Mesna, Doxorubicin, Ifosfamide and Dacarbazine (MAID) Combination Chemotherapy for Retroperitoneal Sarcoma: A Single-center Experience.

BACKGROUND/AIM: There is limited evidence regarding the systemic treatment of retroperitoneal soft-tissue sarcoma, and the current Japanese guidelines fail to make definitive suggestions. Here, we report our experience with combination chemotherapy of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) in this population. PATIENTS AND METHODS: We retrospectively reviewed the records of eight patients (three male and five female) who received MAID for pathologically diagnosed metastatic unresectable retroperitoneal sarcoma (either leiomyosarcoma or pleomorphic sarcoma) between October 2019 and January 2022. Treatment efficacy, tolerability (need for dose reduction), and safety profiles were evaluated and summarized. RESULTS: At initiation, the median age was 56.0 years, and the body mass index was 20.0 kg/cm2 Six patients had Eastern Cooperative Oncology Group performance status scores of 0. The net clinical benefit was a partial response in three (37.5%) patients, stable disease in four (50.0%), and progressive disease in one (12.5%). During the median 90.8 weeks of follow-up, disease in five patients progressed, resulting in a median progression-free survival of 48.4 weeks, and five deaths occurred, resulting in an overall survival of 95.1 weeks. Commonly observed adverse events were neutropenia (eight patients), anemia (eight patients), and decreased platelet count (seven patients), which led to dose reduction (60-80%) in six patients. CONCLUSION: MAID combination therapy may be an acceptable option for advanced retroperitoneal sarcoma; however, its benefits must be carefully assessed owing to its not insignificant toxicity.

Effects of remote ischemic preconditioning on renal protection in patients undergoing robot-assisted laparoscopic partial nephrectomy.

We aimed to evaluate the renoprotective effects of remote ischemic preconditioning (RIPC) in patients undergoing robot-assisted laparoscopic partial nephrectomy (RAPN). Data from 59 patients with solitary renal tumors who underwent RAPN with RIPC comprising three cycles of 5-min inflation to 200 mmHg of a blood pressure cuff applied to one lower limb followed by 5-min reperfusion by cuff deflation, from 2018 to 2020 were analyzed. Patients who underwent RAPN for solitary renal tumors without RIPC between 2018 and 2020 were selected as controls. The postoperative estimated glomerular filtration rate (eGFR) at the nadir during hospitalization and the percentage change from baseline were compared using propensity score matching analysis. We performed a sensitivity analysis with imputations for missing postoperative renal function data weighted by the inverse probability of the data being observed. Of the 59 patients with RIPC and 482 patients without RIPC, 53 each were matched based on propensity scores. No significant differences in the postoperative eGFR in mL/min/1.73 m2 at nadir (mean difference 3.8; 95% confidence interval [CI] - 2.8 to 10.4) and its percentage change from baseline (mean difference 4.7; 95% CI - 1.6 to 11.1) were observed between the two groups. Sensitivity analysis also indicated no significant differences. No complications were associated with the RIPC. In conclusion, we found no significant evidence of the protective effect of RIPC against renal dysfunction after RAPN. Further research is required to determine whether specific patient subgroups benefit from RIPC.Trial registration number: UMIN000030305 (December 8, 2017).

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

OBJECTIVES: To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. PATIENTS AND METHODS: Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. RESULTS: During a median follow-up period of 12.0 months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4 months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P = 0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P = 0.0613). CONCLUSIONS: The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

Assessment of Feasibility of Robot-assisted Radical Cystectomy in Patients With Advanced Bladder Cancer Treated With Maintenance Hemodialysis Therapy.

BACKGROUND/AIM: To clarify the perioperative and oncological outcomes of robot-assisted radical cystectomy (RARC) in advanced bladder cancer (BC) patients treated with maintenance hemodialysis (HD) therapy. PATIENTS AND METHODS: We retrospectively evaluated patients receiving HD therapy who had undergone RARC or open radical cystectomy (ORC) for BC between April 1988 and December 2021 at two affiliated institutions. We compared the surgical outcomes and survival after radical cystectomy between patients treated with RARC and those treated with ORC. RESULTS: Thirty-six patients were evaluated, and eight (22%) and 28 (78%) received RARC and ORC, respectively. RARC was more frequently conducted than ORC in elderly patients (median: 75.5 vs. 68.2 years, p<0.05). Regarding postoperative surgical outcomes, the estimated blood loss volume (median: 75 ml vs. 627 ml, p<0.05) was significantly lower in the RARC group than that in the ORC group. A lower blood transfusion rate (25% vs. 67%, p=0.170) was observed. Moreover, there were no differences in operative time (median: 255 vs. 294 min, p=0.232) or complication rate (Clavien-Dindo grade, any grade: 50% vs. 46%, p=0.858; grade 3 or more: 13% vs. 14%, p=0.897). The 11-year overall survival rate did not differ between the two groups (88% vs. 74%, p=0.365). CONCLUSION: The perioperative outcomes of RARC in patients undergoing HD therapy were comparable to those of ORC. RARC is a potentially feasible surgical option even in patients with high comorbidities.

Urinary Tract Infection in Hemodialysis-Dependent End-Stage Renal Disease Patients.

INTRODUCTION: The aim of this study was to analyze urinalysis findings and urinary bacterial culture in hemodialysis-dependent end-stage renal disease patients. The research goal was to understand the proportion, risk factors, and the causative organisms of urinary tract infection in hemodialysis-dependent end-stage renal disease patients. MATERIALS AND METHODS: Between May 2020 and June 2021, this study included 100 hemodialysis-dependent end-stage renal disease patients (50 male patients and 50 female patients). The urine underwent microscopic examination, pyuria was defined as ≥5 white blood cells per high-power field, and urinary bacterial cultures were conducted for patients with pyuria. Bacteriuria was defined as ≥104 colony-forming units/mL in men and ≥105 colony-forming units/mL in women. Daily urine output was investigated by oral listening. Postvoiding residual urine volume was measured. RESULTS: Fifty-six percent of male patients and 30% of female patients had normosthenuria, 24% of male patients and 38% of female patients had pyuria, and 20% of male patients and 32% of female patients had a urinary tract infection. A comparison of normosthenuria and urinary tract infection revealed no statistically significant difference in age, time on dialysis, daily urine output, and postvoiding residual urine volume. The proportion of female patients among those with normosthenuria was 34.8%, whereas the proportion of female patients among those with UTI was 61.5%. Urinary bacterial cultures showed that the major causative organisms were Escherichia coli (45%; 18/40 cultures) and extended spectrum beta-lactamase-producing Escherichia coli (17.5%; 7/40 cultures). CONCLUSION: The incidence of urinary tract infection was higher in female patients than in male patients. The proportion of resistant bacteria as the causative organisms was high in hemodialysis-dependent end-stage renal disease patients. Urinary bacterial culture should be checked while patients are able to void urine.

Albumin-to-Alkaline Phosphatase Ratio as a Novel Prognostic Marker of Nivolumab Monotherapy for Previously Treated Metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: The relationship between albumin-to-alkaline phosphatase ratio (AAPR) and the outcome of patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors remains unresolved. We aimed to clarify the prognostic role of AAPR in nivolumab monotherapy for previously treated mRCC. PATIENTS AND METHODS: We retrospectively evaluated 60 patients with mRCC treated with nivolumab after failure of at least one molecular targeted therapy. The patients were stratified into two groups based on the baseline AAPR. The threshold of AAPR was determined using receiver-operating characteristics and Youden index analyses. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) of nivolumab therapy were compared between the high and low AAPR groups. RESULTS: The threshold of AAPR was set at 0.3, and 20 patients (33%) were assigned to the low AAPR group. The median OS and PFS were significantly lower in the low AAPR group than those in the high group (OS: 8.3 months vs. not reached, p<0.0001; PFS: 2.9 vs. 10.4 months, p=0.0006). Moreover, ORR was significantly lower in the low AAPR group than in the high group (16% vs. 45%, p=0.0397). Multivariate analyses further showed that AAPR was an independent factor for OS [HR=0.27 (95% CI=0.09-0.77), p=0.0151] but not for PFS (p=0.174). CONCLUSION: Baseline AAPR was significantly associated with outcome in patients with mRCC receiving nivolumab monotherapy and may, therefore, constitute an effective prognostic factor for nivolumab treatment.

A specific promoter-type in ribonuclease L gene is associated with phagocytic activity in pigs.

We have previously generated Large White pigs with high immune competence using a selection strategy based on phagocytic activity (PA), capacity of alternative complement pathway, and antibody response after vaccination against swine erysipelas. In this study, to identify the genetic changes caused by the immune selection pressure, we compared gene expression and polymorphisms in the promoter region between pigs subjected to the immune selection (immune-selected pigs) and those that were not (non-selected pigs). After lipid A stimulation, using a microarray analysis, 37 genes related to immune function and transcription factor activity showed a greater than three-fold difference in expression between macrophages derived from immune-selected and non-selected pigs. We further performed a polymorphic analysis of the promoter region of the differentially expressed genes, and elucidated the predominant promoter-types in the immune-selected and non-selected pigs, respectively, in the genes encoding ribonuclease L (RNASEL), sterile α motif and histidine-aspartate domain containing deoxynucleoside triphosphate triphosphohydrolase 1, signal transducer and activator of transcription 3, and tripartite motif containing 21. Analysis of the association between these promoter genotypes and the immune phenotypes revealed that the immune-selected promoter-type in RNASEL was associated with increased PA and was inherited recessively. Considering that RNASEL has been reported to be involved in antimicrobial immune response of mice, it may be possible to enhance the PA of macrophages and improve disease resistance in pig populations using RNASEL promoter-type as a DNA marker for selection.

Efficacy of Cabozantinib in Metastatic Papillary Renal Cell Carcinoma Following Ineffective Treatment With Initial Therapy of Nivolumab and Ipilimumab.

Sunitinib is listed as first-line therapy for non clear-cell renal cell carcinoma (RCC) in several guidelines. However, in the era of immunotherapy, there is an urgent need for updated evidence for the treatment of metastatic non clear-cell RCC. Herein, we present three cases of patients with type 2 papillary RCC who were effectively treated with cabozantinib. The first case was a 48-year-old woman who underwent radical nephrectomy (pT3aN0M0). The tumor relapsed in the retroperitoneum 3 months postoperatively and was unresponsive to first-line nivolumab plus ipilimumab (NI). After the use of cabozantinib, the tumors drastically shrunk in 2 weeks, and complete response was achieved 3 months later. The second case was a 55-year-old man who underwent radical nephrectomy (pT3aN2M1). Metastatic lesions continued to grow with first-line NI, and cabozantinib was used as the second-line therapy. All metastatic lesions had shrunk by 50% after 4 months. The third case was a 36-year-old man with multiple tumors in the left solitary kidney and iliopsoas muscle metastasis. First-line therapy with NI was ineffective; subsequently, second-line axitinib was used for 5 months, and the disease was identified as progressive. Cabozantinib was started as third-line therapy. Multiple tumors shrunk in 2 weeks. There is little evidence concerning the treatment of papillary RCC. We experienced low efficacy of NI for first-line treatment of papillary RCC for three patients who were subsequently effectively treated with cabozantinib. Cabozantinib inhibits multiple tyrosine kinase receptors, which may suppress aggressive tumor progression of type 2 papillary RCC. Cabozantinib or combination with immuno-oncological drugs may be a promising treatment option for papillary RCC.

Influence of a low-dose tacrolimus protocol on the appearance of de novo donor-specific antibodies during 7 years of follow-up after renal transplantation.

BACKGROUND: Tacrolimus (TAC) is a key immunosuppressant drug for kidney transplantation (KTx). However, the optimal serum trough level of TAC for good long-term outcomes remains unclear. This study aimed to investigate the relationship between the maintenance TAC trough level and the appearance of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSAs). METHODS: A total of 584 KTx recipients were enrolled in this study, of whom 164 developed dnDSAs during the follow-up period and 420 did not. RESULTS: We found no significant relationship between TAC trough level during the follow-up period and dnDSA incidence. Patients who developed dnDSAs had a significantly greater number of HLA-A/B/DR mismatches (3.4 ± 1.3 versus 2.8 ± 1.5; P < 0.001), were more likely to have preformed DSAs (48.2% versus 27.1%; P < 0.001) and showed poor allograft outcome. CONCLUSIONS: There was no clear relationship between TAC trough level and dnDSA incidence for KTx recipients whose TAC trough levels were kept within the narrow range of 4-6 ng/mL during the immunosuppression maintenance period.

Characterization of the Porcine CLEC12A and Analysis of Its Expression on Blood Dendritic Cell Subsets.

CLEC12A has been proposed as a suitable target for delivering antigen to dendritic cells (DCs) to enhance vaccine efficacy both in human and mouse. In this study, we have characterized the porcine homolog of CLEC12A (poCLEC12A). Using new monoclonal antibodies (mAb), raised against its ectodomain, poCLEC12A was found to be expressed on alveolar macrophages, blood conventional type 1 and type 2 DCs and plasmacytoid DCs, but not on monocytes, T cells, B cells or NK cells, in contrast to its human and murine homologs. Western blot analysis showed that in alveolar macrophages this receptor is expressed both as a monomer and a dimer. After binding to DCs, anti- poCLEC12A mAb was efficiently internalized. No significant changes were observed in TNFα or IFNα secretion by plasmacytoid DCs stimulated with either CpGs (ODN2216) or polyinosinic-polycytidylic acid (poly I:C), upon incubation with mAb. These results provide the basis for future investigations aimed to assess the ability of anti-poCLEC12A mAbs to improve vaccine efficacy by targeting antigen to DCs.

Porcine CLEC12B is expressed on alveolar macrophages and blood dendritic cells.

CLEC12B is a C-type lectin-like receptor expressed on myeloid cells. In this study, we have characterized the porcine homologue of CLEC12B (poCLEC12B). To this end, we have generated constructs encoding a c-myc tagged version of the whole receptor, or its ectodomain fused to the Fc portion of human IgG1, from a cDNA clone obtained from an alveolar macrophage library, and raised monoclonal antibodies (mAb) against this molecule. Using these mAbs, poCLEC12B was found to be expressed on alveolar macrophages and, at lower levels, on blood conventional type 1 dendritic cells (cDC1) and plasmacytoid DCs. No binding was detected on monocytes, monocyte-derived macrophages or monocyte-derived DCs. Engagement of CLEC12B on alveolar macrophages with mAbs had no apparent effect on cytokine production (TNF-α, IL-8) induced by LPS. These results provide the basis for future investigations aimed to assess the role of poCLEC12B in different microbial infections and to evaluate its potential in vaccination strategies targeting DCs.

Multiple myeloma with testicular involvement: A case report.

A case of multiple myeloma with testicular involvement is rare. We report a 72-year-old male with testicular infiltration as extramedullary disease of IgD λ-type multiple myeloma. The patient received systemic treatment, which included high orchiectomy, anticancer chemotherapy, and radiation therapy for bone metastasis. Eight months after the initial diagnosis, he remains alive. The testis is a rare location for extramedullary disease of multiple myeloma. Testicular involvement of multiple myeloma indicates a poor prognosis. The particular treatment strategy for extramedullary disease in multiple myeloma remains unclear. Testicular involvement of multiple myeloma is reviewed and discussed in this paper.

Q969R polymorphism in NLRP3 is associated with immune responses to vaccination against bacterial infections in pigs.

Nucleotide-binding domain, leucine-rich-containing family, pyrin-domain containing-3 (NLRP3) is an important pattern recognition receptor involved in various inflammatory responses and adjuvant effects upon vaccination. We previously identified the Q969R (A2906G) gain-of-function polymorphism in porcine NLRP3, which increased production of interleukin-1ß in in vitro gene transfection experiments. Here, we explored the associations between the A2906G polymorphism and antibody responses after vaccination against bacteria in Large White pigs maintained under specific pathogen-free conditions. The NLRP3-2906A/G pigs had a greater antibody response to vaccine antigens than NLRP3-2906A/A pigs. We observed a significant association of the antibody response against Haemophilus parasuis serotype 2 and 5 with NLRP3 genotypes. As the A2906G polymorphism in NLRP3 is widely distributed in commercial pig breeds, Landrace, Large White and Berkshire pigs, there is potential for improvement in vaccine efficiency and disease resistance using this polymorphism in various pig populations.

Distribution of the CD4 Alleles in Sus scrofa Demonstrates the Genetic Profiles of Western Breeds and Miniature Pigs.

Widely used antipig CD4 monoclonal antibodies (mAbs) fail to recognize CD4 alleles characteristic of miniature pig lines such as the National Institutes of Health (NIH) miniature pigs and microminipigs. We surveyed polymorphisms in the coding sequence of the porcine CD4 gene among Western and Oriental pig breeds and Japanese wild boars and investigated their distribution. Of the 13 alleles that we identified among the 47 animals, 2 in group I and 3 in group II were found exclusively in Western breed pigs. Group IV alleles, which included mAb-nonbinding alleles, were found frequently in Oriental breed pigs, suggesting that the mAb-nonbinding allele arose from the gene pool of Oriental pigs. Group IV alleles were also found in Duroc and Large White pigs, suggesting genetic inflow from Oriental pig breeds into Western breeds. Comparison of the CD4 sequences of species in Cetartiodactyla suggested that the group IV alleles in Sus scrofa occurred before the divergence of this species from the other artiodactyls. The different antibody specificities of the various CD4 alleles may facilitate the discrimination of T-cell populations in transplantation studies using miniature pigs. The significance of the preservation of CD4 polymorphisms to immune function in pigs warrants further investigation.

Complex glomerular pathology of thrombotic microangiopathy and focal segmental glomerulosclerosis forms tumor-like mass in a renal transplant donor with severe renovascular hypertension.

The pathogenesis of glomerular hypertension-mediated FSGS and its histological variations in humans remains unknown. A 47-year-old man developed nephrotic syndrome, renal dysfunction, and malignant hypertension 2 years after donating a kidney to his son. The donor's remnant kidney developed renal mass at an upper pole which was fed by an aberrant artery that branched from the root of the renal artery. Furthermore, the main non-aberrant renal artery demonstrated severe stenosis that caused renovascular hypertension, resulting in malignant hypertension. Upon radiological examinations, a tumorous mass was detected. Because of progressive renal dysfunction, nephrectomy was performed. The kidney revealed a diffuse distribution of complex FSGS lesions, i.e., a random combination of cellular/collapsing FSGS and glomerular thrombotic microangiopathy, confined to the renal mass, whereas such lesions were absent in the non-mass portion. This indicated that severe glomerular hypertension alone caused FSGS with TMA features. Heterogeneous FSGS lesions let us surmise that glomerular hypertension promoted simultaneous damages in endothelial cells and podocytes, which synergistically progressed to glomerulosclerosis. This unique case uncovers causal relationships between unusual glomerular hypertension and severe forms of FSGS that was possibly caused by the disruption of homeostasis sustained by podocytes and endothelial cells.

Pig lacks functional NLRC4 and NAIP genes.

The NLRC4 inflammasome, which recognizes flagellin and components of the type III secretion system, plays an important role in the clearance of intracellular bacteria. Here, we examined the genomic sequences carrying two genes encoding key components of the NLRC4 inflammasome-NLR family, CARD-containing 4 (NLRC4), and NLR apoptosis inhibitory protein (NAIP)-in pigs. Pigs have a single locus encoding NLRC4 and NAIP. Comparison of the sequences thus obtained with the corresponding regions in humans revealed the deletion of intermediate exons in both pig genes. In addition, the genomic sequences of both pig genes lacked valid open reading frames encoding functional NLRC4 or NAIP protein. Additional pigs representing multiple breeds and wild boars also lacked the exons that we failed to find through genome sequencing. Furthermore, neither the NLRC4 nor the NAIP gene was expressed in pigs. These findings indicate that pigs lack the NLRC4 inflammasome, an important factor involved in monitoring bacterial proteins and contributing to the clearance of intracellular pathogens. These results also suggest that genetic polymorphisms affecting the molecular functions of TLR2, TLR4, TLR5, and other pattern recognition receptors associated with the recognition of bacteria have a more profound influence on disease resistance in pigs than in other species.

Identification of the Q969R gain-of-function polymorphism in the gene encoding porcine NLRP3 and its distribution in pigs of Asian and European origin.

The nucleotide-binding domain, leucine-rich-containing family, pyrin-domain containing-3 (NLRP3) inflammasome comprises the major components caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and NLRP3. NLRP3 plays important roles in maintaining immune homeostasis mediated by intestinal microorganisms and in the immunostimulatory properties of vaccine adjuvants used to induce an immune response. In the present study, we first cloned a complementary DNA (cDNA) encoding porcine ASC because its genomic sequence was not completely determined. The availability of the ASC cDNA enabled us to reconstitute porcine NLRP3 inflammasomes using an in vitro system that led to the identification of the immune functions of porcine NLRP3 and ASC based on the production of interleukin-1ß (IL-1ß). Further, we identified six synonymous and six nonsynonymous single-nucleotide polymorphisms (SNPs) in the coding sequence of NLRP3 of six breeds of pigs, including major commercial breeds. Among the nonsynonymous SNPs, the Q969R polymorphism is associated with an increased release of IL-1ß compared with other porcine NLRP3 variants, indicating that this polymorphism represents a gain-of-function mutation. This allele was detected in 100 % of the analyzed Chinese Jinhua and Japanese wild boars, suggesting that the allele is maintained in the major commercial native European breeds Landrace, Large White, and Berkshire. These findings represent an important contribution to our knowledge of the diversity of NLRP3 nucleotide sequences among various pig populations. Moreover, efforts to exploit the gain of function induced by the Q969R polymorphism promise to improve pig breeding and husbandry by conferring enhanced resistance to pathogens as well as contributing to vaccine efficacy.

Post-Transplant Lymphoproliferative Disorder in Kidney Transplant Recipients: A Single-Center Experience in Japan.

Post-transplant lymphoproliferative disorder is a serious complication of solid organ transplantation; however, few large studies have been performed in Asian institutions. We review our single-center experience with post-transplant lymphoproliferative disorder patients in Japan. We retrospectively evaluated patients with post-transplant lymphoproliferative disorder following kidney transplantation between January 1985 and December 2013. The patients were divided into early-onset post-transplant lymphoproliferative disorder (<1 year) and late-onset post-transplant lymphoproliferative disorder (≥1 year) groups. Thirteen patients had the disorder, an incidence rate of 0.75% (13/1730). Early-onset post-transplant lymphoproliferative disorder (N = 3) had not occurred for the last two decades. In the late-onset group (N = 10), the median time of onset was 108.7 months. The Kaplan-Meier 10-year overall survival rates were 76.9% and 95.4% in patients with and without the disorder, respectively (P = 0.0001). Post-transplant lymphoproliferative disorder significantly affected transplant recipients' mortality. Late-onset occurred even > 10 years after transplantation; therefore, long-term monitoring of patients is needed.