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Human papillomavirus (HPV) is an important causative factor of cervical cancer and is associated with nonsmall cell lung cancer (NSCLC). Merkel cell polyomavirus (MCPyV) is a rare and highly fatal cutaneous virus that can cause Merkel cell carcinoma (MCC). Although coinfection with oncogenic HPV and MCPyV may increase cancer risk, a definitive etiological link has not been established. Recently, genomic variation and genetic diversity in the MCPyV noncoding control region (NCCR) among ethnic groups has been reported. The current study aimed to provide accurate prevalence information on HPV and MCPyV infection/coinfection in NSCLC patients and to evaluate and confirm Korean MCPyV NCCR variant genotypes and sequences. DNA from 150 NSCLC tissues and 150 adjacent control tissues was assessed via polymerase chain reaction (PCR) targeting regions of the large T antigen (LT-ag), viral capsid protein 1 (VP1), and NCCR. MCPyV was detected in 22.7% (34 of 150) of NSCLC tissues and 8.0% (12 of 150) of adjacent tissues from Korean patients. The incidence rates of HPV with and without MCPyV were 26.5% (nine of 34) and 12.9% (15 of 116). The MCPyV NCCR genotype prevalence in Korean patients was 21.3% (32 of 150) for subtype I and 6% (nine of 150) for subtype IIc. Subtype I, a predominant East Asian strain containing 25 bp tandem repeats, was most common in the MCPyV NCCR data set. Our results confirm that coinfection with other tumor-associated viruses is not associated with NSCLC. Although the role of NCCR rearrangements in MCPyV infection remains unknown, future studies are warranted to determine the associations of MCPyV NCCR sequence rearrangements with specific diseases., (© 2024 Wiley Periodicals LLC.)

Background: Colorectal cancer (CRC) is a cancer type that is thought to be influenced by human papillomaviruses (HPVs) and human polyomaviruses (HPyVs). In Egypt, CRC ranks as the 7th most common cancer, accounting for 3.47% of male cancers and 3% of female cancers. However, there is currently a lack of information regarding the presence of PyVs and HPVs co-infection specifically in CRC cases in Egypt. Therefore, the aim of this study was to investigate the occurrence of HPVs and HPyVs (JCPyV, BKPyV, and SV40) infections, as well as co-infections, among CRC patients in Egypt. Additionally, the study aimed to assess any potential association between these viral infections and tumor stages., Methods: In the present study, we analyzed a total of 51 tissue samples obtained from Egyptian CRC patients, along with 19 polyps' samples. Our investigation focused on the detection and genotyping of HPyVs using Real-Time PCR. Additionally, we employed real-time PCR for the detection of HPVs, and for their genotyping, we utilized a combination of PCR amplification followed by sequencing., Results: In our study, we found evidence of HPyVs infection in the CRC patients, specifically SV40 (25.5%) and BKPyV (19.6%). However, JCPyV was not detected in the samples that were examined. Additionally, we discovered that HPV was present in 43.1% of the CRC patients. When considering viral co-infections, 19.6% of the CRC samples showed coexistence of multiple viruses, while no co-infections were found in the polyps samples. Importantly, we observed a significant correlation between the presence of HPVs and advanced colorectal tumor grades B2 and D., Conclusion: Our findings provide valuable data for the detection of oncogenic viruses in colorectal cancer (CRC) and underscore the association of viral co-infections with advanced tumor stages. However, further research with larger cohorts is necessary to validate these findings and strengthen their significance in the field of CRC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Darwish et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score., Methods: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups., Results: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF., Conclusions: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk., (© 2024 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Although it is known that BK polyomavirus (BKPyV) causes hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of BKPyV viremia has not been fully evaluated. We retrospectively analyzed the results of quantitative polymerase chain reaction (PCR) evaluations for detecting BKPyV in the whole blood samples of patients undergoing allogeneic HSCT during the period from January 2010 to June 2020 at a single institute, Tokyo Medical and Dental University. BKPyV was detected in the blood of 28 of the 107 evaluated patients, and the cumulative incidence of was 27.9% (95%CI: 20.2-37.9%). HC due to BKPyV developed in four of the 28 patients with BKPyV viremia (14.3%) and in two of the 79 patients without it (2.5%; P < 0.05). BKPyV viremia itself did not affect the patients' post-transplant estimated glomerular filtration rate (eGFR), but BKPyV viremia with a high viral load was significantly associated with decreased eGFR values (P < 0.05). BKPyV viremia was also associated with significantly lower progression-free survival at 3 years (35.1% [95%CI: 17.8-53.1%] vs. 60.4% [95%CI: 48.4-70.5], P < 0.05). Our findings demonstrated that BKPyV viremia was associated with onset of HC, an early decline of renal function, and poorer survival after allogeneic HSCT. Further studies are needed to test these results and elucidate the mechanisms of renal dysfunction associated with BKPyV viremia., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

JC polyomavirus (JCPyV) is a human polyomavirus that can establish lifelong persistent infection in the majority of adults. It is typically asymptomatic in immunocompetent individuals. However, there is a risk of developing progressive multifocal leukoencephalopathy (PML) in immunocompromised or immunosuppressed patients. Though JCPyV commonly resides in the kidney-urinary tract, its involvement in urinary system diseases is extremely rare. Here, we reported a case of a 60-year-old male patient with coronavirus disease 2019 (COVID-19) infection who developed hemorrhagic cystitis after receiving treatment with nirmatrelvir 300 mg/ritonavir 100 mg quaque die (QD). Subsequent metagenomic next-generation sequencing (mNGS) confirmed the infection to be caused by JCPyV type 2. Then, human immunoglobulin (PH4) for intravenous injection at a dose of 25 g QD was administered to the patient. Three days later, the hematuria resolved. This case illustrates that in the setting of compromised host immune function, JCPyV is not limited to causing central nervous system diseases but can also exhibit pathogenicity in the urinary system. Moreover, mNGS technology facilitates rapid diagnosis of infectious etiology by clinical practitioners, contributing to precise treatment for patients., (© 2024. The Author(s).)

Background: BK polyomavirus (BKV) can cause permanent loss of allograft function due to BKV-associated nephropathy (BKVN) in kidney transplant recipients. Besides immunosuppression reduction, there are no consistently effective interventions for BKV infection. Study purpose was to define natural history of BKV infection, identify risk factors for BKV reactivation and BKVN in kidney transplant recipients, and inform the design/conduct of future clinical trials of BKV-targeted therapeutics., Methods: We conducted a multicenter prospective observational study of incident kidney transplant recipients at six U.S. transplant centers. Participants were monitored every 4 weeks for BKV reactivation and followed for up to 24 months post-transplant. We used regression models (logistic, survival, mixed models) to study relationships between BK viremia/BKVN, clinical characteristics, and allograft function., Results: We enrolled 335 participants. Fifty-eight (17%) developed BK viremia, 6 (2%) developed biopsy-proven BKVN, and 29 (9%) developed suspected/presumed BKVN (defined as BKV viral load > 10,000 copies/mL without biopsy). Male donor sex was associated with lower odds for BK viremia, whereas recipient Black race was associated with two-fold increased odds for BK viremia. Recipient female sex was associated with more rapid clearance of BK viremia. Persistent BK viremia/BKVN was associated with poorer allograft function by 24 months post-transplant., Conclusions: We identified multiple donor and recipient demographic factors associated with risk for BKV infection and poorer allograft function by 24 months post-transplant. This may help design future clinical trials of therapies to prevent or mitigate the deleterious impact of BKV reactivation on kidney transplant outcomes., (© 2024 Wiley Periodicals LLC.)

Mitochondria are essential organelles that possess their own DNA. Mitochondrial dysfunction has been revealed in many kidney diseases, including BK polyomavirus-associated nephropathy (BKPyVAN). In this study, we introduce an innovative approach for non-invasive monitoring of mitochondrial impairment through urinary donor-derived cell-free mitochondrial DNA (ddcfmtDNA), addressing the crucial challenge of BKPyVAN diagnosis. Urinary samples were collected at the time of biopsy from a total of 60 kidney transplant recipients, comprising 12 with stable function, 22 with T cell-mediated rejection, and 21 with biopsy-proven BKPyVAN. Our findings reveal that the ddcfmtDNA-to-ddcfDNA ratio exhibits superior capability in distinguishing BKPyVAN from other conditions, with a cutoff value of 4.96% (area under curve = 0.933; sensitivity: 71.4%; and specificity: 97.1%). Notably, an elevation of ddcfmtDNA levels is associated with mitochondrial damage, as visualized through electron microscopy. These results underscore the promise of non-invasive monitoring for detecting subtle mitochondrial damage and its potential utility in BKPyVAN diagnosis. Further investigations are required to advance this field of research.

Aims: Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV). Characteristic for these virus-positive (VP) MCC is MCPyV integration into the host genome and truncation of the viral oncogene Large T antigen (LT), with full-length LT expression considered as incompatible with MCC growth. Genetic analysis of a VP-MCC/trichoblastoma combined tumour demonstrated that virus-driven MCC can arise from an epithelial cell. Here we describe two further cases of VP-MCC combined with an adnexal tumour, i.e. one trichoblastoma and one poroma., Methods and Results: Whole-genome sequencing of MCC/trichoblastoma again provided evidence of a trichoblastoma-derived MCC. Although an MCC-typical LT-truncating mutation was detected, we could not determine an integration site and we additionally detected a wildtype sequence encoding full-length LT. Similarly, Sanger sequencing of the combined MCC/poroma revealed coding sequences for both truncated and full-length LT. Moreover, in situ RNA hybridization demonstrated expression of a late region mRNA encoding the viral capsid protein VP1 in both combined as well as in a few cases of pure MCC., Conclusion: The data presented here suggest the presence of wildtype MCPyV genomes and VP1 transcription in a subset of MCC., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Introduction: MicroRNAs (miRNAs), short noncoding RNAs, are involved in the modulation of gene expression, mainly by inhibiting the translation of mRNAs. Under physiological conditions, miRNAs are involved in viral infections and immune responses, among others; aberrant miRNA expression has been associated with kidney transplant pathologies, but a comprehensive comparison of later, particularly in tissue sections, is still pending., Methods: We used the genome-wide screening of miRNAs to identify those potentially involved in the disease processes after kidney transplantation. RNA was isolated from formalin-fixed paraffin-embedded kidney biopsy samples. Study included 8 patients with acute tubular necrosis (ATN), 8 patients with antibody-mediated rejection (ABMR), 10 patients with T-cell-mediated rejection (TCMR), 10 patients with BK polyomavirus-associated nephropathy (BKPyVAN), and 12 surveillance biopsies from patients with stable allograft function and no major abnormalities (normal allografts, CTRL)., Results: We found 136 miRNAs differentially expressed in diseased kidney transplant tissue compared with normal allografts; of these, 74 miRNAs were differentially expressed in ABMR, 65 in ATN, 62 in BKPyVAN, 69 in TCMR, and 16 miRNAs were not associated with a specific disease phenotype. In addition, 29 miRNAs were differently expressed between ABMR and ATN, 39 between BKPyVAN and TCMR, and 20 between BKPyVAN and ABMR, and 38 between ABMR and TCMR., Conclusion: Our findings show that miRNA derived from kidney allograft biopsy samples represent an additional diagnostic tool to distinguish different disease phenotypes. This finding has the potential to assist clinicians in therapeutic decision-making and to translate to noninvasive monitoring of patients, e.g., blood samples., (© 2023 S. Karger AG, Basel.)

BK virus (BKV) is a small DNA virus, a member of the polyomavirus family, that causes an opportunistic infection in immunocompromised patients, especially kidney transplant patients. This virus establishes a lifelong infection in most of the population, and once it reactivates in an immunocompromised state, leads to BKV nephropathy. This review seeks to assess the correlation between severe immunosuppression, evident by low CD4 cell counts in HIV-positive patients, and the reactivation of BKV, causing nephropathy. A literature review was conducted, extracting, and analyzing case reports of HIV-positive patients showing correlations between their degree of immunosuppression, as evidenced by their CD4 counts, and the degree of BKV infectivity, confirmed by kidney biopsy. A total of 12 cases of BKV nephropathy in HIV-infected patients were reviewed. A common finding was the presence of profound immunosuppression, with most patients having CD4 counts ≤50 cells/ mm 3 . A substantial number also had comorbid malignancies, with some undergoing chemotherapy, potentially increasing the risk of BKV reactivation. In addition to the HIV status and malignancies, other risk factors for BKV reactivation included older age, male gender, diabetes mellitus, Caucasian race, and ureteral stent placement. BKV nephropathy in HIV patients with native kidneys is closely correlated with severe immunosuppression. Although therapeutic strategies exist for post-transplant patients, aside from the treatment of HIV with highly active anti-retroviral therapy (HAART), which potentially helps with clearing BKV by increasing CD4 count, there is no definitive treatment for a native kidney BKV nephropathy in patients with AIDS. The complexity of the cases and severity of comorbidities indicate the need for further research to develop therapeutic strategies tailored to this population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Kidney transplant recipients (KTR) have a three-to-four-fold increased risk of developing urothelial carcinoma (UC) compared to the general population. BK polyoma virus (BKV) infection is known to affect approximately 15% of KTR. In vitro models support a potential pathogenic role for BKV in the development of UC. We describe a series of UC in kidney transplant recipients., Methods: Electronic patient records were searched to identify KTR with UC who had undergone kidney only or simultaneous kidney and pancreas transplantation in a single UK center between 2009 and 2015. Where available, stored pathological samples were retrieved, re-examined and stained for SV40 as a marker of BKV using standard staining protocols for kidney biopsy samples., Results: Fourteen KTR had developed UC post-transplant. Of these, 10 KTR had a history of BKV infection post-transplant. Six of these 10 KTR developed a rare micropapillary tumor subtype of UC which is typically only found in <1% of UC cases. All six micropapillary tumor samples stained positive for SV40, including samples from metastases. Three tumor samples were available from the four KTR with no history of BKV infection and were not micropapillary subtype and were negative for SV40. Three micropapillary tumors from immunocompetent patients were examined as controls and were negative for SV40., Conclusions: These findings would support a pathogenic role for BK virus in the development of rare micropapillary subtype urothelial tumors in the kidney transplant population., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Viral infections such as adenovirus (ADV), BK virus (BKV), and cytomegalovirus (CMV) after kidney transplantation negatively impact outcomes in transplant recipients despite advancements in screening and antiviral therapy. We describe our experience of using the virus-specific T cell therapy (VSTs) in kidney transplant recipients (KTR) at our transplant center., Methods: This is a retrospective, single center review of KTR with ADV, BKV and CMV infections between June 2021 and December 2022. These patients received third party VSTs as part of the management of infections. The immunosuppression, details of infection and outcome data were obtained from electronic medical records., Results: Two cases of ADV infection resolved after one infusion of VSTs. The response rate of BKV and CMV infection was not as robust with close to 50% reduction in median viral load after VSTs. Out of 23 patients, two patients developed chronic allograft nephropathy from membranoproliferative glomerulonephritis and acute rejection., Conclusion: Patients that are resistant to antivirals or who have worsening viremia despite conventional management may benefit from VSTs therapy to treat underlying viral infection. Additional studies are needed to ascertain efficacy and short- and long-term risks secondary to VSTs., (© 2023 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Competing Interests: The authors declare no conflicts of interest.

Abstract: Merkel cell carcinoma (MCC) is a rare and aggressive type of metastatic, nonmelanoma skin cancer derived from Merkel cells in the epidermis. MCC can be induced by sun exposure or via Merkel cell polyomavirus (MCV) gene expression. MCV is found in most patients with MCC and is associated with a lower recurrence rate of MCC. MCC has a wide range of clinical presentations that make diagnosis challenging. Histologic examination is performed using unique markers to differentiate it from other diagnoses. This article reviews the pathogenesis, clinical presentation, histopathology, differential diagnosis, and treatment of MCC., (Copyright © 2023 American Academy of Physician Associates.)

Background: BK polyomavirus-associated nephropathy (BKPyVAN) has become a major cause of kidney dysfunction and graft loss in kidney transplant recipients. On rare occasion, polyomavirus has also been known to affect native kidneys of immunocompromised individuals. Only a small number of opportunistic infections have been reported in the carrier phase of human T-lymphotropic virus type 1 (HTLV-1). This is the first reported case of BKPyVAN in native kidneys of an HTLV-1 carrier., Case Presentation: A 61-year-old man was referred to our hospital from a primary care physician for work-up and treatment of pneumonia. He was diagnosed with Pneumocystis pneumonia and identified as a HTLV-1 carrier who had not yet developed adult T-cell leukemia (ATL). The pneumonia was successfully treated with sulfamethoxazole-trimethoprim. He had never been diagnosed with any kind of kidney dysfunction. Laboratory investigations showed a serum creatinine of 5.3 mg/dL, and urinary sediment showed cells with nuclear enlargement and inclusion bodies suggesting viral infection. The urinary Papanicolaou stain showed inclusions in swollen, ground-glass nuclei, typical of "decoy cells". Renal biopsy showed degeneration of tubules with epithelial enlargement, vacuolar degeneration, nuclear inclusion bodies, and detachment from the tubular basement membrane. Tubular nuclei showed positive staining positive for simian virus 40 large-T antigen. Polymerase chain reaction tests for BK polyomavirus DNA of both urine and plasma were positive. These findings confirmed a diagnosis of BKPyVAN. Intravenous immunoglobulin therapy did not improve renal function, necessitating maintenance hemodialysis therapy., Conclusions: BKPyVAN should be considered when acute kidney injury occurs with opportunistic infection. HTLV-1 carriers can develop opportunistic infections even before the onset of ATL., (© 2023. The Author(s).)

Objectives: To explore the risk factors for hemorrhagic cystitis (HC) in children with β-thalassemia major (TM) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT)., Methods: A retrospective analysis was conducted on clinical data of 247 children with TM who underwent allo-HSCT at Shenzhen Children's Hospital from January 2021 to November 2022. The children were divided into an HC group (91 cases) and a non-HC group (156 cases) based on whether HC occurred after operation. Multivariable logistic regression analysis was used to explore the risk factors for HC, and the receiver operating characteristic curve was used to analyze the predictive efficacy of related factors for HC., Results: Among the 247 TM patients who underwent allo-HSCT, the incidence of HC was 36.8% (91/247). Univariate analysis showed age, incompatible blood types between donors and recipients, occurrence of acute graft-versus-host disease (aGVHD), positive urine BK virus deoxyribonucleic acid (BKV-DNA), and ≥2 viral infections were associated with the development of HC after allo-HSCT ( P <0.05). Multivariable analysis revealed that incompatible blood types between donors and recipients ( OR =3.171, 95% CI : 1.538-6.539), occurrence of aGVHD ( OR =2.581, 95% CI : 1.125-5.918), and positive urine BKV-DNA ( OR =21.878, 95% CI : 9.633-49.687) were independent risk factors for HC in children with TM who underwent allo-HSCT. The receiver operating characteristic curve analysis showed that positive urine BKV-DNA alone or in combination with two other risk factors (occurrence of aGVHD, incompatible blood types between donors and recipients) had a certain accuracy in predicting the development of HC after allo-HSCT (area under the curve >0.8, P <0.05)., Conclusions: Incompatible blood types between donors and recipients, occurrence of aGVHD, and positive urine BKV-DNA are risk factors for HC after allo-HSCT in children with TM. Regular monitoring of urine BKV-DNA has a positive significance for early diagnosis and treatment of HC.

Oral microbiome studies have mainly focussed on bacteria, with the relationship between viruses and oral cancers remaining poorly understood. Oral cancers can develop even in the absence of any history of daily smoking or drinking. Oral cancer patients frequently have multiple primary cancers in the oral cavity and other organs, such as the upper gastrointestinal tract. Merkel cell polyomavirus (MCPyV) is a novel oncovirus identified from a subtype of skin cancer in 2008. In this study, we investigated the potential involvement of MCPyV in the pathogenesis of oral squamous cell carcinoma (OSCC). Participants comprised 115 Japanese patients with OSCC (single primary: 109 tumours in 109 patients; multiple primaries: 16 tumours in 6 patients) treated in our department between 2014 and 2017. DNA was extracted from formalin-fixed paraffin-embedded specimens of primary lesions. MCPyV DNA copy counts were analysed by quantitative real-time polymerase chain reaction. Twenty-four of the 115 patients (20.9%) were positive for MCPyV DNA. No association was found between presence or absence of MCPyV DNA and clinical characteristics other than number of primary lesions. The MCPyV DNA-positive rate was significantly higher for multiple primary OSCCs (62.5%, 10/16 tumours) than for single primary OSCCs (16.5%, 18/109 tumours; P < 0.001). Furthermore, MCPyV DNA load was significantly higher for patients with multiple primaries (P < 0.05). MCPyV was observed more frequently and DNA load was significantly higher with multiple primary OSCCs than with single primary OSCC. MCPyV may play some role as an oncovirus for multiple primary OSCCs., (© 2023. The Author(s).)

Background: This study aimed to explore the risk factors for BK virus (BKV) infection in renal transplant recipients (RTRs) routinely treated with tacrolimus., Methods: Forty-two cases with BKV infections and 51 patients without BKV infections were enrolled in the study. Eighty-seven healthy individuals and 77 patients undergoing dialysis were randomly included as controls. A logistic regression model was used to analyze potential variables in order to evaluate factors related to BKV infection in the renal transplant recipients., Results: The number of individuals with acute rejection in BKV positive RTRs is significantly higher than that in BKV negative RTRs. Hemoglobin levels in BKV positive RTRs were significantly lower than those in BKV negative RTRs (109.61 ± 20.11 vs. 130.16 ± 26.297, p < 0.001). There was a positive correlation between tacrolimus levels and hemoglobin concentration in RTRs (r = 0.329, p = 0.023). The results of a multivariate regression analysis indicated that a history of acute rejection (OR = 4.157, p = 0.031) and low hemoglobin (OR = 0.963, p < 0.001) were risk factors for BKV infection., Conclusions: Acute rejection and low hemoglobin were risk factors for BKV infection after renal transplantation.

The identification of the first human polyomavirus BK (BKV) has been over half century, The previous epidemiological and phylogenetic studies suggest that BKV prevailed and co-evolved with humans, leading to high seroprevalence all over the world. In general, BKV stays latent and symptomless reactivation in healthy individuals. BKV has been mainly interlinked with BKV-associated nephropathy (BKVAN) in kidney-transplant recipients and hemorrhagic cystitis (HC) in hematopoietic stem cell transplant recipients (HSCTRs). However, the mechanisms underlying BKV latency and reactivation are not fully understood and lack of extensive debate. As Merkel cell polyomavirus (MCV) was identified as a pathogenic agent of malignant cutaneous cancer Merkel cell carcinoma (MCC) since 2008, linking BKV to tumorigenesis of urologic tumors raised concerns in the scientific community. In this review, we mainly focus on advances of mechanisms of BKV latency and reactivation, and BKV-associated diseases or tumorigenesis with systematical review of formerly published papers following the PRISMA guidelines. The potential tumorigenesis of BKV in two major types of cancers, head and neck cancer and urologic cancer, was systematically updated and discussed in depth. Besides, BKV may also play an infectious role contributing to HIV-associated salivary gland disease (HIVSGD) presentation. As more evidence indicates the key role of BKV in potential tumorigenesis, it is important to pay more attention on its etiology and pathogenicity in vitro and in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Zhu and Li.)

Background: Viral infection is an oncogenic factor in many hematolymphoid malignancies. We sought to determine the diagnostic yield of aligning off-target reads incidentally obtained during targeted hematolymphoid next-generation sequencing to a large database of viral genomes to screen for viral sequences within tumor specimens., Methods: Alignment of off-target reads to viral genomes was performed using magicBLAST. Localization of Merkel cell polyomavirus (MCPyV) RNA was confirmed by RNAScope in situ hybridization. Integration analysis was performed using Virus-Clip., Results: Four cases of post-cardiac-transplant folliculotropic mycosis fungoides (fMF) and one case of peripheral T-cell lymphoma (PTCL) were positive in off-target reads for MCPyV DNA. Two of the four cases of posttransplant fMF and the case of PTCL showed localization of MCPyV RNA to malignant lymphocytes, whereas the remaining two cases of posttransplant fMF showed MCPyV RNA in keratinocytes., Conclusions: Our findings raise the question of whether MCPyV may play a role in rare cases of T-lymphoproliferative disorders, particularly in the skin and in the heavily immunosuppressed posttransplant setting., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Two accepted possible pathways for Merkel cell carcinoma (MCC) pathogenesis include the clonal integration of the Merkel cell polyomavirus (MCPyV) into the neoplastic cells and by UV irradiation. We hypothesize that, in UV etiology, the expression of genes associated with epithelial-mesenchymal transition (EMT) would be higher in MCPyV-negative MCCs. We compared RNA expression in 16 MCPyV-negative with that in 14 MCPyV-positive MCCs in 30 patients using NanoString panel of 760 gene targets as an exploratory method. Subsequently, we confirmed the findings with a publicly available RNA sequencing data set. The NanoString method showed that 29 of 760 genes exhibited significant deregulation. Ten genes (CD44, COL6A3, COL11A1, CXCL8, INHBA, MMP1, NID2, SPP1, THBS1, and THY1) were part of the EMT pathway. The expression of CDH1/E-cadherin, a key EMT gene, and TWIST1, regulator gene of EMT, was higher in MCPyV-negative tumors. To further investigate the expression of EMT genes in MCPyV-negative MCCs, we analyzed publicly available RNA sequencing data of 111 primary MCCs. Differential expression and gene set enrichment analysis of 35 MCPyV-negative versus 76 MCPyV-positive MCCs demonstrated significantly higher expression of EMT-related genes and associated pathways such as Notch signaling, TGF-β signaling, and Hedgehog signaling, and UV response pathway in MCPyV-negative MCCs. The significance of the EMT pathway in MCPyV-negative MCCs was confirmed independently by a coexpression module analysis. One of the modules (M3) was specifically activated in MCPyV-negative MCCs and showed significant enrichment for genes involved in EMT. A network analysis of module M3 revealed that CDH1/E-cadherin was among the most connected genes (hubs). E-cadherin and LEF1 immunostains demonstrated significantly more frequent expression in MCPvV-negative versus MCPyV-positive tumors (P < .0001). In summary, our study showed that the expression of EMT-associated genes is higher in MCPyV-negative MCC. Because EMT-related proteins can be targeted, the identification of EMT pathways in MCPyV-negative MCCs is of potential therapeutic relevance., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: This review aims to determine the potential role of Merkel Cell Polyomavirus (MCPyV) in the pathogenesis of cervical squamous cell carcinomas and adenocarcinomas., Methods: A PRISMA systematic search appraisal was conducted. The Scopus, Web of Science, PubMed, EMBASE, Google Scholar, and MEDLINE databases for publications in English were searched up to September 2022 for all relevant articles. All articles that have outlined the contributions of the MCPyV to cervical squamous cell carcinomas and adenocarcinomas were included., Results: The six databases produced 6806 articles. Only six articles met the inclusion criteria and were included. The protocol of this review was submitted and registered with the PROSPERO (Code no. CRD42022369197). The total sample size across the articles was 1135; the age of the participants ranged between 18 and 75 years. In addition, the included articles were conducted between 2012 to 2016. All included articles have a cross-sectional design.Furthermore, different kinds of samples were collected in the reviewed articles, namely cervical tissue biopsies, cervical smears, formalin-fixed paraffin-embedded resection specimens, and cervical adenocarcinomas. Moreover, five articles showed no statistically significant association between the MCPyV and cervical squamous cell carcinomas and adenocarcinomas. In contrast, one article revealed a positive association between MCPyV and cervical squamous cell carcinomas and adenocarcinomas., Conclusions: MCPyV could not be associated with the pathogenesis of cervical squamous cell carcinomas and adenocarcinomas. Further attention should be given to examining this association, and further studies with a large sample size are recommended to confirm these findings., (© 2023 Hatim M., et al.)

Background: Merkel cell carcinoma (MCC) is a rare, aggressive, primary neuroendocrine carcinoma of the skin whose main risk factors are immunosuppression, UV radiation exposure, and Merkel cell polyomavirus. Programmed death-1/programmed death ligand-1 (PD-L1)-based immunotherapy is currently the first choice for treating patients with metastatic MCC., Methods: MCC biopsies (17) were evaluated for their nucleus and cytoplasm characteristics and growth patterns, as well as for intratumor lymphocytes, mitotic number, and lymphovascular invasion. Paraffin-embedded tissue samples of the biopsies were stained with MCPyV large T-antigen (LTag), RB1, p53, and PD-L1., Results: We observed MCPyV LTag expression in 9 out of the 17 tumors, and all 9 cases were positive for RB1 ( P <0.000). p53 staining was not significantly correlated with MCPyV LTag. We observed no relationship between p53 expression and any other parameters, and PD-L1 expression was low in the MCC samples. We evaluated PD-L1 using both the combined positive score and tumor proportion score (TPS), and found that TPS was correlated with MCPyV LTag expression ( P =0.016). Tumors with tumor-infiltrating lymphocytes showed a better prognosis than those without these lymphocytes ( P =0.006)., Discussion: Our data demonstrated that RB1 was effective for immunohistochemically investigating the MCPyV status of tumors. TPS was superior to the combined positive score in evaluating PD-L1 in MCC. Tumor-infiltrating lymphocytes were the only parameters that were associated with survival. Further studies with larger series are required to confirm these results., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

BK polyomavirus-associated nephropathy occurs in kidney transplant recipients under immunosuppressive treatment. BK polyomavirus is implicated in cancer development and invasion, and case reports of renal cell carcinoma and urothelial carcinoma possibly associated with BK polyomavirus has been reported. Further, it has been suggested that the immune responses of KT-related diseases could play a role in the pathogenesis and progression of renal cell carcinoma. Thus, we thought to examine the relationship between BK polyomavirus-associated nephropathy and renal cell carcinoma in terms of gene expression. To identify the common and specific immune responses involved in kidney transplantation-related diseases with a specific focus on BK polyomavirus-associated nephropathy, we performed consensus weighted gene co-expression network analysis on gene profile datasets of renal biopsy samples from different institutions. After the identification of gene modules and validation of the obtained network by immunohistochemistry of the marker across kidney transplantation-related diseases, the relationship between prognosis of renal cell carcinoma and modules was assessed. We included the data from 248 patients and identified the 14 gene clusters across the datasets. We revealed that one cluster related to the translation regulating process and DNA damage response was specifically upregulated in BK polyomavirus-associated nephropathy. There was a significant association between the expression value of hub genes of the identified cluster including those related to cGAS-STING pathway and DNA damage response, and the prognosis of renal cell carcinoma. The study suggested the potential link between kidney transplantation-related diseases, especially specific transcriptomic signature of BK polyomavirus associated nephropathy and renal cell carcinoma., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: K.P.M. is employed by the TMK Project, which is a collaboration project between Kyoto University and Mitsubishi Tanabe Pharma. M.Y. receives research grants from Mitsubishi Tanabe Pharma and Boehringer Ingelheim. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Sato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

BK virus (BKV; human polyomavirus 1) infections are asymptomatic in most individuals, and the virus persists throughout life without harm. However, BKV is a threat to transplant patients and those with immunosuppressive disorders. Under these circumstances, the virus can replicate robustly in proximal tubule epithelial cells (PT). Cultured renal proximal tubule epithelial cells (RPTE) are permissive to BKV and have been used extensively to characterize different aspects of BKV infection. Recently, lines of hTERT-immortalized RPTE have become available, and preliminary studies indicate they support BKV infection as well. Our results indicate that BKV infection leads to a similar response in primary and immortalized RPTE. In addition, we examined the patterns of global gene expression of primary and immortalized RPTE and compared them with uncultured PT freshly dissociated from human kidney. As expected, PT isolated from the healthy kidney express a number of differentiation-specific genes that are associated with kidney function. However, the expression of most of these genes is absent or repressed in cultured RPTE. Rather, cultured RPTE exhibit a gene expression profile indicative of a stressed or injured kidney. Inoculation of cultured RPTE with BKV results in the suppression of many genes associated with kidney stress. In summary, this study demonstrated similar global gene expression patterns and responses to BKV infection between primary and immortalized RPTE. Moreover, results from bulk transcriptome sequencing (RNA-seq) and SCT experiments revealed distinct transcriptomic signatures representing cell injury and stress in primary RPTE in contrast to the uncultured, freshly dissociated PT from human kidney. IMPORTANCE Cultured primary human cells provide powerful tools for the study of viral infectious cycles and host virus interactions. In the case of BKV-associated nephropathy, viral replication occurs primarily in the proximal tubule epithelia in the kidney. Consequently, cultured primary and immortalized renal proximal tubule epithelial cells (RPTE) are widely used to study BKV infection. In this work, using bulk and single-cell transcriptomics, we found that primary and immortalized RPTE responded similarly to BKV infection. However, both uninfected primary and immortalized RPTE have gene expression profiles that are markedly different from healthy proximal tubule epithelia isolated directly from human kidney without culture. Cultured RPTE are in a gene expression state indicative of an injured or stressed kidney. These results raise the possibility that BKV replicates preferentially in injured or stressed kidney epithelial cells during nephropathy., Competing Interests: The authors declare no conflict of interest.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that is frequently divided into Merkel cell polyomavirus negative and positive tumors due their distinct genomic and transcriptomic profiles, and disease outcomes. Although some prognostic factors in MCC are known, tumorigenic pathways, which that explain outcome differences in MCC are not fully understood. We investigated transcriptomes of 110 tissue samples of a formalin-fixed, paraffin-embedded MCC series by RNA sequencing to identify genes showing a bimodal expression pattern and predicting outcome in cancer and that potentially could play a role in tumorigenesis. We discovered 19 genes among which IGHM, IGKC, NCAN, OTOF, and USH2A were associated also with overall survival (all p-values < 0.05). From these genes, NCAN (neurocan) expression was detected in all 144 MCC samples by immunohistochemistry. Increased NCAN expression was associated with presence of Merkel cell polyomavirus DNA (p = 0.001) and viral large T antigen expression in tumor tissue (p = 0.004) and with improved MCC-specific survival (p = 0.027) and overall survival (p = 0.034). We conclude that NCAN expression is common in MCC, and further studies are warranted to investigate its role in MCC tumorigenesis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Salmikangas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

BK virus (BKV) associated with hemorrhagic cystitis (HC) is the most important complication that develops after hematopoietic stem cell transplantation (HSCT) in patients with hematological malignancies. This study aims to investigate BKV infections and HC in pediatric patients after allogeneic hematopoietic stem cell transplantation. Between November 2018 and November 2019, a total of 51 patients between the ages of 11 months and 17 years were included in the study. BKV Bosphore ® v1 quantification kit (Geneworks Anatolia, Turkey) was used for the detection of BKV DNA in urine and blood samples. Among the total of 51 patients, the incidence of BKV infection was found to be 86.3%. Allogeneic HSCT was performed in 40 patients and autologous HSCT in 11 patients. BK viruria and/or viremia were detected in 85% (44) of patients who underwent allogeneic HSCT and in 90% in the autologous group. High-level BK viruria (>107 copies/mL) was found in 41% (9) of 22 patients who were BKV positive before transplantation, while in 27.5% (8) of 29 patients who were BKV negative before transplantation; thus, BKV positivity before transplantation was considered a risk factor for high-level BK viruria. Acute GVHD developed in 6 of 40 patients in the allogeneic group. HC was prevented in 12 (67%) of 18 patients who received preemptive treatment, while HC developed in 6 (33%). HC occurred at a median of 35 days (17-49 days) post-transplant. Despite preemptive treatment, 6 (15%) patients who developed HC associated with BKV were in the allogeneic group but not in the autologous group. Of these patients with HC, 5 received a myeloablative treatment regimen, and 1 patient was given a reduced-intensity treatment regimen. The viral load in urine was found to be 107-9 copies/mL within 2 weeks before the development of HC and has been identified as a prognostic indicator. In conclusion, early diagnosis of viral infections by monitoring BKV viral load in HSCT patients will be effective in preventing the progression of complications such as BKV-associated HC by providing timely initiation of preemptive treatment.

Purpose: Merkel cell polyomavirus (MCPyV) infection is a known to be a critical risk factor for the development of Merkel cell carcinoma (MCC). Various reports on cutaneous MCC have shown that the differences in clinicohistopathological characteristics depend on the presence of MCPyV, but the situation in eyelid MCC is unknown. This study aimed to assess the prevalence of MCPyV in patients with eyelid MCC and examine the clinicohistopathological characteristics of MCPyV-associated eyelid MCC., Design: Retrospective observational case series with laboratory investigations., Methods: Ten patients treated for eyelid MCC were included. Histopathological characteristics were examined by immunohistochemical staining using 12 antibodies. MCPyV infection was evaluated by PCR using primer sets targeting large T antigens of the MCPyV genome and by immunohistochemical staining using CM2B4 and Ab3 monoclonal antibodies. The MCPyV viral load was also quantified by PCR using 3 primer sets., Results: All patients (4 males and 6 females) were Japanese with mean age of 79 (range: 63 to 87) years. One patient died due to distant metastasis 8 months after surgery for MCC. Immunohistochemical studies showed typical MCC findings in all cases, including CK20 and neuroendocrine marker positivity. PCR and immunohistochemistry with CM2B4 and Ab3 detected MCPyV antigen in all tumors. Quantitative PCR using sT, LT4, and TAg primers yielded 0.94, 1.72, and 1.05 copies per cell, respectively., Conclusion: Clinical and histopathological characteristics of 10 patients with eyelid MCC were elucidated. MCPyV infection was detected in all eyelids. These results provide insight for understanding the tumorigenesis of eyelid MCC., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest the authors declare no conflicts of interest.

Abstract: Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neoplasm that is almost always intradermal. Immunosuppression increases the risk of MCC, which is believed to be due to increased susceptibility to Merkel cell polyomavirus (MCPyV). Intraepidermal MCC, or MCC in situ (MCCis), is extremely rare and usually associated with other cutaneous lesions. Here, we describe a case of MCPyV-negative MCCis arising in an immunocompromised patient. This case adds to only 9 previously reported cases of MCCis without a coexisting neoplasm and suggests that immunosuppression can lead to MCCis by mechanisms other than MCPyV. Although previously reported cases of MCCis demonstrated excellent prognosis, local recurrence and metastasis are still possible. Prognostication, treatment, and follow-up of MCCis should be similar to MCC., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine cutaneous carcinoma with a high mortality rate. The MCC etiology is not fully understood. Merkel cell-associated polyomavirus (MCPyV) was found in MCC patients, indicating a risk factor for the tumor. Caucasian, elderly, and immunocompromised individuals are more likely to develop this tumor. HLA-G consists of a non-classical class I (Ib) HLA molecule with an immunoregulatory function and was associated with tumor escape in different types of tumors, nonetheless, never been studied in MCC. The purpose of this study was to evaluate the HLA-G expression and also to detect the MCPyV in MCC patients and correlate it with the clinical course of the disease. Forty-five MCC patients were included in a retrospective study. Formalin-fixed paraffin-embedded cutaneous skin biopsies were used by immunohistochemistry and RT-PCR to verify the HLA-G expression and MCPyV infection. HLA-G expression was found in 7 (15.6%), while the presence of MCPyV was detected in 28 (62.2%) of the studied patients. No significant association was found between HLA-G expression and MCPyV infection (p = 0.250). The presence of MCPyV was associated with areas of low sunlight exposure (p = 0.042) and the HLA-G expression with progression to death (p = 0.038). HLA-G expression was detected in MCC patients, as well as the MCPyV presence was confirmed. These markers could represent factors with a possible impact on patient survival; however, further studies with a greater number of patients are needed, to better elucidate the possible role in disease progression., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A small percentage of bladder cancers in the general population have been found to harbor DNA viruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer and have an overall poorer outcomes, harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from potential oncoviruses, we performed whole genome and transcriptome sequencing on bladder cancer specimens from 43 transplant patients. Nearly half of the tumors from this patient population contained viral sequences. The most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). Immunohistochemistry revealed variable Large T antigen expression in BKPyV-positive tumors ranging from 100% positive staining of tumor tissue to less than 1%. In most cases of BKPyV-positive tumors, the viral genome appeared to be clonally integrated into the host chromosome consistent with microhomology-mediated end joining and coincided with focal amplifications of the tumor genome similar to other virus-mediated cancers. Significant changes in host gene expression consistent with the functions of BKPyV Large T antigen were also observed in these tumors. Lastly, we identified four mutation signatures in our cases, with those attributable to APOBEC3 and SBS5 being the most abundant. Mutation signatures associated with an antiviral drug, ganciclovir, and aristolochic acid, a nephrotoxic compound found in some herbal medicines, were also observed. The results suggest multiple pathways to carcinogenesis in solid organ transplant recipients with a large fraction being virus-associated., Competing Interests: GS, KY, MP, DP, MD, AI, BH, TT, IC, LG, CM, SH, CL, LP, PM, CB, EE No competing interests declared, YG, PL is affiliated with Leidos Biomedical Research Inc. The author has no financial interests to declare, RH is a co-founder, shareholder, and consultant of ApoGen Biotechnologies Inc

Background: BKV-HC is one of the most significant complications of HSCT. This retrospective study aimed to determine the frequency of BKV-HC in pediatric patients undergoing HSCT, detect the associated risk factors for the development of BKV-HC, and explore the effects of post-transplantation Cy use., Methods: Three hundred twenty-seven patients (girls: 121, boys: 206) were analyzed according to sex, conditioning regimen, transplantation type, donor relatedness, stem cell source, the presence and grade of aGVHD, CMV co-existence, and Cy use., Results: Multivariate analysis confirmed the prognostic importance of age (OR: 4.865), TBI use, the presence of aGVHD (OR: 2.794), CMV coinfection (OR: 2.261), and Cy use (OR: 27.353). A statistically significant difference was found between the mean BKV-HC follow-up times compared with post-transplantation Cy intake (p < .001). The BKV-HC rate increased as the number of risk factors of the patient increased., Conclusion: BKV-HC is an essential complication of HSCT primarily associated with Cy use, the presence of aGVHD, and donor relatedness. The present study shows that the use of Cy in the post-transplantation period further increases BKV-HC risk in pediatric patients, regardless of dose., (© 2022 Wiley Periodicals LLC.)

Background: BK polyomavirus-associated nephropathy (PVAN) is a frequent complication in the early phase after kidney transplantation. The most important risk factor for PVAN is the intensity of immunosuppression. A recent study suggests that exposure to valganciclovir (VGC) could also be a risk factor., Methods: We performed a retrospective, single-center study to investigate the effect of valganciclovir exposure on the risk for PVAN during the first 100 days post transplant. Cytomegalovirus (CMV) seronegative recipients of a CMV seropositive donor kidney received VGC prophylaxis, whereas CMV seropositive recipients were managed by a pre-emptive CMV strategy. Cox regression analysis was used to identify risk factors for PVAN development with VGC treatment and strength of immunosuppressive therapy as time-dependent variables., Results: A total of 211 adults who received a kidney transplant between 2014 and 2019 were included. Eighteen (9%) developed PVAN. Multivariate regression analysis showed that women have a lower risk of developing PVAN (hazard ratio [HR] 0.08 (confidence interval [CI] 0.01-0.58), P = .013), whereas age was associated with an increased risk for PVAN (HR 1.04 for every additional year [CI 1.00-1.08], P = .029). There was a trend toward a lower risk of PVAN for patients on reduced immunosuppressive therapy (HR 0.44 [CI 0.15-1.24], P = .12). VGC use was not associated with the risk for PVAN (HR 0.99 [CI 0.35-2.78], P = .98)., Conclusions: In our study, VGC exposure was not associated with the risk for PVAN. Our study is the first to reassess in depth the hypothesis that VGC treatment increases the risk of PVAN. The unique strength of this study is the correction for the degree of immunosuppression and the statistical use of time-dependent covariates. This methodological approach can provide a foundation for further studies needed to confirm our findings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

BK polyomavirus nephropathy (BKVN) is a common cause of nephropathy in kidney transplant patients and is typically seen within the first year after transplantation. BK polyomavirus nephropathy can occur in the native kidneys of patients with nonrenal solid-organ transplants (NRSOT). However, this is rare, especially outside the early post-transplant period, and BKVN is not usually considered in the differential diagnosis for acute kidney injury in NRSOT patients. We present a case of a 75-year-old man who had undergone orthotopic heart transplant 13 years prior with stable allograft function who developed progressive renal dysfunction in the setting of recent unilateral obstructive nephrolithiasis requiring ureteral stenting. Kidney biopsy demonstrated evidence of polyomavirus nephritis. Serum BK viral load was elevated. Despite reducing immunosuppression and initiating leflunomide, viral clearance was never achieved. The patient experienced progressive failure to thrive before ultimately transitioning to hospice care and dying. The intensity of immunosuppression is a well-known risk factor for viral replication; ureteral stenting has also been associated with BKVN. However, since clinical manifestations of BK viral infections often include a genitourinary (GU) tract pathology, it is important for clinicians to consider BKVN in patients with NRSOT with progressive renal dysfunction, especially in the clinical context of known GU disease.

Aim: The aim of this study was to investigate the prevalence and potential association between the infection with some members of the polyomaviridae family of viruses and development of the brain tumors., Methods: A systematic literature search was performed by finding relevant cross-sectional and case-control studies from a large online database. Heterogeneity, OR, and corresponding 95% CI were applied to all studies by meta-analysis and forest plots. The analysis was performed using Stata Software v.14., Results: Twenty-three articles (33 datasets) were included in the meta-analysis, four (four datasets) of which were case/control studies and the rest were cross-sectional. The pooled prevalence of polyomaviruses among brain cancer patients was 13% (95% CI: 8-20%; I 2  = 96.91%). In subgroup analysis, the pooled prevalence of JCV, SV40, BKV and Merkel cell polyomavirus was 20%, 8%, 6%, and 16%, respectively. An association was found between polyomavirus infection and brain cancer [summary OR 7.22 (95% CI (2.36-22.05); I 2  = 0%)]. The subgroup analysis, based on the virus type, demonstrated a strong association between JCV infection and brain cancer development [summary OR 10.34 (95% CI 1.10-97.42; I 2  = 0%)]., Conclusion: The present study showed a significant association between polyomavirus infection and brain tumors. Moreover, these results suggest that polyomavirus infection may be a potential risk factor for the development of brain cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: BK polyomavirus infection (BKVi) is an important cause of kidney transplant (KT) loss, but there is scarce evidence on the impact of BK plasma viral load on graft function and long-term KT survival., Methods: A retrospective cohort study including all KT recipients with BKVi (BK viremia identified in ≥3 consecutive samples by polymerase chain reaction) in our center from January 2010 to December 2020 was performed. A case-control study (1:2) was performed. We grouped the cases according to their highest peak viral load: low-level viremia (<10,000 copies/mL) and high-level viremia (≥10,000 copies/mL). To identify risk factors for BKVi, a logistic regression analysis was achieved, and a multivariable Cox regression was used to describe risk factors for graft loss., Results: A total of 849 KTs were performed, and 67 presented BKVi (low-level viremia, n = 35 and high-level viremia, n = 26). In logistic regression analysis male sex (odds ratio [OR], 4.226; 95% CI, 1.660-10.758, P = .002), age (OR, 1.047; 95% CI, 1.008-1.088; P = .018), and retransplant (OR, 4.162; 95% CI, 1.018-17.015; P = .047) were predictors of BKVi. Acute rejection was more frequent in the BKVi group (18% vs 4.9%, P = .004), and graft survival was lower in patients with BKVi and high-level viremia (P = .027). In Cox regression analysis, BKVi (hazard ratio, 3.657; 95% CI, 1.146-11.670; P = .029) and specific BKV (BK polyomavirus) high-level viremia (hazard ratio, 1.988; 95% CI, 1.012-3.907; P = .046) were predictors of shorter graft survival., Conclusions: BKV high-level viremia was associated with BKV nephropathy and poorer graft survival. Additionally, acute rejection is more frequent after BKVi. It is necessary to develop strategies safe and effective for these patients., (Copyright © 2022. Published by Elsevier Inc.)

BACKGROUND The interaction of viral infection may be associated with increased morbidity after renal transplantation. This study aimed to identify the incidence and risk factors of viruria infections in renal transplant recipients. MATERIAL AND METHODS In this longitudinal study, 502 episodes recorded in 81 kidney transplant patients from 1/2019 to 12/2021 in a hospital in Vietnam were included. BK, JC polyomaviruses, CMV, EBV, and HSV were detected. Multivariable Cox regression analysis was performed to evaluate risk factors for the viruria infection. RESULTS Fifty-six patients (69.1%) had viruria co-infection. The incidence of JC, CMV, and BK infection was the most common viruria, with 67.9%, 61.7%, and 56.8%, respectively. Cox regression revealed that the risk factors for JC were single infection, dose of MMF (HR 1.002), corticoid (HR 1.02), hypertension (HR 1.65), and hematuria (HR 2.03); risk factors for CMV infection were male sex (HR 1.92) and eGFR (HR 0.98); risk factors for BK single infection were hypertension (HR 1.67), proteinuria (HR 3.80), higher tacrolimus trough level (HR 1.17), and dose of MMF (HR 1.002). Hypertension (HR 1.68), fasting plasma glucose (HR 1.13), proteinuria (HR 6.01), tacrolimus trough level (HR 1.12), and dose of MMF (HR 1.004) were independent risk factors for the viruria co-infection. CONCLUSIONS Kidney function was associated with the incidence of viruria. Higher tacrolimus trough level and dose of MMF were associated with higher risk of BK, JC, and co-infection.

BK virus (BKV) is one of the most common pathogens in post-transplantation infections. For kidney transplantation, BKV infection results in the impairment of allograft function and thus increases the risk of allograft loss. However, clinical evaluation of the prognosis of BKV-associated allograft impairment is difficult. In the present study, differential plasma proteins were screened using proteomic methods from ten patients with a transition from BKV-negative to BKV activation. We identified 12 differentially expressed proteins, and S100A8 and S100A9 were the top two upregulated proteins. Data from a cross-sectional study with 66 BKV-negative and 66 BKV-positive recipients of renal transplantation indicated that plasma S100A8/A9 was upregulated in BKV-infected recipients. Plasma S100A8/A9 positively correlated with the 1 month creatinine increase (ρ = 0.499, P = 0.021) and negatively correlated with the 1 month estimated glomerular filtration rate change (ρ = -0.618, P = 0.003) in recipients with BK viremia. Using least absolute shrinkage and selection operator regression models, we found that S100A8/A9 was an independent risk factor for the decrease in allograft function after BKV infection. In conclusion, S100A8/A9 is a potential host biomarker for the clinical evaluation of BKV-associated allograft function impairment in kidney transplantation.

Bovine polyomavirus-1 (BoPyV-1, Epsilonpolyomavirus bovis ) is widespread in cattle and has been detected in commercialized beef at supermarkets in the USA and Germany. BoPyV-1 has been questioned as a probable zoonotic agent with documented increase in seropositivity in people exposed to cattle. However, to date, BoPyV-1 has not been causally associated with pathology or disease in any animal species, including humans. Here we describe and illustrate pathological findings in an aborted bovine fetus naturally infected with BoPyV-1, providing evidence of its pathogenicity and probable abortigenic potential. Our results indicate that: (i) BoPyV-1 can cause severe kidney lesions in cattle, including tubulointerstitial nephritis with cytopathic changes and necrosis in tubular epithelial cells, tubular and interstitial inflammation, and interstitial fibroplasia; (ii) lesions are at least partly attributable to active viral replication in renal tubular epithelial cells, which have abundant intranuclear viral inclusions; (iii) BoPyV-1 large T (LT) antigen, resulting from early viral gene expression, can be detected in infected renal tubular epithelial cells using a monoclonal antibody raised against Simian Virus-40 polyomavirus LT antigen; and (iv) there is productive BoPyV-1 replication and virion assembly in the nuclei of renal tubular epithelial cells, as demonstrated by the ultrastructural observation of abundant arrays of viral particles with typical polyomavirus morphology. Altogether, these lesions resemble the "cytopathic-inflammatory pathology pattern" proposed in the pathogenesis of Human polyomavirus-1 -associated nephropathy in immunocompromised people and kidney allograft recipients. Additionally, we sequenced the complete genome of the BoPyV-1 infecting the fetus, which represents the first whole genome of a BoPyV-1 from the Southern Hemisphere. Lastly, the BoPyV-1 strain infecting this fetus was isolated, causing a cytopathic effect in Madin-Darby bovine kidney cells. We conclude that BoPyV-1 is pathogenic to the bovine fetus under natural circumstances. Further insights into the epidemiology, biology, clinical relevance, and zoonotic potential of BoPyV-1 are needed.

Introduction: Merkel cell carcinoma (MCC) is an aggressive skin cancer, related to the Merkel Cell Polyomavirus (MCPyV) in 80% of cases. Immune checkpoint inhibitors provide sustained benefit in about 50% of MCC patients with advanced disease. Glypican-3 (GPC3) is an oncofetal tumor antigen that is an attractive target for chimeric antigen receptor T cell therapy due to its highly restricted expression on normal tissue and high prevalence in several solid tumors. GPC3 is known to be expressed in MCC but its association with tumor characteristics or prognosis has not been reported. We investigated MCC GPC3 expression by immunohistochemistry (IHC) and its association with tumor characteristics, MCPyV status, and patient outcome., Methods: The GC33 antibody clone was validated for GPC3 IHC staining of tumor specimens in comparison to an established GPC3 IHC antibody. An MCC tissue microarray was stained for GPC3 by IHC using GC33 antibody. Association of GPC3+ IHC with baseline characteristics, MCPyV status (qPCR) and outcome (death from MCC/recurrence) were assessed., Results: Forty-two of 62 samples (67.7%) were GPC3+. GPC3 expression was more frequently observed in females ( p = 0.048) and MCPyV-negative tumors ( p = 0.021). By multivariate analysis, GPC3 expression was associated with increased death from disease (CSS) (hazard ratio [HR] 4.05, 95% CI 1.06-15.43), together with advanced age (HR 4.85, 95% CI 1.39-16.9) and male gender (HR 4.64, 95% CI 1.31-16.41)., Conclusions: GPC3 expression is frequent in MCC tumors, especially MCPyV-negative cases, and is associated with increased risk of death. High prevalence of surface GPC3 makes it a putative drug target., Competing Interests: CONFLICTS OF INTEREST SM is a current employee of SOTIO Biotech Inc. and a former employee of Kiniksa Pharmaceuticals. TK has no other disclosures to declare. GJW is an employee of SOTIO Biotech Inc., a former employee of Unum Therapeutics; reports personal fees from Imaging Endpoints II, MiRanostics Consulting, Gossamer Bio, Paradigm, International Genomics Consortium, Angiex, IBEX Medical Analytics, GLG Council, Guidepoint Global, Oncacare, Genomic Health, Rafael Pharmaceuticals, and SPARC-all outside this submitted work; has ownership interest in Unum Therapeutics (now Cogent Biosciences), MiRanostics Consulting, Exact Sciences, Moderna, Agenus, Aurinia Pharmaceuticals, and Circulogene-outside the submitted work; and has issued patents: PCT/US2008/072787, PCT/US2010/043777, PCT/US2011/020612, and PCT/US2011/037616-all outside the submitted work. MS has received fees from Amgen for speaking at an educational meeting; has received fees from Merck-Pfizer for advisory board; has received reimbursement for travel and accommodation expenses from Abbvie, Amgen SAS, Bristol Myers Squibb, Celgene SAS, Galderma International, Lilly France SAS, MSD France, and Pierre Fabre Médicaments France., (Copyright: © 2022 Muralidharan et al.)

Background BK polyomavirus-associated nephropathy (BKPyVAN) is an important cause of chronic renal allograft dysfunction. However, US features indicative of BKPyVAN have not been fully evaluated. Purpose To assess the value of high-frequency US for the diagnosis of BKPyVAN in kidney transplant recipients. Materials and Methods In this prospective cohort study, participants who tested positive for BK viruria after kidney transplant from September 2019 to January 2021 were evaluated with high-frequency US 1 day before biopsy. Clinical characteristics and US features were compared between participants with and without BKPyVAN. Significant predictors associated with BKPyVAN were determined using logistic regression analyses. The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic performance. Results A total of 105 participants who underwent kidney transplant (mean age, 38 years ± 11 [SD]; 63 men) were evaluated; 45 participants were diagnosed with BKPyVAN. Multivariable analysis demonstrated that eccentric hydronephrosis and subcapsular hypoechoic areas were independent factors for BKPyVAN. The AUC for predicting BKPyVAN according to subcapsular hypoechoic areas was 0.66 (95% CI: 0.55, 0.77), with a specificity of 92% (55 of 60 participants). The AUC of combined US (eccentric hydronephrosis plus subcapsular hypoechoic area) and clinical (urine BKPyV DNA load [BKPyV-DNA] plus BK viremia) features was 0.90, with a specificity of 92% (55 of 60 participants). Parenchymal hyperechoic and subcapsular hypoechoic areas were independent factors for differentiating BKPyVAN from transplant rejection. The pooled specificity of subcapsular hypoechoic areas was 96% (21 of 22 participants), with an AUC of 0.67 (95% CI: 0.54, 0.80). For the combination of US (parenchymal echogenicity plus subcapsular hypoechoic area) and clinical (urine BKPyV-DNA plus time since transplant) features, the AUC reached 0.92 and specificity was 82% (18 of 22 participants). Conclusion High-frequency US characteristics are valuable for diagnosing BK polyomavirus-associated nephropathy (BKPyVAN) and distinguishing BKPyVAN from rejection in kidney transplant recipients. © RSNA, 2022 Online supplemental material is available for this article .