Several human polyomaviruses of unknown prevalence and pathogenicity have been identified, including human polyomavirus 9 (HPyV9). To determine rates of HPyV9 infection among immunosuppressed... Show moreSeveral human polyomaviruses of unknown prevalence and pathogenicity have been identified, including human polyomavirus 9 (HPyV9). To determine rates of HPyV9 infection among immunosuppressed patients, we screened serum samples from 101 kidney transplant patients in the Netherlands for HPyV9 DNA and seroreactivity. A total of 21 patients had positive results for HPyV9 DNA; positivity rates peaked at 3 months after transplantation, but the highest viral loads were measured just after transplantation. During 18 months of follow-up, HPyV9 seroprevalence increased from 33% to 46% among transplant patients; seroprevalence remained stable at ≈30% in a control group of healthy blood donors in whom no HPyV9 DNA was detected. Further analysis revealed an association between detection of HPyV9 and detection of BK polyomavirus but not of cytomegalovirus. Our data indicate that HPyV9 infection is frequent in kidney transplant patients, but the nature of infection-endogenous or donor-derived-and pathogenic potential of this virus remain unknown. Show less
BACKGROUND: Cryotherapy is effective for common warts, but for plantar warts available treatments often fail. OBJECTIVES: Within a pragmatic randomised controlled trial, we examined whether... Show moreBACKGROUND: Cryotherapy is effective for common warts, but for plantar warts available treatments often fail. OBJECTIVES: Within a pragmatic randomised controlled trial, we examined whether subgroups of common and plantar warts have a favourable natural course or response to treatment based on wart-associated HPV type. STUDY DESIGN: Consecutive patients with new common or plantar warts were recruited in 30 Dutch family practices. Patients (n=250) were randomly allocated to liquid-nitrogen cryotherapy, 40% salicylic acid self-application, or wait-and-see policy. Before treatment, swabs were taken from all separate warts and analysed by a broad spectrum HPV genotyping assay. At 13 weeks, cure rates with 95% confidence intervals of common and plantar warts on intention to treat basis were compared between treatment arms for the different wart-associated HPV types. RESULTS: In total, 7% of swabs tested negative for HPV DNA and 16% contained multiple types, leaving 278 of 371 common swabs (75%) and 299 of 373 plantar swabs (80%) with a single type for analysis. After wait-and-see policy, cure rates were 2/70 (3%, 95% confidence interval 1-10) for HPV 2/27/57-associated common warts, 4/58 (7%, 3-16) for HPV 2/27/57-associated plantar warts, and 21/36 (58%, 42-73) for HPV 1-associated plantar warts. After cryotherapy, cure rates were 30/44 (68%, 53-80), 6/56 (11%, 5-21), and 15/23 (65%, 45-81); after salicylic acid 16/87 (18%, 12-28), 15/60 (25%, 16-37), and 24/26 (92%, 76-98), respectively. CONCLUSIONS: HPV type influenced the natural course and response to treatment for plantar warts. HPV testing potentially optimises wart treatment in primary care. Show less
Antonsson, A.; Pawlita, M.; Feltkamp, M.C.W.; Bavinck, J.N.B.; Euvrard, S.; Harwood, C.A.; ... ; Waterboer, T. 2013
PURPOSEIn light of the significant morbidity and mortality of cutaneous invasive squamous cell carcinomas (SCCs) in renal transplant recipients, we investigated whether conversion to sirolimus... Show morePURPOSEIn light of the significant morbidity and mortality of cutaneous invasive squamous cell carcinomas (SCCs) in renal transplant recipients, we investigated whether conversion to sirolimus-based immunosuppression from standard immunosuppression could diminish the recurrence rate of these skin cancers. PATIENTS AND METHODSIn a 2-year randomized controlled trial, 155 renal transplant recipients with at least one biopsy-confirmed SCC were stratified according to age (< 55 v ≥ 55 years) and number of previous SCCs (one to nine v ≥ 10) and randomly assigned to conversion to sirolimus (n = 74) or continuation of their original immunosuppression (n = 81). Development of a new SCC within 2 years after random assignment was the primary end point.ResultsAfter 2 years of follow-up, the risk reduction of new SCCs in the multivariable analysis was not significant, with a hazard ratio (HR) of 0.76 (95% CI, 0.48 to 1.2; P = .255), compared with a non-sirolimus-based regimen. After the first year, there was a significant 50% risk reduction, with an HR of 0.50 (95% CI, 0.28 to 0.90; P = .021) for all patients together and an HR of 0.11 (95% CI, 0.01 to 0.94; P = .044) for patients with only one previous SCC. The tumor burden of SCC was reduced during the 2-year follow-up period in those receiving sirolimus (0.82 v 1.38 per year; HR, 0.51; 95% CI, 0.32 to 0.82; P = .006) if adjusted for the number of previous SCCs and age. Twenty-nine patients stopped taking sirolimus because of various adverse events. CONCLUSIONConversion to sirolimus-based immunosuppression failed to show a benefit in terms of SCC-free survival at 2 years. Show less
BACKGROUND The aim of this study was to investigate whether the number of transplantations, as a marker of the graft rejection status of the patient, is associated with an increased risk of... Show moreBACKGROUND The aim of this study was to investigate whether the number of transplantations, as a marker of the graft rejection status of the patient, is associated with an increased risk of malignancies. METHODS In a cohort study, 1213 patients, receiving a kidney transplantation between 1966 and 1995 at the Leiden University Medical Center, were analyzed. All cutaneous squamous cell carcinoma and internal malignancies, which had developed between 1966 and 2007, were recorded. The influence of number of transplantations, age, sex and time on immunosuppression on the risk of squamous cell carcinoma and internal malignancies was investigated by time-dependent multivariate Cox's proportional hazard models. RESULTS Of the 1213 kidney transplant recipients, 319 received a second kidney, 78 a third; 13 of them a fourth and 4 of them a fifth transplantation. After adjustment for potentially confounding factors, including age, sex and years on immunosuppressive therapy we did not detect an increased risk of cancer in patients with multiple transplantations. On the contrary, patients with three or more transplantations had a 1.6-fold decreased risk of squamous cell carcinomas and a 3.6-fold decreased risk of internal malignancies. CONCLUSION We conclude that kidney transplant recipients with three or more transplantations do not have an increased risk of cutaneous squamous cell carcinoma and internal malignancies. Show less
Immunosuppressive drugs are thought to cause the dramatically increased risk of carcinomas in sun-exposed skin of organ transplant recipients. These drugs differ in local effects on skin. We... Show moreImmunosuppressive drugs are thought to cause the dramatically increased risk of carcinomas in sun-exposed skin of organ transplant recipients. These drugs differ in local effects on skin. We investigated whether this local impact is predictive of skin cancer risk and may thus provide guidance on minimizing the risk. Immunosuppressants (azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil and rapamycin) were assessed on altering the UV induction of apoptosis in human skin models, and of p53 mutant cell clones (putative tumor precursors) and ensuing skin carcinomas (with mutant p53) in the skin of hairless mice. Rapamycin was found to increase apoptosis (3 fold) whereas cyclosporine decreased apoptosis (3 fold). Correspondingly, a 1.5-5 fold reduction (p=0.07) or a 2-3 fold increase (p<0.001) was found in cell clusters overexpressing mutant p53 in chronically UV-exposed skin of mice that had been fed rapamycin or cyclosporine, respectively. Deep sequencing showed, however, that the allelic frequency (~5%) of the hotspot mutations in p53 (codons 270 and 275) remained unaffected. The majority of cells with mutated p53 appeared not to overexpress the mutated protein. Unexpectedly, none of the immunosuppressants admixed in high dosages to the diet accelerated tumor development, and cyclosporine even delayed tumor onset by ~15% (p<0.01). Thus, in contrast to earlier findings, the frequency of p53-mutant cells was not predictive of the incidence of skin carcinoma. Moreover, the lack of any accelerative effect on tumor development suggests that immunosuppressive medication is not the sole cause of the dramatic increase in skin cancer risk in organ transplant recipients. Show less
This study aimed to investigate whether the occurrence of cutaneous squamous cell carcinomas (SCCs) is associated with an increased risk of internal malignancies (IMs) in kidney transplant... Show moreThis study aimed to investigate whether the occurrence of cutaneous squamous cell carcinomas (SCCs) is associated with an increased risk of internal malignancies (IMs) in kidney transplant recipients (KTRs). In a cohort study, all patients receiving kidney transplantation in Leiden, the Netherlands, between 1966 and 2006 were followed up. All malignancies that had developed between 1966 and 2007 were recorded. Time-dependent Cox regression analyses were used to calculate the association between the development of cutaneous SCCs and IMs. The incidence of IMs in the KTRs after transplantation was also compared with the general Dutch population by calculating standardized morbidity ratios (SMRs) and was matched for age, sex, and time period in which the malignancy had occurred. Among 1,800 KTRs, 176 (9.8%) developed cutaneous SCCs and 142 (7.9%) developed IMs after transplantation. In patients with prior cutaneous SCCs, the adjusted risk to develop IMs was 3.0 (1.9; 4.7). In KTRs without cutaneous SCCs, the risk of IM compared with the general population was hardly increased. KTRs with cutaneous SCCs have an increased risk to develop IMs, and this information can be used to identify KTRs who are at an increased risk for IMs. Show less
Because of its antitumor effect, the immunosuppressant rapamycin holds great promise for organ transplant recipients in that it may lower their cancer risk. In a mouse model, we showed previously... Show moreBecause of its antitumor effect, the immunosuppressant rapamycin holds great promise for organ transplant recipients in that it may lower their cancer risk. In a mouse model, we showed previously that rapamycin inhibits the outgrowth of primary skin carcinomas induced by UV radiation. However, the tumors that did grow out showed an altered p53 mutation spectrum. Here, we investigated whether this shift in p53 mutations already occurred in the smallest tumors, which were not affected in onset. We found that rapamycin did not alter the mutational spectrum in small tumors and in preceding microscopic clusters of cells expressing mutant-p53. However, rapamycin did reduce the number of these cell clusters. As this reduction did not affect tumor onset, we subsequently investigated whether rapamycin merely suppressed expression of mutated p53. This was not the case, as we could demonstrate that switching from a diet with rapamycin to one without, or vice versa, did not affect the number of existing mutant-p53 expressing cell clusters. Hence, rapamycin actually reduced the formation of mutant-p53 cell clusters. In wild-type and p53-mutant mice, we could not measure a significant enhancement of UV-induced apoptosis, but we did observe clear enhancement in human skin equivalents. This was associated with a clear suppression of HIF1α accumulation. Thus, we conclude that rapamycin reduces the formation of mutant-p53-expressing cell clusters without affecting tumor onset, suggesting that tumors grow out of a minor subset of cell clusters, the formation of which is not affected by rapamycin. Show less
