Concurrent JCPyV-DNAemia Is Correlated With Poor Graft Outcome in Kidney Transplant Recipients With Polyomavirus-associated Nephropathy.

BACKGROUND: Co-infection of JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) is uncommon in kidney transplant recipients, and the prognosis is unclear. This study aimed to investigate the effect of concurrent JCPyV-DNAemia on graft outcomes in BKPyV-infected kidney transplant recipients with polyomavirus-associated nephropathy (PyVAN). METHODS: A total of 140 kidney transplant recipients with BKPyV replication and PyVAN, 122 without concurrent JCPyV-DNAemia and 18 with JCPyV-DNAemia were included in the analysis. Least absolute shrinkage and selection operator regression analysis and multivariate Cox regression analysis were used to identify prognostic factors for graft survival. A nomogram for predicting graft survival was created and evaluated. RESULTS: The median tubulitis score in the JCPyV-DNAemia-positive group was higher than in JCPyV-DNAemia-negative group ( P  = 0.048). At last follow-up, the graft loss rate in the JCPyV-DNAemia-positive group was higher than in the JCPyV-DNAemia-negative group (50% versus 25.4%; P  = 0.031). Kaplan-Meier analysis showed that the graft survival rate in the JCPyV-DNAemia-positive group was lower than in the JCPyV-DNAemia-negative group ( P  = 0.003). Least absolute shrinkage and selection operator regression and multivariate Cox regression analysis demonstrated that concurrent JCPyV-DNAemia was an independent risk factor for graft survival (hazard ratio = 4.808; 95% confidence interval: 2.096-11.03; P  < 0.001). The nomogram displayed favorable discrimination (C-index = 0.839), concordance, and clinical applicability in predicting graft survival. CONCLUSIONS: Concurrent JCPyV-DNAemia is associated with a worse graft outcome in BKPyV-infected kidney transplant recipients with PyVAN.

Clinical features of BK-polyomavirus and cytomegalovirus co-infection after kidney transplantation.

BK polyomavirus (BKPyV) and cytomegalovirus (CMV) are the main viral pathogens affecting the graft and recipient outcome after allogenic kidney transplantation. It has recently been found that infection with both viruses has a greater impact on kidney graft function than a single infection. We retrospectively analyzed a cohort of 723 recipients who received kidney transplantation between 2007 and 2015 after living and postmortal donation for differences in risk and outcome parameters regarding BKPyV (DNAemia) and CMV (CMV DNAemia) co-infection compared to sole viremias and to patients without viremia. Of all kidney allograft recipients in our cohort, 8.2% developed co-infection with BKPyV DNAemia and CMV DNAemia, 15.1% showed BKPyV viremia alone and 25.2% sole CMV DNAemia. Acute rejection was closely linked with co-infection (multivariable analysis, p = 0.001). Despite the fact that the estimated glomerular filtration rate of patients with co-infection was noticeably reduced compared to patients with BKV or CMV infection alone, transplant survival and patient survival were not significantly reduced. Co-infection with BKPyV and CMV in kidney transplanted patients is significantly associated with inferior allograft function. Since co-infection is strongly associated with acute rejection, co-infected individuals should be considered a risk collective.

Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6-7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A.

Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6-7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L'Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6-7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6-7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6-7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6-7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6-7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study.

TdT Expression Is a Marker of Better Survival in Merkel Cell Carcinoma, and Expression of B-Cell Markers Is Associated With Merkel Cell Polyomavirus.

OBJECTIVES: Merkel cell carcinoma is a rare but very aggressive cutaneous tumor. We evaluated the prognostic potential of B-cell markers (terminal deoxynucleotidyl transferase [TdT], PAX5, CD117), follicular stem cell markers (CK15, CK19), p63, p53, RB, and Merkel cell polyomavirus (MCPyV; CM2B4) in 136 primary cutaneous Merkel cell carcinomas. METHODS: Clinical, histopathologic, and immunohistochemical analyses were performed. The results were correlated with patient outcomes by Fisher exact test, log-rank tests, and Cox multivariate models. RESULTS: By Fisher exact test, although TdT significantly correlated with both lack of progression (P = .0087) and alive status (P = .0056), MCPyV status correlated only with alive status (P = .031). In univariate analyses, TdT, MCPyV, and RB significantly correlated with improved overall survival, whereas p63 and CK15 correlated with worse overall survival. However, in multivariate analyses, only TdT expression remained as an independent predictor of improved overall survival, Merkel cell carcinoma-specific survival, and progression-free survival. By linear regression analyses, significant correlations between MCPyV vs TdT, PAX5, and CD117 were observed. CONCLUSIONS: TdT expression is a potential marker of better survival in Merkel cell carcinoma. Expression of B-cell markers is associated with MCPyV, suggesting that clonal viral integration might play a role in the expression of these markers.

Screening for BK Viremia/Viruria and the Impact of Management of BK Virus Nephropathy in Renal Transplant Recipients.

OBJECTIVES: The prevalence of BK-induced nephritis in renal transplant recipients is estimated to be 1% to 10%; the rate of graft loss within 1 year is 30% to 65%. We conducted this study to evaluate screening of BK virus in blood and/or urine among renal transplant recipients and to assess the effects of different therapeutic modalities in renal transplant recipients with BK nephropathy. MATERIALS AND METHODS: Kidney transplant recipients were screened at the time of transplant and then at 1, 2, 3, 6, 9, 12, 18, and 24 months posttransplant. Fiftynine patients were diagnosed with BK virus viremia. Patients were divided into 2 groups according to treatment: group 1 (n = 29) received an active treatment and group 2 (n = 30) received minimized immunosuppression. RESULTS: Most patients required graft biopsies to confirm diagnosis (86.2% in group 1 vs 50% in group 2; P = .03). Both groups were comparable regarding demographic data. Initial posttransplant graft function was significantly better in group 1 (P = .017); ultimately, there was no significant difference between both groups regarding graft survival (P= .51). Fifty percent of patients had biopsy-proven acute T-cell-mediated rejection before BK virus-associated nephropathy diagnosis (significantly higher in group 1). Serum creatinine levels were significantly better in group 2 at 3, 4, and 5 years after BK nephropathy (P = .001, .017, and .003, respectively). CONCLUSIONS: The prevalence of BK nephropathy in our renal transplant recipients was 5.9% with a rate of graft loss ranging from 43% to 51%. Regular screening, less intensive immunosuppressive therapy, and early intervention by reduction of immunosuppressive medications are advisable to obtain early diagnosis and to have better outcomes of BK virus-associated nephropathy with antiviral agents.

Outcome of renal transplant recipients with cytomegalovirus and BK polyomavirus co-infection nephropathy.

Reactivation of cytomegalovirus (CMV) and BK polyomavirus (BKV) can result in virus-associated tubulointerstitial nephritis in renal allografts. All those renal biopsies reported as viral cytopathic were isolated and examined by two independent renal histopathologists from our institute and classified as CMV, BKV, and CMV-BKV coinfection-associated viral cytopathic changes with confirmation through polymerase chain reaction technology in either serum or urine or both. All twenty patients were categorized as 10 in CMV, four in BKV, and six were in CMV-BKV coinfection. One patient each had received antithymocyte globulin and basiliximab as induction all patients received triple-drug immunosuppression. The mean graft survival was 69, 61, and 59 months in CMV, BKV, and CMV-BKV coinfection group, respectively. At the end of the study period, 10 (50%) patients died. 1-, 3-and 5-year patient survival was 94%, 88% and 76% among CMV group, 75%, 75% and 50% in BKV group, and 96%, 83% and 62%, in CMV-BKV coinfection group (P = 0.157). CMV and BK virus are not so common infections in postrenal transplant patients yet an important cause of graft dysfunction. Coinfection did not pose an increased risk for acute rejection or patients and death-censored and uncensored graft survival among compared groups.

Tumor stromal desmoplasia and inflammatory response uniquely predict survival with and without stratification for HPV tumor infection in OPSCC patients.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) positive for human papillomavirus (HPV) increases wolrd wide. AIMS/OBJECTIVES: The objective for this study has been to evaluate tumor phenotypes and tumor host responses with respect to five-year disease-specific survival (DSS) in HPV(+) and HPV(-) patients. MATERIAL AND METHODS: Two hundred patients with OPSCC have been treated between 1992 and 2010. Histopathology slides from these patients have been morphologically evaluated in formalin-fixed, paraffin-embedded (FFPE) stained with hematoxylin-eosin (HE). From HE-stained sections tumor phenotype (keratinization, fraction of mature cancer cells and pattern of invasion) and tumor host responses (inflammation and stromal desmoplasia) were evaluated with respect to five years DSS. RESULTS: High tumor inflammatory response and low stromal desmoplasia had an independent effect predicting better five-year DSS among all patients and when analyzed separately in the HPV(-) and HPV(+) cohort of patients using a Cox regression survival analysis that also included standard clinical prognostic variables among OPSCC patients. CONCLUSION: Tumor host responses, inflammation and stromal desmoplasia may become part of routine work-up in OPSCC patients due to prognostic value. SIGNIFICANCE: We present a method, accessible in most clinical locations and would give important additional information about prognosis in OPSCC patients.

Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas.

Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine tumor of the skin whose molecular pathogenesis is not completely understood, despite the role that Merkel cell polyomavirus can play in 55-90% of cases. To study potential mechanisms driving this disease in clinically characterized cases, we searched for somatic mutations using whole-exome sequencing, and extrapolated our findings to study functional biomarkers reporting on the activity of the mutated pathways. Confirming previous results, Merkel cell polyomavirus-negative tumors had higher mutational loads with UV signatures and more frequent mutations in TP53 and RB compared with their Merkel cell polyomavirus-positive counterparts. Despite important genetic differences, the two Merkel cell carcinoma etiologies both exhibited nuclear accumulation of oncogenic transcription factors such as NFAT or nuclear factor of activated T cells (NFAT), P-CREB, and P-STAT3, indicating commonly deregulated pathogenic mechanisms with the potential to serve as targets for therapy. A multivariable analysis identified phosphorylated CRE-binding protein as an independent survival factor with respect to clinical variables and Merkel cell polyomavirus status in our cohort of Merkel cell carcinoma patients.

Oncologic outcomes of selective neck dissection in HPV-related oropharyngeal squamous cell carcinoma.

OBJECTIVES: To examine outcomes of selective neck dissection (SND) in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) who present with clinical neck disease. STUDY DESIGN: Multi-institutional retrospective review. METHODS: Two institutional databases of patients with HPV-related OPSCC were reviewed to identify patients with clinical (c) N1-N3 neck disease who underwent SND ± adjuvant therapy. RESULTS: Three hundred and twenty-four patients were identified with a median follow-up of 49 months (range 3-199 months). All patients underwent transoral resection of the primary tumor and SND, including levels II-IV and ± levels I or V, with resection of additional nonlymphatic tissue (extended SND) as indicated by extent of disease, including the spinal accessory nerve (7%), the internal jugular vein (13%), and the sternocleidomastoid muscle (8%). Two hundred and seventy (83%) patients underwent adjuvant radiation. There were 13 (4%) regional recurrences and 19 (6%) distant recurrences. Regional control following salvage was 98%. On univariable analysis, absence of radiation was associated with regional recurrence (odds ratio [OR] 9.2, 95% confidence interval [CI] 2.9-29.4). On multivariable analysis, adjuvant radiation was associated with improved disease-free survival (DFS) (OR 0.27, 95% CI 0.14-0.53) but lost significance for overall (OS) and disease-specific survival (DSS) (P > 0.05). Five-year Kaplan-Meier estimates for OS, DSS, and DFS were 88% (95% CI 84%-92%), 93% (95% CI 89%-96%), and 83% (95% CI 78%-87%), respectively. CONCLUSION: In HPV-related OPSCC presenting with clinical neck disease, a SND ± additional tissue resection and adjuvant therapy, when indicated, provides excellent long-term regional control. Omission of radiotherapy increases the risk of regional recurrence, although it may not significantly impact OS or DSS. It appears unnecessary to routinely perform a comprehensive neck dissection. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:623-630, 2017.

Polyomavirus-Negative Merkel Cell Carcinoma: A More Aggressive Subtype Based on Analysis of 282 Cases Using Multimodal Tumor Virus Detection.

Previous studies have reached conflicting conclusions regarding the proportion of Merkel cell carcinomas (MCCs) that contain the Merkel cell polyomavirus (MCPyV) and the clinical significance of tumor viral status. To address these controversies, we detected MCPyV large T antigen using immunohistochemistry with two distinct antibodies and MCPyV DNA using quantitative PCR. Tumors were called MCPyV-positive if two or more of these three assays indicated presence of this virus. A total of 53 of 282 (19%) MCC tumors in this cohort were virus-negative using this multimodal system. Immunohistochemistry with the CM2B4 antibody had the best overall performance (sensitivity = 0.882, specificity = 0.943) compared with the multimodal classification. Multivariate analysis including age, sex, and immunosuppression showed that, relative to MCC patients with virus-positive tumors, virus-negative MCC patients had significantly increased risk of disease progression (hazard ratio = 1.77, 95% confidence interval = 1.20-2.62) and death from MCC (hazard ratio = 1.85, 95% confidence interval = 1.19-2.89). We confirm that approximately 20% of MCCs are not driven by MCPyV and that such virus-negative MCCs, which can be quite reliably identified by immunohistochemistry using the CM2B4 antibody alone, represent a more aggressive subtype that warrants closer clinical follow-up.

Risk Factors for BK Polyoma Virus Treatment and Association of Treatment With Kidney Transplant Failure: Insights From a Paired Kidney Analysis.

BACKGROUND: Identification of risk factors for BK polyoma virus (BKPyV) without confounding by donor factors and era effects in paired analysis may inform strategies to prevent BKPyV. METHODS: In this analysis of 21,575 mate kidney pairs in the Scientific Registry of Transplant Recipients between 2004 and 2010, the presence of a treatment code for BKPyV virus in follow-up forms was used to identify pairs in which 1 of 2 mate kidneys was treated (discordant treatment) or both mate kidneys were treated (concordant treatment). RESULTS: Among 1975 discordant pairs, younger than 18 years or 60 years or older, male sex, HLA mismatch or 4 greater, acute rejection, and depleting antibody induction had a higher odds of treatment, whereas diabetes and sirolimus had a lower odds of treatment, and treatment was associated with a higher risk of allograft failure (hazards ratio, 2.01; 95% confidence interval, 1.63-2.48). The rate of concordant treatment (0.81%) was 2.8 times higher than expected. Concordant treatment was associated with nonwhite donor ethnicity, donation after circulatory death, transplantation after 2008, and transplantation of mate kidneys in the same center. CONCLUSIONS: This analysis of kidneys from the same donor in which only 1 transplant was treated for BKPyV identifies specific risk factors (age <18 or ≥ 60 years, male sex, depleting antibody, HLA mismatch ≥ 4) for BKPyV and provides an estimate of the BKPyV-associated risk of allograft failure (hazards ratio = 2.01) without confounding by donor factors or era effects. The higher than expected rate of concordant treatment suggests the importance of donor factors in BKPyV pathogenesis and warrants further study.

Cidofovir in the Treatment of BK Virus-Associated Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation.

After allogeneic hematopoietic stem cell transplantation (HSCT), BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication. Although supportive measures have been the standard of care for many years, several studies suggested the efficacy of cidofovir. The aim of this study was to assess the safety profile and efficacy of cidofovir. A retrospective study was conducted on all patients treated with cidofovir in our HSCT unit between March 2011 and May 2013. Data for efficacy (partial [PR] or complete response [CR]), prescription (dose, frequency, number of doses, and administration route), and toxicity were collected from published reports and medical files. Renal toxicity was evaluated using creatinine clearance calculated with the Cockcroft and Gault formula. A parallel literature search using PubMed (last search, May 2015) was performed. From March 2011 to June 2013, 27 of 181 patients undergoing allogeneic HSCT in our department received cidofovir for BKV-HC: 24 (88.9%) intravenously, 1 intravesically, and 2 via both routes. Mean dose was 5 mg/kg per administration, for a median of 4 injections (range, 1 to 11), from twice a week to once every 2 weeks. CR was achieved in 22 patients (81.5%), PR in 2, and no response in 2 patients. Eight patients presented renal failure (29.6%): 6 moderate (creatinine clearance < 60 mL/min) and 2 severe (creatinine clearance < 30 mLmin). Mean decrease in creatinine clearance after cidofovir was 27% (35 mL/min; range, 2 to 159). In 3 cases renal insufficiency and hematologic toxicity led to discontinuation of treatment or switch to intravesical instillation. For 3 patients cidofovir dose was reduced because of nephrotoxicity. Thirteen studies have reported on the use of cidofovir for BKV-HC (204 patients) since 2005. Intravenous cidofovir was used for 91.3% of patients, with doses ranging from .5 to 5 mg/kg. The main toxicity reported was renal failure (9% to 50% in 9 studies). Between 60% and 100% of CRs were observed independently of cidofovir dose or administration route. Cidofovir is an effective therapy for BKV-HC but requires very precise renal function management to avoid toxicity. Cidofovir treatment modalities (high dose, intravesical instillation, or low dose [≤1 mg/kg]) needs to be investigated in randomized controlled trials.

Reactivation of polyomavirus in the genitourinary tract is significantly associated with severe GvHD and oral mucositis following allogeneic stem cell transplantation.

PURPOSE: BK-virus and JC-virus are the most common polyomaviridae associated with hemorrhagic cystitis in the allogeneic transplant setting. Hemorrhagic cystitis and symptomatic viruria caused by these viruses are a major cause of morbidity in patients undergoing allogeneic stem cell transplantation. METHODS: We performed a retrospective evaluation on a highly uniform study population of 73 patients receiving allogeneic stem cell transplantation. Patients were treated according to the FLAMSA-RIC-protocol, and were examined for the incidence of BK-/JC-viruria and late-onset BK-positive hemorrhagic cystitis within a two-year period. RESULTS: The occurrence of BK-viruria was correlated with published risk factors (acute GvHD, oral mucositis, donor type, conditioning, age, gender). Thirty patients (41 %) were found to excrete either BK-virus (n = 17), JC-virus (n = 3) or both (n = 10), of whom 18 patients (60 %) developed higher-grade hemorrhagic cystitis as opposed to none in the virus-negative control group. Higher grade GvHD (grade B-D) was more common in patients with viruria (p = 0.013) and also more common in patients with manifest hemorrhagic cystitis (p = 0.048). Similarly, oral mucositis was associated both with viruria (p = 0.014) and hemorrhagic cystitis (p = 0.005). Manifest cystitis but not viruria was significantly associated with male gender (p = 0.016). No significant correlation was found with age, conditioning with busulfane vs total body irradiation or related vs unrelated donor. CONCLUSIONS: Severe GvHD and oral mucositis are significantly associated with reactivation of polyomaviridae in the genitourinary-tract already at the level of asymptomatic viruria.

Simultaneous pancreas/kidney transplant recipients present with late-onset BK polyomavirus-associated nephropathy.

BACKGROUND: Infections have increased in simultaneous pancreas/kidney transplant recipients (SPKTRs) with BK polyomavirus (BKV)-associated nephropathy (BKVN) being the most important infectious cause of allograft loss. Comparisons of BKVN with kidney transplant recipients (KTRs), however, are lacking. METHODS: We studied all SPKTRs and KTRs at our transplant centre between 2003 and 2012. Eleven of 106 SPKTs (10.4%) and 21 of 1062 KTRs (2.0%) were diagnosed with BKVN with allograft loss in 1 SPKTR (9.1%) and 2 KTRs (9.5%). A control of 95 SPKTRs without BKVN was used for comparison. RESULTS: SPKTRs showed an increased incidence of BKVN compared with KTRs (P < 0.001). Onset of BKVN in SPKTRs was significantly later compared with KTRs (P = 0.033). While 67% of KTRs showed early-onset BKVN, 64% of SPKTRs developed late-onset BKVN. Older recipient age and male gender increased the risk of BKVN in SPKTRs (P < 0.05). No differences were observed for patient and allograft survival (P > 0.05). However, SPKTRs with BKVN showed inferior estimated glomerular filtration rate and a higher incidence of de novo donor-specific antibodies compared with SPKTRs without BKVN in long-term follow-up (P < 0.05). SPKTRs showed higher peak BKV loads, a need for more intense therapeutic intervention and were more likely not to recover to baseline creatinine after BKVN (P < 0.05). CONCLUSIONS: Our results suggest a higher incidence, more severe course and inferior outcome of BKVN in SPKTRs. An increased vulnerability of the allograft kidney due to inferior organ quality may predispose KTRs to early-onset BKVN. In contrast, SPKTRs present with late-onset BKVN in the presence of high-dose immunosuppression.

Symptomatic BK Virus Infection Is Associated With Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients.

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

Management of human papillomavirus-related unknown primaries of the head and neck with a transoral surgical approach.

BACKGROUND: Amidst a rising incidence of p16-positive (p16+) oropharyngeal cancer, a significant number of cases present as regionally metastatic disease with an "unknown" primary. Preliminary data support transoral surgery as an effective method of primary detection/treatment. METHODS: An observational cohort study of 65 p16+ unknown primary patients treated with transoral surgery and neck dissection (2001-2012) was performed. Adjuvant therapy and recurrence data were collected. Kaplan-Meier estimates were computed for disease-specific survival (DSS) and overall survival (OS). RESULTS: The primary detection rate was 89% (58 of 65). Five-year DSS and OS were 98% and 97% for the detected group and 100% for the undetected, respectively. Seventeen patients were treated with surgery alone. Of the 47 patients receiving adjuvant therapy, radiation to the pharynx was spared in 36. CONCLUSION: The transoral approach was highly effective for the diagnosis and treatment of the p16+ unknown primary and laid the foundation for deescalated radiation by elimination of the pharyngeal field.

Factors influencing survivorship of rehabilitating green sea turtles (Chelonia mydas) with fibropapillomatosis.

Marine turtle fibropapillomatosis (FP) is a debilitating, infectious neoplastic disease that has reached epizootic proportions in several tropical and subtropical populations of green turtles (Chelonia mydas). FP represents an important health concern in sea turtle rehabilitation facilities. The objectives of this study were to describe the observed epidemiology, biology, and survival rates of turtles affected by FP (FP+ turtles) in a rehabilitation environment; to evaluate clinical parameters as predictors of survival in affected rehabilitating turtles; and to provide information about case progression scenarios and potential outcomes for FP+ sea turtle patients. A retrospective case series analysis was performed using the medical records of the Georgia Sea Turtle Center (GSTC), Jekyll Island, Georgia, USA, during 2009-2013. Information evaluated included signalment, morphometrics, presenting complaint, time to FP onset, tumor score (0-3), co-morbid conditions, diagnostic test results, therapeutic interventions, and case outcomes. Overall, FP was present in 27/362 (7.5%) of all sea turtles admitted to the GSTC for rehabilitation, either upon admittance or during their rehabilitation. Of these, 25 were green and 2 were Kemp's ridley turtles. Of 10 turtles that had only plaque-like FP lesions, 60% had natural tumor regression, all were released, and they were significantly more likely to survive than those with classic FP (P = 0.02 [0.27-0.75, 95% CI]). Turtles without ocular FP were eight times more likely to survive than those with ocular FP (odds ratio = 8.75, P = 0.032 [1.21-63.43, 95% CI]). Laser-mediated tumor removal surgery is the treatment of choice for FP+ patients at the GSTC; number of surgeries was not significantly related to case outcome.

Viruses and human cancers: a long road of discovery of molecular paradigms.

About a fifth of all human cancers worldwide are caused by infectious agents. In 12% of cancers, seven different viruses have been causally linked to human oncogenesis: Epstein-Barr virus, hepatitis B virus, human papillomavirus, human T-cell lymphotropic virus, hepatitis C virus, Kaposi's sarcoma herpesvirus, and Merkel cell polyomavirus. Here, we review the many molecular mechanisms of oncogenesis that have been discovered over the decades of study of these viruses. We discuss how viruses can act at different stages in the complex multistep process of carcinogenesis. Early events include their involvement in mutagenic events associated with tumor initiation such as viral integration and insertional mutagenesis as well as viral promotion of DNA damage. Also involved in tumor progression is the dysregulation of cellular processes by viral proteins, and we describe how this has been investigated by studies in cell culture and in experimental animals and by molecular cellular approaches. Also important are the molecular mechanisms whereby viruses interact with the immune system and the immune evasion strategies that have evolved.

Outcomes of kidney transplant tourism and risk factors for de novo urothelial carcinoma.

BACKGROUND: To date, the outcomes of transplant tourism have not been reported extensively. In addition, data about the accuracy of urine cytology for the detection and the role of the BK virus (BKV) in the carcinogenesis of urothelial carcinoma (UC) after renal transplantation are lacking. METHODS: Three hundred seven patients who received deceased donor kidney transplants between January 2003 and December 2009 were retrospectively studied. The clinical parameters and outcomes between the domestic and tourist groups were compared. We also investigated the risk factors and role of BKV in the carcinogenesis of de novo UC by quantitative real-time polymerase chain reaction. RESULTS: The subjects in the tourist group were older at transplantation and had a shorter dialysis time before transplantation. There were significantly higher incidence rates of BKV viruria, Pneumocystis jiroveci pneumonia, and malignancy in the tourist group. Graft and patient survival were superior in the domestic group. A total of 43 cancers were identified, and the most common type of malignancy was UC (23 patients, 53.5%). The tourist group had a significantly higher incidence of tumors. The sensitivity and specificity of urine cytology for detecting UC were 73.9% and 94.7%, respectively. Independent predictors of UC included female sex, use of Chinese herbal medicine, and transplant tourism. Only two patients (8.7%) with UC had detectable BKV. CONCLUSIONS: Transplant tourism was a risk factor for infection and de novo malignancy. Urothelial carcinoma was the most common malignancy after kidney transplantation. Regular screening for the early detection of UC by urine cytology or periodic sonographic surveys is mandatory, especially for those at high risk.

Transient versus persistent BK viremia and long-term outcomes after kidney and kidney-pancreas transplantation.

BACKGROUND AND OBJECTIVES: The objective was to study the long-term impact of transient versus persistent BK viremia on kidney transplant outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 609 recipients who underwent kidney transplant from 2007 to 2011 were screened at months 1-12 for the occurrence of polyomavirus BK viremia; 130 patients (21.7%) developed BK viremia during the first year post-transplant. BK viremia patients were classified according to duration of infection (more or less than 3 months), and BK viral loads (more or less than 10,000 copies/ml) were classified as transient low viremia (n=42), transient high viremia (n=18), persistent low viremia (n=23), and persistent high viremia (n=47). All patients were followed a median of 36 (3-66) months. The rates of BK polyomavirus-associated nephropathy, acute rejection, and 1-year graft function were compared with the polyomavirus BK-negative control group. RESULTS: Patient and graft survival were not significantly different among the groups. Graft function (creatinine; milligrams per deciliter) at 1 year was significantly worse in the persistent high viremia (1.75±0.6) and transient high viremia (1.85±0.7) groups compared with aviremic controls (1.47±0.4; P=0.01 and P=0.01, respectively). The incidence of BK polyomavirus-associated nephropathy was limited to the persistent high viremia group (1.3%, P<0.001). The transient high viremia (50%) and persistent high viremia (34%) groups showed significantly (P=0.01) increased incidence of acute rejection versus aviremic controls (21.5%), transient low viremia (19%), or persistent low viremia (17.3%) groups. CONCLUSION: Low viral load BK viremia, either transient or persistent, was not associated with long-term transplant outcomes. Persistent high viremia was associated with a greater risk for BK polyomavirus-associated nephropathy and subsequent graft dysfunction. Although transient high viremia was not associated with BK polyomavirus-associated nephropathy, it was associated with worse graft function. These data support the role of surveillance for BK viremia after transplant.