Rapamycin promotes autophagy cell death of Kaposi's sarcoma cells through P75NTR activation.

The mammalian target of rapamycin inhibitor (mTOR-I) Rapamycin, a drug widely used in kidney transplantation, exerts important anti-cancer effects, particularly in Kaposi's Sarcoma (KS), through several biological interactions. In this in vivo and in vitro study, we explored whether the activation of the autophagic pathway through the low-affinity receptor for nerve growth factor, p75NTR , may have a pivotal role in the anti-cancer effect exerted by Rapamycin in S. Our Kimmunohistochemistry results revealed a significant hyper-activation of the autophagic pathway in KS lesions. In vitro experiments on KS cell lines showed that Rapamycin exposure reduced cell viability by increasing the autophagic process, in the absence of apoptosis, through the transcriptional activation of p75NTR via EGR1. Interestingly, p75NTR gene silencing prevented the increase of the autophagic process and the reduction of cell viability. Moreover, p75NTR activation promoted the upregulation of phosphatase and tensin homolog (PTEN), a tumour suppressor that modulates the PI3K/Akt/mTOR pathway. In conclusion, our in vitro data demonstrated, for the first time, that in Kaposi's sarcoma, autophagy triggered by Rapamycin through p75NTR represented a major mechanism by which mTOR inhibitors may induce tumour regression. Additionally, it suggested that p75NTR protein analysis could be proposed as a new potential biomarker to predict response to Rapamycin in kidney transplant recipients affected by Kaposi's sarcoma.

Non-Bullous Pemphigoid: A Single-Center Retrospective Study.

INTRODUCTION: Bullous pemphigoid (BP) is an autoimmune disease that typically presents with blisters, but sometimes early lesions may be eczematous, maculopapular, or urticarial. The aim of the present study was to highlight possible differences between typical bullous and non-bullous pemphigoid (NBP) and compare results with the literature. Material & methods: Patients receiving a diagnosis of BP between January 2000 and December 2019 were analyzed. Patients who developed a blister after 3 months from the onset of pruritus were considered as NBP. Demographic features, clinical findings at diagnosis and at 2-year follow-up, histological features, auto-antibodies titers, comorbidities and their treatment were retrieved. Categorical variables were evaluated for normal distribution using a histogram and a Q-Q plot. The χ2 and Fisher's exact tests were used to compare categorical variables between the groups. Continuous variables were compared between the groups using analysis of variance and the independent-samples t test. For multivariate analysis, logistic regression was performed. RESULTS: A total of 532 patients received a diagnosis of BP. A total of 122 patients were enrolled in the study; 63 were females, and the mean age at the diagnosis was 77.2 years (±11.9 SD). 98 were affected by BP and 24 were categorized as NBP. Mean time to diagnosis was 2.9 months (±5.8 SD) for BP and 30.4 months (±59.8 SD) for NBP (p = 0.0001). Skin manifestations in NBP patients were, in order of frequency: urticarial, papular or nodular, eczematous, and excoriations. Pruritus intensity was high but similar in the two groups (Numerical Rating Scale - NRS, 9.3 vs. 8.9). Seven out of 24 NBP patients (29%) never developed blisters; the other patients developed blisters after a mean follow-up time of 24.9 months (±54.9 SD). NBP patients had a more frequent history of myocardial infarction than BP patients (37.5 vs. 10.2%; p < 0.003). More NBP patients were taking diuretics than BP patients (66.7 vs. 49%; p = 0.03). NBP patients had a worse response to pruritus compared to BP patients at 2 years (NRS 3.7 vs. 11; p 0.001). CONCLUSIONS: NBP patients have a delayed diagnosis and may be at an increased risk of cardiovascular disease, especially myocardial infarction. Severely and persistently itchy skin disorders in aged patients should be investigated for BP diagnosis.

Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study.

Organ transplant recipients (OTRs) have a 100-fold increased risk of cutaneous squamous cell carcinoma (cSCC). We prospectively evaluated the association between ß genus human papillomaviruses (ßPV) and keratinocyte carcinoma in OTRs. Two OTR cohorts without cSCC were assembled: cohort 1 was transplanted in 2003-2006 (n = 274) and cohort 2 was transplanted in 1986-2002 (n = 352). Participants were followed until death or cessation of follow-up in 2016. ßPV infection was assessed in eyebrow hair by using polymerase chain reaction-based methods. ßPV IgG seroresponses were determined with multiplex serology. A competing risk model with delayed entry was used to estimate cumulative incidence of histologically proven cSCC and the effect of ßPV by using a multivariable Cox regression model. Results are reported as adjusted hazard ratios (HRs). OTRs with 5 or more different ßPV types in eyebrow hair had 1.7 times the risk of cSCC vs OTRs with 0 to 4 different types (HR 1.7, 95% confidence interval 1.1-2.6). A similar risk was seen with high ßPV loads (HR 1.8, 95% confidence interval 1.2-2.8). No significant associations were seen between serum antibodies and cSCC or between ßPV and basal cell carcinoma. The diversity and load of ßPV types in eyebrow hair are associated with cSCC risk in OTRs, providing evidence that ßPV is associated with cSCC carcinogenesis and may present a target for future preventive strategies.

Melanoma risk alleles are associated with downregulation of the MTAP gene and hypermethylation of a CpG island upstream of the gene in dermal fibroblasts.

Several association studies and GWAS on melanoma skin cancer risk have reported statistically significant signals on 9p21.3 region, where MTAP gene maps. None of the associated SNPs identified in these studies lie in the coding region of the gene and the causative relation of risk alleles with melanoma predisposition has not been elucidated. MTAP has a tumor suppressor activity and epigenetic silencing has been described in melanoma cell lines. In the present study, we show that melanoma risk alleles correlate with a MTAP allele-specific hyper-methylation and down-regulation of gene expression.

Skin cancer in solid organ transplant recipients: still an open problem.

In the last two decades, the optimization of organ preservation and surgical techniques, and the personalized immunosuppression have reduced the rate of acute rejections and early post-transplant complications. However, long-term graft survival rates have not improved over time, and evidence suggest a role of chronic calcineurin inhibitor toxicity in this failure. Solid organ transplant recipients may develop chronic dysfunction/damage and several comorbidities, including post-transplant malignancies. Skin cancers, mostly non-melanoma skin cancers (squamous cell carcinoma and basal cell carcinoma), are the most common malignancies in Caucasian solid organ transplant recipients. Several factors, together with immunosuppression, may contribute to the susceptibility for skin cancers which, although often treatable, could be associated with a much higher mortality rate than in the general population. The rapid identification and treatment (including reduction of immunosuppression and early surgical treatments) have an important role to avoid an aggressive behavior of these malignancies. Organ transplant recipients with a history of skin cancer should be followed closely for developing new and metastatic lesions. Additionally, patient education on the daily use of sun-protective measures and the recognition of the early signs (self-diagnosis) of coetaneous malignancies are useful preventive measures. Finally, clinicians should make themselves aware of the problem and build, in every clinical follow-up center, collaborative network involving transplant clinicians, dermatologists and surgeons who should work together to easily identify and rapidly treat these complications. In this review, we discuss the current literature regarding the epidemiology, risk factors, diagnosis, preventive strategies and treatments of skin cancer in organ transplantation.

Beta-papillomavirus DNA loads in hair follicles of immunocompetent people and organ transplant recipients.

There is increasing evidence of an association between human papillomaviruses (HPV) of the beta-genus (beta-PV) and the development of cutaneous squamous cell carcinoma (SCC). The viral DNA load may be an important determinant of pathogenicity, but there are currently no baseline epidemiological data relating to load in people without SCC. We investigated DNA-loads of eight beta-PV types previously associated with risk of SCC. We collected eyebrow hairs from immunocompetent people (ICP) and organ transplant recipients (OTR), determined load by quantitative PCR and obtained demographic, phenotypic, and sun exposure information. Viral loads for ICP from Australia (n = 241) and Italy (n = 223) and OTR from across Europe (n = 318) spanned seven orders of magnitude. The median loads for all types were below one viral DNA copy per 60 cells and were highest for HPV5, HPV8 and HPV20. None of the populations had consistently higher viral loads for all 8 types. However, a higher proportion of OTR were in the top deciles of viral load distributions for six of the eight beta-PV types examined. In a nested analysis of Italian OTR and ICP, this finding was significant for six beta-PV types and cumulative load. Increasing age was significantly associated with higher viral loads in Australia, and there was a weak trend for higher loads with the time elapsed since transplantation in the OTR. We observed a wide distribution of beta-PV loads with OTR significantly more likely to have the highest viral loads. Thus, viral loads may be an important contributor to the higher risk of SCC in OTR.

Weight reduction alone may not be sufficient to maintain disease remission in obese patients with psoriasis: a randomized, investigator-blinded study.

BACKGROUND: The relative risk of psoriasis and its severity are directly related to the body mass index. OBJECTIVE: To investigate the effects of a hypoenergetic diet to maintain disease remission in obese patients. METHODS: A questionnaire was administered to 200 patients with moderate-to-severe chronic plaque psoriasis asking whether diet could influence psoriasis severity. Forty-two obese patients in remission (PASI improvement ≥75%) for at least 12 weeks after methotrexate therapy were randomly assigned to receive a hypocaloric diet or free diet for 24 weeks, and were then followed up for an additional 12 weeks. RESULTS: Most of the patients considered that a diet regimen could influence their psoriasis, and desired to enter a dietary program. Obese patients who were in disease remission and entered a hypocaloric diet regimen showed a significant body weight reduction after 12 weeks which was maintained at week 24. However, patients under hypocaloric and free diets did not significantly differ in the maintenance of psoriasis remission, with relapse observed already at week 12, but with a trend in favor of the intervention group. CONCLUSIONS: Body weight reduction alone may not be sufficient for maintaining remission of moderate-to-severe psoriasis in obese patients.

Nonmelanoma skin cancer in solid organ transplant recipients: update on epidemiology, risk factors, and management.

BACKGROUND: Nonmelanoma skin cancers (NMSC) are the most frequently observed cancers in solid organ transplant recipients (SOTR) and may have a significant disease burden. OBJECTIVE: To provide an update regarding the epidemiology and management of NMSC in SOTR. RESULTS: Ten-year incidence rates range from 10% in Italy to 20% in Northern Europe to 70% in Australia. More than 50% of NMSC are located on sun-exposed areas (head, dorsum of hands). Many risk factors have been identified, including age at transplantation, fair skin, type of immunosuppressive drugs, cumulative sun exposure, viral infections, and various genetic markers. Patients with a first NMSC have a 49 times higher risk of developing a subsequent NMSC. Skin self-examination and photoprotection should be encouraged in all transplanted patients. Long-term skin surveillance, early diagnosis and aggressive treatment of any suspicious lesion, reduction of immunosuppressive therapy, and conversion to m-TOR inhibitors can be also effective measures for reduction of NMSC incidence. CONCLUSIONS: NMSC is the most frequent cancer observed in SOTR. Early diagnosis, patient education, and modification of immunosuppression are effective measures for reduction of NMSC incidence.

Analysis of the 3'UTR of the prostaglandin synthetase-2 (PTGS-2/COX-2) gene in non-melanoma skin cancer after organ transplantation.

To define the potential involvement of polymorphisms in the 3'untranslated region (3'UTR) of the prostaglandin synthetase-2 (PTGS-2) gene to non-melanoma skin cancer (NMSC) predisposition after transplantation, we screened for genetic variant, relevant parts of this region. It contains binding sites for trans-acting factors, an alternative polyadenylation site and putative target sequences for miRNAs. Variant +8473T>C did not appear to play a functional role in the regulation of gene expression in human keratinocyte-transfected cells. In addition to the well-known +8473T>C, we identified four polymorphisms: +8293G>C, +10259T>G, +10267G>A and +10335G>A. No allele frequency differences were observed between cases and controls neither for +8473T>C nor for any of the identified polymorphisms, suggesting that polymorphisms in the 3'UTR of the PTGS2 gene are rare and unlikely to represent risk factor for NMSC after transplantation.

Leprosy initially misdiagnosed as sarcoidosis, adult-onset still disease, or autoinflammatory disease.

Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae. We describe the case of a 20-year-old man from India living in Italy since 2003, who presented with erythematous papules and nodules distributed on his arms, legs, and face in 2006. He also had episodes of high fever, polyarthritis, and episcleritis. Sarcoidosis was suspected on the basis of elevated angiotensin-converting enzyme and bronchoalveolar lavage fluid, and the patient was treated with corticosteroids for about a year. A flare of the disease occurred each time corticosteroid was tapered or suspended. An autoinflammatory disease was then suspected and treated with immunosuppressant. Only the third deep skin biopsy revealed the presence of M. leprae. The lack of clinical suspicion and the unfamiliarity with the histology of leprosy delayed diagnosis and treatment. Leprosy should be considered in the differential diagnoses of patients presenting with rheumatic and cutaneous manifestations especially when they come from countries where the disease is endemic.

Incidence and clinical predictors of primary opportunistic deep cutaneous mycoses in solid organ transplant recipients: a multicenter cohort study.

BACKGROUND: Primary opportunistic deep cutaneous fungal infections may cause significant morbidity and mortality in solid organ transplant recipients (OTR), but no data exist about their incidence, timing, and clinical predictors in a long-term follow-up. PATIENTS AND METHODS: A series of 3293 consecutive OTR including 1991 kidney, 929 heart, and 373 liver transplant recipients were enrolled. Patients were regularly followed up since time at transplantation (mean 5.5 yr +/-5.9 SD) and primary opportunistic fungal infections registered. Persons-year at risk (PYs), incidence rates (IR), incidence rate ratios (IRR), and 95% confidence intervals were computed. RESULTS: Twenty-two cases of deep cutaneous mycoses were detected, (IR 1.2 cases per 1000 PYs) after a mean follow-up time since transplantation of 2.5 yr +/- 2.0 SD (median 1.8 yr). Six patients had subsequent systemic involvement and three patients died of systemic dissemination. A higher risk for mycoses was observed in the first two yr after transplantation, (IRR 35.9, p < 0.0001), in renal transplant recipients (IRR 5.1 p = 0.030), and in patients transplanted after the age of 50 (IRR 11.5 p = 0.020). CONCLUSIONS: Primary deep cutaneous opportunistic mycoses in OTR occur mainly in the first two yr after transplantation, in renal transplant recipients, and in older patients.

Mortality from cancer is not increased in elderly kidney transplant recipients compared to the general population: a competing risk analysis.

BACKGROUND: The impact of cancer on death of elderly kidney transplant recipients has been extensively investigated, but with conflicting results. Unlike their younger counterparts, in elderly kidney transplant recipients cardiovascular and infectious disease may outweigh cancer in causing the patient's death. METHODS: Using competing risk analysis on a large retrospective cohort of kidney transplant recipients, we estimated the cause-specific cumulative incidence and hazard of death in different age categories and calculated standardized mortality ratios (SMRs) to compare mortality rates with the general population. RESULTS: Six thousand seven hundred eighty-nine kidney transplant recipients were followed-up for a median of 9 years. Ten years after transplantation, in transplant recipients aged 20-39, 40-59, and 60+, the cumulative incidence of cancer-related death was 0.6 (95% confidence interval [CI]: 0.3-1.0), 2.9 (2.3-3.6) and 5.3% (3.5-7.5), whereas the SMR was 9.1 (5.5-15.0), 2.0 (1.6-2.5), and 0.8 (0.6-1.0), respectively. At variance with young recipients, the hazard and the cumulative incidence of cardiovascular-related death in elderly recipients was well above that of cancer-related death. CONCLUSIONS: Relative to the general population, cancer-related death is increased in young but not in elderly kidney transplant recipients because of the more marked increased incidence of competing cause of death in the latter category.

The impact of pruritus on the quality of life of patients undergoing dialysis: a single centre cohort study.

BACKGROUND: Pruritus is common in dialysis patients, but no studies have addressed its impact on the patients' quality of life (QoL). OBJECTIVE: We sought to measure the impact of pruritus on the QoL of patients undergoing chronic hemodialysis (HHD) or peritoneal dialysis (PPD). METHODS: Pruritus intensity was measured on a 10-point visual analog scale. QoL was investigated with the 36-item Short Form of the Medical Outcomes Study questionnaire (SSF-336), the 12-item General Health Questionnaire (GHQ-12) and a dermatological questionnaire (Skindex-29). RESULTS: One hundred and thirty-nine patients on HD and 30 on PD were recruited. Pruritus was found in 88/169 patients (52.1%),with no differences between HD and PD patients. Prevalence of poor sleep in patients with pruritus was higher than in those without (559% vs. 11%; p<0.001). Both physical and mental scores of SF-36 did not correlate with the presence and the intensity of pruritus. Pruritus intensity was significantly related to poor scores in all 3 subscales of Skindex-29 (symptoms, social function and emotions). In the subscales of social function and emotions, worse scores were observed in patients undergoing HD and with minor psychiatric disorders (GHQpos). CONCLUSIONS: Pruritus had a high level of impact on all aspects of QoL and was a predictor of poor sleep. Type of dialysis and minor psychiatric disorders affect the emotional and social aspects of QoL.

Incidence and ten-year follow-up of primary cutaneous lymphomas: a single-centre cohort study.

BACKGROUND: Primary cutaneous lymphomas (PCLs) are a rare group of extranodal non-Hodgkin lymphomas, and epidemiological data in Mediterranean countries are scarce. OBJECTIVE: To investigate the incidence and characteristics of PCL in a single tertiary referral centre in Italy. MATERIALS & METHODS: A total of 141 PCL patients, seen over a 10-year follow-up period, were investigated. RESULTS: Incidence rate of PCL was 0.8 cases/100,000 person years. T-cell lymphoma represented 78.7% of all cases, the majority being early mycosis fungoides (MF) (64%; median age: 66 years), followed by lymphomatoid papulosis (LyP) (19%; median: age 48 years), and others (median age: 72 years), including eight cases of anaplastic large CD30+ T-cell lymphoma, four CD4+ small-medium pleomorphic T-cell lymphoproliferative disorder, four Sézary syndrome, one subcutaneous panniculitis-like T-cell lymphoma, one extranodal NK/T-cell lymphoma nasal-type, and one angioimmunoblastic T-cell lymphoma. B-cell lymphoma accounted for 21.3% of PCL, with 20 cases of cutaneous follicular centre B-cell (median age: 63 years), four primary cutaneous marginal zone, three primary cutaneous diffuse large B-cell, and three leg-type lymphoma. Complete remission within the first year after diagnosis occurred in 70.4% of MF, 61.9% of LyP, 78.9% of other T-cell lymphoma, and 93.1% of B-cell lymphoma cases. Based on a Cox proportional hazard regression model, age, gender, stage, and lactate dehydrogenase and ß2-microglobulin blood levels did not predict clinical remission of MF or LyP. CONCLUSIONS: The incidence and characteristics of PCL in Italy are similar to those in other European countries. PCLs may be diagnosed at very early stages with good prognosis.

Incidence and clinical predictors of Kaposi's sarcoma among 1721 Italian solid organ transplant recipients: a multicenter study.

Kaposi's sarcoma (KS) can be a complication of solid organ transplantation, but with an important incidence rate variability in different geographical areas. Here we analyzed the incidence rate, timing and clinical correlates of KS, in a cohort of Italian solid organ transplant recipients from four distinct transplantation centers. A total of 1721 renal, heart and liver transplant recipients were recruited between 1997 and 2004. KS was diagnosed in 40 patients, after a median follow up of 1 year (range 0.8-5.1). Visceral involvement was detected in 7/40 patients. Incidence rate of KS in the whole population was 2.3 cases per 1000 individuals per year. The standardized incidence rate (SIR) for KS in renal transplant recipients was 149.9 (95% CI 103.0-212.0), with the excess risk greater among women (SIR 316.0) than among men (SIR 133.6). In a Cox proportional hazard regression model, age at transplantation equal or older than 30 years and only combined immunosuppressive therapy with mycophenolate mofetil + cyclosporine + prednisolone were independently associated with KS. Italian organ transplant recipients have an increased risk (about 100 times greater) for KS compared to the general population, especially during the first two years after transplantation. Age older than 30 years at transplantation and a more aggressive immunosuppressive regimen were both independent risk factors for the disease.

The facial grid analysis for filler injection: a cohort study of 300 patients.

BACKGROUND: Filler injection is widely used for facial rejuvenation. Global skin rejuvenation requires the precise sequential injections of different areas, but a standardized and reproducible method is lacking. The purpose of the study was to develop a new method for a precise measurement of the degree of facial defect before and after full-face rejuvenation with injectable fillers, so called facial filler (FAFI) grid. METHODS: Three hundreds patients were included. There were 76 males and 224 females with a median age of 30.5 years. A grid of horizontal and vertical lines was drawn on the patients' face with a rigid meter and a surgical pen to identify some precise areas for sequential filler injections. The grid was also used to measure the defects and the corrections obtained. Three different formulations of hyaluronic acid were used for treating specific facial areas. RESULTS: Correction was judged adequate in 77% and 90% of cases by the physician and patients, respectively. Prevalence of adverse events was 8.8%, with mostly mild, with resolution in few weeks. CONCLUSIONS: FAFI grid proved to be helpful in guiding sequential injections for total facial rejuvenation.

Predictive model for delayed graft function based on easily available pre-renal transplant variables.

Identification of pre-transplant factors influencing delayed graft function (DGF) could have an important clinical impact. This could allow clinicians to early identify dialyzed chronic kidney disease (CKD) patients eligible for special transplant programs, preventive therapeutic strategies and specific post-transplant immunosuppressive treatments. To achieve these objectives, we retrospectively analyzed main demographic and clinical features, follow-up events and outcomes registered in a large dedicated dataset including 2,755 patients compiled collaboratively by four Italian renal/transplant units. The years of transplant ranged from 1984 to 2012. Statistical analysis clearly demonstrated that some recipients' characteristics at the time of transplantation (age and body weight) and dialysis-related variables (modality and duration) were significantly associated with DGF development (p ≤ 0.001). The area under the receiver-operating characteristic (ROC) curve of the final model based on the four identified variables predicting DGF was 0.63 (95 % CI 0.61, 0.65). Additionally, deciles of the score were significantly associated with the incidence of DGF (p value for trend <0.001). Therefore, in conclusion, in our study we identified a pre-operative predictive model for DGF, based on inexpensive and easily available variables, potentially useful in routine clinical practice in most of the Italian and European dialysis units.

Primary cutaneous plasmacytoma after rejection of a transplanted kidney: case report and review of the literature.

Immunosuppressed organ allograft recipients are at risk of developing lymphomas and lymphoproliferative disorders as a consequence of immunosuppressive therapy and long-term antigenic stimulation from both the graft and possible viral infections. No more than 4% of the malignant tumors detected in organ recipients are plasmacytomas. Primary cutaneous plasmacytoma is a rare type of cutaneous B-cell lymphoma arising primarily in the skin. It is derived from clonally expanded plasma cells with various degrees of maturation and atypia. We report the occurrence of a solitary cutaneous plasmacytoma in a 56-year-old male patient undergoing hemodialysis after rejection of a grafted kidney. The diagnosis was made a few months after the kidney had been surgically removed. A thorough examination showed no evidence of systemic disease. Skin lesions were successfully treated with local radiotherapy. After 2 years of follow-up there were no local or systemic recurrences.