. We matched datasets from national transplant centers with Irish National Cancer Registry data from 1994 to 2014. Eligible participants were divided into 4 groups; “cSCC only,” “BCC only,” “cSCC and BCC,” and “No cSCC or BCC” and compared using multinomial logistic regression analysis (Supplemental Appendix 1). The analysis included 3580 organ transplant recipients over a 21-year follow-up period. The total follow-up time was 28,407 person years with a median follow up of 7.1 years (interquartile range = 9.1; Supplemental Table I). Of these patients, 231 (6%) had “cSCC only,” 239 (7%) had “BCC only,” 174 (5%) had “cSCC and BCC,” and 2936 (82%) had “No cSCC or BCC” (Table I). Female sex was significantly associated with “BCC only” compared with “cSCC only” (P = .001; relative risk ratio = 1.99; 95% CI = 1.31-3.01). There was no significant effect of organ transplant type, age at the time of transplant, year of transplant, and follow-up time on “cSCC only” versus that on “BCC only” risk (P = .487, P = .066, P = .149, and P = .427, respectively; Fig 1).Table IPatient demographic details for each of the 4 outcome groupsTotalcSCC onlyBCC onlycSCC and BCCNo cSCC or BCC3580231 (6%)239 (7%)174 (5%)2936 (82%)Male2256180 (8%)155 (7%)154 (7%)1767 (78%)Female132451 (4%)84 (6%)20 (2%)1169 (88%)Follow up (person years)28,40723362546221821,306Median follow up (years)7.19.410.813.26.2 IQR9.18.18.27.48.4Mean age at the time of transplant (years)44.853.750.555.243.0 Range0.8-77.416.7-76.613.7-77.421.7-76.30.8-75.9Median age at the time of transplant (years)47.255.051.755.945.0 IQR24.515.618.213.925.4Age at the time of transplant (years) <3070210 (1%)11 (2%)4 (1%)677 (96%) 30-3956023 (4%)37 (7%)6 (1%)494 (88%) 40-4971439 (5%)56 (8%)38 (5%)581 (81%) 50-5991678 (9%)74 (8%)62 (7%)702 (77%) >6068881 (12%)61 (9%)64 (9%)482 (70%)Transplant type Renal2446166 (7%)165 (7%)130 (5%)1985 (81%) Heart21618 (8%)23 (11%)21 (10%)154 (71%) Lung19210 (5%)11 (6%)7 (4%)164 (85%) Liver72637 (5%)40 (6%)16 (2%)633 (87%)Year of transplant 1994-199641042 (10%)38 (9%)50 (12%)280 (68%) 1997-199939335 (9%)34 (9%)36 (9%)288 (93%) 2000-200248833 (7%)41 (8%)38 (8%)376 (77%) 2003-200550940 (8%)42 (8%)17 (3%)410 (81%) 2006-200858536 (6%)34 (6%)19 (3%)496 (85%) 2009-201158337 (6%)32 (5%)11 (2%)503 (86%) 2012-20146128 (1%)18 (3%)3 (1%)583 (95%)BCC, Basal cell carcinomas; cSCC, cutaneous squamous cell carcinomas; IQR, interquartile range. Open table in a new tab BCC, Basal cell carcinomas; cSCC, cutaneous squamous cell carcinomas; IQR, interquartile range. Our study showed that the ratio of “BCC only” to “cSCC only” was statistically significantly higher in women than in men. Despite this, men in our study still had overall higher rates of “BCC only” compared to women (7% vs 6%). Similar trends are observed in the non-transplant population.1NCRI Cancer trends.https://www.ncri.ie/sites/ncri/files/pubs/Trends%20report%20skin%20cancer%20final180717.pdfDate accessed: February 23, 2021Google Scholar Heart transplant recipients generally receive a higher level of immunosuppression than renal and liver transplant recipients, which has been associated with higher rates of cSCC, but not BCC, than in the general population.3Fortina A.B. Piaserico S. Caforio A.L. et al.Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients.Arch Dermatol. 2004; 140: 1079-1085Crossref PubMed Scopus (100) Google Scholar However, our study showed no significant effect of organ transplant type on “cSCC only” versus “BCC only” risk. The cumulative incidence of keratinocyte carcinoma increases with time after transplantation4Bavinck J.N. Hardie D.R. Green A. et al.The risk of skin cancer in renal transplant recipients in Queensland, Australia. a follow-up study.Transplantation. 1996; 61: 715-721Crossref PubMed Scopus (443) Google Scholar; however, the year of transplant and follow-up time did not impact “cSCC only” versus “BCC only” risk. The year of transplant can indirectly reflect trends in immunosuppressive protocols and impact on keratinocyte carcinoma risk. The latter supports our recent findings that rates of both cSCC and BCC reduced equally over the last 20 years, maintaining the standardized incidence ratio of cSCC to BCC.5Menzies S. O'Leary E. Callaghan G. et al.Declining incidence of keratinocyte carcinoma in organ transplant recipients.Br J Dermatol. 2019; 181: 983-991Crossref PubMed Scopus (15) Google Scholar The limitations of the study include not adjusting for non-registry variables, which may impact differently on “cSCC only” versus “BCC only” risk, such as immunosuppressive protocols, skin type, and prior UV exposure. Additionally, the outcome groups used in our study are not static, eg, in a patient in the “BCC only” group, a cSCC developed after the study period. Finally, our data relies upon histologically confirmed keratinocyte carcinoma. This study examines keratinocyte cancer risk factors in organ transplant recipients subgroups in which BCC, cSCC, or both developed exclusively. Sex was found to be an independent risk factor, with women at increased risk of “BCC only” relative to “cSCC only” when compared to men. Further studies are required to explore whether different patterns of UV exposure or different responses to immunosuppression in male and female organ transplant recipients might explain our findings. None disclosed.

Introduction: An increased risk of malignancy post-lung transplant (LTx) is established as a complication related to reduced immunosurveillance and patient demographics. Aims: To identify the incidence, risk factors and clinical characteristics of solid-organ malignancy following LTx at The Irish National Lung Transplant Centre. Methods: A retrospective single centre review of all 216 patients transplanted between 2005-2017. Data collected included patient demographics, transplant indication, surgery, smoking status, histological sub-type, TNM staging and outcomes. Results: Nineteen patients were diagnosed with a solid-organ malignancy following LTx during follow-up (8.8%). The median time interval between transplant and cancer diagnosis was 32 months (range 12-133 months). Age at the time of transplant was significantly higher in those who subsequently developed malignancy (p=0.028, mean 58.3 v 49.7 years). Single LTx recipients appear at higher risk compared to double LTx recipients (OR 3.17, 95% CI 1.10-9.14). No single indication for LTx was identified as an independent risk factor. Bronchogenic carcinoma was the most common malignancy (n=11, 5.1%); the majority were identified in the native lung of single transplant recipients (9 of 11). 82% were ex-smokers. Squamous cell carcinoma was the most common subtype (n=5). Five patients were stage IV at diagnosis with an overall 1-year mortality of 82%. Conclusions: Bronchogenic carcinoma is the most common solid organ malignancy post LTx and has a high mortality. Risk factors include older age and single LTx. Despite close prospective monitoring, early detection remains challenging and adequate adequate screening guidelines post-transplant are currently lacking.

BACKGROUND:The incidence of post-transplant diabetes (PTDM) is variable primarily due to a lack of standardised diagnostic criteria.AIM:This study aimed to assess the incidence of PTDM in heart and lung transplant (HLT) patients and to review if the management of these patients is in accordance with the 2014 American Society of Transplantation guidelines.METHODS:This was a retrospective study in the Mater Misericordiae University Hospital, Dublin, Ireland. Data was collected from the patients who had undergone HLT.RESULTS:All patients who had a heart and/or lung transplant between 2005 and 2017 were identified. The majority of our patients had lung 111 (53.9%), heart 94 (45.6%) and combined heart/lung 1(0.5%) transplants. A total of 174 (84.5%) patients were screened for diabetes pre-transplantation. Two hundred five (99.9%) patients were screened for PTDM post-surgery. The cumulative incidence for PTDM was 19.4% (40/206). All patients with PTDM were on prednisolone, 32 (80%) on tacrolimus and 4 (10%) on cyclosporine.CONCLUSIONS:The cumulative incidence of post-transplant diabetes in our cohort was 19.4%. The majority of the patients were screened before and after transplant for glucose abnormality. The authors recommend that all patients should be managed in a multidisciplinary setting including transplant physicians, endocrinlogist, diabetes nurse specialists, transplant nurses and dietitians.

Introduction: Identification of risk factors that predict poor survival can aid clinical decision making and allow optimization of any potentially modifiable factors (Stephenson, A.L. et al. J Heart Lung Transplant 2015;34:1139–1145). This may facilitate improved patient selection and ultimately improve overall outcomes. Aims: To describe the Irish experience of co-morbidity post-transplant for cystic fibrosis and to investigate potential non-pulmonary pre-transplant risk factors that could impact on long term survival. Methods: We performed a retrospective review of all 61 patients who received a lung transplant for cystic fibrosis between 2008-2017 at The Irish National Lung Transplant Centre. We recorded patient demographics, co-morbidities and survival. A t-test was used for comparison of mean values. Results: The overall 5-year survival post-transplant is 73.8%. The mean age at transplant is 29.8 years (range 17.8-59.9) with a male predominance (69%). 64% were homozygous ∆F508 genotype. When comparing the 13 patients who have subsequently died to the 48 patients currently alive, the mean age at transplant was significantly lower (25 vs 31 years, p=0.034), mean BMI prior to transplant was lower (19.1 v 20.8, p=0.045) and creatinine clearance prior to transplant was reduced (103 v 136, p=0.031). Of the 48 patients who remain under review, chronic kidney disease is common with 54% of patients having an eGFR <60ml/min. The prevalence of diabetes increased from 38% at listing to 71% at follow–up. Conclusions: There is a high prevalence of non-graft complications post-transplant. Pre-transplant factors that are most predictive poor outcomes in our centre include younger age, lower BMI and reduced renal function.

Alpha-1 antitrypsin deficiency (AATD) accounts for 5% of lung transplants performed worldwide. Ireland has a high frequency of 1 in 25 for the Z allele and 1 in 10 for the S allele [1]. These variants are associated with decreased production of alpha-1 antitrypsin (AAT), which predisposes to unprotected proteolytic activity of neutrophil elastase (NE) and proteinase 3 (PR3), linked to an increased risk of emphysema and hepatic disease. Associated inflammatory conditions such as vasculitis, panniculitis and inflammatory bowel disease are also suspected to be caused by uncontrolled neutrophil proteinase activity [2–4]. Vascular problems, including aortic aneurysm, in AATD patients are more severe and may reflect abnormal elastic tissue properties potentially impacting on wound healing [5]. Our study suggests an association between timing of withdrawal of replacement therapy and bronchial anastomotic complications after lung transplantation

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.

AIM OF THE STUDY:Nucleic acid-based therapies have the potential to provide clinically meaningful benefit across a wide spectrum of lung disease. However, in vivo delivery remains a challenge. Here we examined the feasibility of using electrospray to deliver nucleic acids to both porcine tracheal tissue sections and whole lung ex vivo. MATERIALS AND METHODS:The effect of electrospray solution, emitter gauge, flow rate and voltage on plasmid DNA integrity was examined by analyzing supercoiled:open circle structure ratio by gel electrophoresis. Optimal parameters were used to deliver luciferase DNA and mRNA and siRNA-FITC to tracheal tissue sections. Luciferase mRNA was delivered to whole porcine lungs ex vivo using a catheter and bronchoscope system. Luciferase activity and fluorescence were analyzed by luminometry and microscopy respectively. RESULTS:The incidence of DNA plasmid nicking was greatest in a low salt solution without ethanol compared with 1% and 20% ethanol with salt. From a range of emitters tested, a 32 gauge emitter produced the best supercoiled:open circle structure ratio, likely because less voltage was required to produce a stable electrospray with this emitter. Lower flow rates also showed a trend towards reduced DNA nicking. GFP DNA electrosprayed at 5 kV and 6 kV resulted in lower levels of GFP expression in A549 lung cells following lipofection compared with 3 kV and 4 kV. Optimised parameters of 20% ethanol solution, 32 gauge emitter, low flow rates and voltages of 3-5 kV, nucleic acid molecules were successful for delivery of luciferase DNA and mRNA as well as siRNA-FITC to porcine tracheal tissue sections and for delivery of luciferase mRNA to whole porcine lungs via bronchoscope. CONCLUSIONS:We report ex vivo delivery of nucleic acids to porcine lung tissue via electrospray and bronchoscopic electrospray delivery of nucleic acid to an ex vivo porcine lung model.

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.

Purpose A double lung donor may be split, with a single lung transplanted sequentially into two different recipients by one team. This minimizes utilization of hospital staff resources, day time theater access and supports donor to transplant conversion rates. This is a retrospective institutional review of the first 12 cases assessing the impact of extended ischemic time (for the delayed second lung transplant recipient) on length of stay (LOS), intermediate term graft function and survival. Methods Twelve sequential single lung transplants were performed from 6 donors between August 2016 and September 2017. Basic data for donors and recipients including outcomes (ischemic time, ICU stay, total hospital stay, 30 day mortality, 12-month survival including pulmonary function tests (PFTs)) were recorded. Borderline lungs were implanted to the EVLP circuit and reperfused using acellular supplemented Steen Solution (Vitrolife, Göteborg, Sweden). Recipients were categorized into 2 groups: G1 for patients who received the 1st lung, hence having a shorter ischemic time (whether they had EVLP or not), G2 for patients who received the 2nd lung, hence a longer ischemic time. 3 patients received EVLP reconditioned lungs. Results Donor data (n = 6) were: age, 44.2 ± 8.33 years; female/male, 5:1; cause of death: intracranial haemorrhage 4(66.6%), hypoxic brain injury 1(16.6%) and traumatic brain injury 1(16.6%). Mean LAS Score was similar for both groups (44.9 G1 and 41.7 G2, p value=0.64). Mean ischemic time from donor cross clamp to reperfusion was 389 minutes for G1 and 708 minutes for G2. There was no significant difference in ICU stay: 14.7 days vs 6.0 days with a quicker discharge from ITU in the G2(p value=0.20). The mean Hospital LOS was 32.3 vs 20.3 days, (p value= 0.35) Mean FEV1 at 3 months in G1 was 2.4 L (79.7%) and in G2 was 2.0 L (68.4%) (p value=0.38). No all cause 30 day mortality in both groups. At 1-year 2 patients had died from an unexpected bradycardic cardiac arrest. Conclusion SLT if limited resources are available maximize on donor to transplant conversion rates. Donor ischemic lung time is not a deterrent in the era of EVLP. SLT into two recipients by a single theater service is feasible, cost-effective and safe. A double lung donor may be split, with a single lung transplanted sequentially into two different recipients by one team. This minimizes utilization of hospital staff resources, day time theater access and supports donor to transplant conversion rates. This is a retrospective institutional review of the first 12 cases assessing the impact of extended ischemic time (for the delayed second lung transplant recipient) on length of stay (LOS), intermediate term graft function and survival. Twelve sequential single lung transplants were performed from 6 donors between August 2016 and September 2017. Basic data for donors and recipients including outcomes (ischemic time, ICU stay, total hospital stay, 30 day mortality, 12-month survival including pulmonary function tests (PFTs)) were recorded. Borderline lungs were implanted to the EVLP circuit and reperfused using acellular supplemented Steen Solution (Vitrolife, Göteborg, Sweden). Recipients were categorized into 2 groups: G1 for patients who received the 1st lung, hence having a shorter ischemic time (whether they had EVLP or not), G2 for patients who received the 2nd lung, hence a longer ischemic time. 3 patients received EVLP reconditioned lungs. Donor data (n = 6) were: age, 44.2 ± 8.33 years; female/male, 5:1; cause of death: intracranial haemorrhage 4(66.6%), hypoxic brain injury 1(16.6%) and traumatic brain injury 1(16.6%). Mean LAS Score was similar for both groups (44.9 G1 and 41.7 G2, p value=0.64). Mean ischemic time from donor cross clamp to reperfusion was 389 minutes for G1 and 708 minutes for G2. There was no significant difference in ICU stay: 14.7 days vs 6.0 days with a quicker discharge from ITU in the G2(p value=0.20). The mean Hospital LOS was 32.3 vs 20.3 days, (p value= 0.35) Mean FEV1 at 3 months in G1 was 2.4 L (79.7%) and in G2 was 2.0 L (68.4%) (p value=0.38). No all cause 30 day mortality in both groups. At 1-year 2 patients had died from an unexpected bradycardic cardiac arrest. SLT if limited resources are available maximize on donor to transplant conversion rates. Donor ischemic lung time is not a deterrent in the era of EVLP. SLT into two recipients by a single theater service is feasible, cost-effective and safe.