<h4>Importance</h4>Topical calcineurin inhibitors (TCIs) are commonly used as second-line treatment for atopic dermatitis. In 2006, the US Food and Drug Administration issued a black box warning against TCI use, citing data from case reports and animal studies indicating a potential risk of cancer.<h4>Objective</h4>To evaluate the association between TCI use and risk of malignant neoplasms compared with nonactive and active comparator groups.<h4>Data sources</h4>Electronic searches were conducted in MEDLINE via Ovid, Embase via Ovid, and Web of Science from database inception to August 21, 2020.<h4>Study selection</h4>Observational studies investigating the association between treatment with TCIs (ie, tacrolimus and pimecrolimus) and the development of cancer with nonactive or active comparators were included. The population of interest was not limited to any specific disease state, age, or sex. All articles were assessed independently and in duplicate by 2 reviewers. Risk of bias was assessed using the Newcastle-Ottawa scale. Of 2464 nonduplicate records retrieved from the search, 11 studies met the inclusion criteria.<h4>Data extraction and synthesis</h4>Data extraction was conducted independently by 2 reviewers according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Random-effects meta-analyses were used to derive pooled relative risk (RR) estimates. Data were analyzed from July 25 to October 25, 2020.<h4>Main outcomes and measures</h4>Risk of cancer overall and risk of specific cancer types (lymphoma, melanoma, and keratinocyte carcinoma).<h4>Results</h4>Eight unique cohort studies (408 366 treated participants [55.1% female], 1 764 313 nonactive comparator controls, and 1 067 280 controls using topical corticosteroids) and 3 unique case-control studies (3898 cases [55.0% male] and 14 026 cancer-free controls [52.4% male]) were included. There was no association between TCI use and cancer overall compared with nonactive comparators (RR, 1.03; 95% CI, 0.92-1.16). Lymphoma risk was elevated with TCI use with both nonactive (RR, 1.86; 95% CI, 1.39-2.49) and topical corticosteroid comparators (RR, 1.35; 95% CI, 1.13-1.61). No significant association was found between TCI use and increased skin cancer (melanoma and keratinocyte carcinoma).<h4>Conclusions and relevance</h4>The findings of this systematic review and meta-analysis suggest an association between TCI use and risk of lymphoma but not other cancers. Combined with the low absolute risk of lymphoma, the potential increased risk attributable to TCI use for any individual patient is likely very small.

In severely ill patients undergoing urgent heart transplant (HTX), immunosuppression carries high risks of infection, malignancy, and death. Low-dose immunosuppressive protocols have higher rejection rates. We combined extracorporeal photopheresis (ECP), an established therapy for acute rejection, with reduced-intensity immunosuppression. Twenty-eight high-risk patients (13 with high risk of infection due to infection at the time of transplant, 7 bridging to transplant via extracorporeal membrane oxygenation, 8 with high risk of malignancy) were treated, without induction therapy. Prophylactic ECP for 6 months (24 procedures) was initiated immediately postoperatively. Immunosuppression consisted of low-dose tacrolimus (8–10 ng/ml, months 1–6; 5–8 ng/ml, >6 months) with delayed start; mycophenolate mofetil (MMF); and low maintenance steroid with delayed start (POD 7) and tapering in the first year. One-year survival was 88.5%. Three patients died from infection (POD 12, 51, 351), and one from recurrence of cancer (POD 400). Incidence of severe infection was 17.9% (n = 5, respiratory tract). Within the first year, antibody-mediated rejection was detected in one patient (3.6%) and acute cellular rejection in four (14.3%). ECP with reduced-intensity immunosuppression is safe and effective in avoiding allograft rejection in HTX recipients with risk of severe infection or cancer recurrence. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Abstract In severely ill patients undergoing urgent heart transplant (HTX), immunosuppression carries high risks of infection, malignancy, and death. Low-dose immunosuppressive protocols have higher rejection rates. We combined extracorporeal photopheresis (ECP), an established therapy for acute rejection, with reduced-intensity immunosuppression. Twenty-eight high-risk patients (13 with high risk of infection due to infection at the time of transplant, 7 bridging to transplant via extracorporeal membrane oxygenation, 8 with high risk of malignancy) were treated, without induction therapy. Prophylactic ECP for 6 months (24 procedures) was initiated immediately postoperatively. Many patients are at high risk for early postoperative infection, and patients with previous malignant disease are more often seen as potential transplant candidates ( 1 , 2 ). Current immunosuppressive protocols are associated with risk of infectious complications and cancer ( 3 , 4 ). Earlier attempts to use low-level immunosuppressive protocols to reduce these risks resulted in higher organ rejection rates ( 5 , 6 ). Extracorporeal photopheresis (ECP) is a successful supportive therapy for the treatment of severe and/or recurrent rejection episodes in solid organ transplantation, including heart transplantation ( 7 ). The green bar highlights the intended target range of tacrolimus (8–10 ng/ml in months 1–6, and 5–8 ng/ml thereafter). All patients who survived the first 6 months received ECP according to the protocol. Overall, ECP was tolerated well. In one patient, elevated potassium levels occurred during the third ECP treatment and could not be attributed to ECP. Most likely, intravenous amphotericin A was administered too quickly, causing a shift of potassium ( 15 , 16 ). Due to invasive fungal infection, maintenance immunosuppression (CNI, MMF, and steroid) and ECP were paused in two patients who died of sepsis leading to MOF on POD 12 and 51, respectively (see below). In both cases, the fungal strains were resistant to empirically administered antifung4al therapy. CMV disease with enteritis occurred in one CMV high-risk (D+/R-) patient 2 months after HTX, after prophylaxis with valganciclovir had been discontinued. However, the patient was successfully treated with valganciclovir in therapeutic dosage for 2 weeks. No other CMV infection was detected. Only one prospective study has examined ECP early after HTX, comparing triple-drug immunosuppression with or without 6 months of ECP therapy ( 13 ). Barr et al. observed significantly lower rejection rates, similar overall infection, and lower CMV infection rates in the ECP group compared with the control group. No increase in rejection was detected after the end of ECP treatment. In both studies, ECP was tolerated very well and not associated with adverse events. Based on the experience of those two studies, we developed our alternative protocol to test in three high-risk groups (infection, bridge to transplant via ECMO, history of cancer). We applied no ATG induction therapy in all but the two of our first patients (100mg ATG once on POD1), assuming this would lower the risk of severe infections early after transplantation without risking higher rates of rejection. We trusted that a combination of tacrolimus/MMF would be more effective than cyclosporine/azathioprine, even at lower tacrolimus target levels and with delayed start of tacrolimus and oral steroid. Therefore, we defined as a secondary outcome an acceptable rate of acute rejections in the first year after transplantation as a rate 1.3–1.5-fold higher than the observed rejection rate with our conventional immunosuppressive protocol (15–20%) ( 37 ). Only one patient had a rejection episode during long-term follow-up, after switching from tacrolimus to cyclosporine for immunosuppression, on day 660. We can only speculate whether ECP induction treatment would allow even further decrease in overall immunosuppression early after transplantation. There is not enough evidence to proof that this protocol is safe in immunological high-risk patients.

Atopic dermatitis (AD) is a pervasive and multifaceted dermatological disorder causing daily distress to afflicted individuals worldwide. This comprehensive review synthesizes the historical and contemporary advancements in therapeutic strategies, offering a critical analysis of their efficacy, safety profiles, and adaptability. The enduring role of topical corticosteroids in managing AD is examined, acknowledging their potent anti-inflammatory properties alongside their potential adverse side effects, particularly in extended usage. The article explores the utilization of topical calcineurin inhibitors like tacrolimus and pimecrolimus, highlighting their novel anti-inflammatory pathways while also scrutinizing concerns over potential malignancies that relegate them to second-line therapy. The present investigation features the emergence of crisaborole, a phosphodiesterase four inhibitor. Its innovative mode of action, benign safety profile, and applicability to mild and moderate AD are thoroughly evaluated. The review also includes challenges, particularly cost considerations, which constrain accessibility and necessitate nuanced implementation in therapeutic regimens. This study underscores the need for persistent investigation, teamwork, and innovations in managing AD. In this regard, AD requires a united approach between clinicians, researchers, affected individuals, and policymakers to refine patient-focused treatment and develop precise, economical strategies to address this chronic and frequently life-altering health condition.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy in the world, representing approximately 20% of all skin cancers. Immunosuppression is a well-established risk factor, contributing not only to the development of new cSCC lesions but also to more aggressive disease and increased mortality. Despite the National Comprehensive Cancer Network (NCCN) and the American Joint Committee on Cancer (AJCC) 8th edition updates recognizing immunosuppression as a risk factor for cSCC, standardized management protocols for these high-risk patients remain limited. As a result, treatment of this already high-risk group remains a significant challenge and highlights the need for dedicated research and attention to improve outcomes in this patient population. This review explores the current knowledge regarding cSCC in IS patients, outlines key gaps in the knowledge, and highlights recent clinical trials to further guide the evaluation and management of these patients.

Study to Compare the Safety and Efficacy of Sirolimus (Rapamune) to Tacrolimus (Advagraf) Associated to Mycophenolate Mofetil (CellCept) Between 12 and 36 Months After Kidney Transplantation The use of tacrolimus in the long term as part of the immunosuppressive regimen after transplantation is associated to complications such as chronic nephrotoxicity, impaired glucose metabolism (diabetes mellitus) and an increase of the incidence of neoplasia. The conversion from a tacrolimus based therapy to a sirolimus based therapy associated with mycophenolate mofetil could improve the incidence of such complications. The aim of this study is to assess the risk/benefit ratio of this switch performed in stable renal transplant recipient between 12 months and 36 months after transplantation. The incidence of a composite endpoint (worsening of GFR evaluated by MDRD formula, incidence of cancer and diabetes) will be assessed 24 months after conversion. Two doses of Sirolimus will be evaluated accorded to the CYP 3A5 genotype. Patients carrying at least CYP 3A5 \*1 allele will receive 4 mg per day whereas the others (CYP 3A5 \*3/\*3) will receive 2 mg.