The synergistic effects of anoikis-related genes and EMT-related genes in the prognostic prediction of Wilms tumor.

Wilms tumor (WT) is the most common type of malignant abdominal tumor in children; it exhibits a high degree of malignancy, grow rapidly, and is prone to metastasis. This study aimed to construct a prognosis model based on anoikis-related genes (ARGs) and epithelial-mesenchymal transition (EMT)-related genes (ERGs) for WT patients; we assessed the characteristics of the tumor microenvironment and treatment efficacy, as well as identifying potential therapeutic targets. To this end, we downloaded transcriptome sequencing data and clinical data for WT and normal renal cortices and used R to construct and validate the prognostic model based on ARGs and ERGs. Additionally, we performed clinical feature analysis, nomogram construction, mutation analysis, drug sensitivity analysis, Connectivity Map (cMAP) analysis, functional enrichment analysis, and immune infiltration analysis. Finally, we screened the hub gene using the STRING database and validated it via experiments. In this way, we constructed a model with good accuracy and robustness, which was composed of seven anoikis- and EMT-related genes. Paclitaxel and mesna were selected as potential chemotherapeutic drugs and adjuvant chemotherapeutic drugs for the WT high-risk group by using the Genomics of Drug Sensitivity in Cancer (GDSC) and cMAP compound libraries, respectively. We proved the existence of a strong correlation between invasive immune cells and prognostic genes and risk scores. Next, we selected NTRK2 as the hub gene, and in vitro experiments confirmed that its inhibition can significantly inhibit the proliferation and migration of tumor cells and promote late apoptosis. In summary, we screened out the potential biomarkers and chemotherapeutic drugs that can improve the prognosis of patients with WT.

Steroidogenic differentiation of human amniotic membrane-derived mesenchymal stem cells into a progesterone-/androgen-producing cell lineage by SF-1 and an estrogen-producing cell lineage by WT1-KTS.

Background: Sex steroid hormones, primarily synthesized by gonadal somatic cells, are pivotal for sexual development and reproduction. Mice studies have shown that two transcription factors, steroidogenic factor 1 (SF-1) and Wilms' tumor 1 (WT1), are involved in gonadal development. However, their role in human gonadal somatic differentiation remains unclear. We therefore aimed to investigate the roles of SF-1 and WT1 in human gonadal steroidogenic cell differentiation. Methods: Using a transient lentivirus-mediated gene expression system, we assessed the effects of SF-1 and WT1 expression on the steroidogenic potential of human amniotic membrane-derived mesenchymal stem cells (hAmMSCs). Results: SF-1 and WT1-KTS, a splice variant of WT1, played distinct roles in human steroidogenic differentiation of hAmMSCs. SF-1 induced hAmMSC differentiation into progesterone- and androgen-producing cell lineages, whereas WT1-KTS promoted hAmMSC differentiation into estrogen-producing cell lineages. Conclusion: Our findings revealed that SF-1 and WT1-KTS play important roles in human gonadal steroidogenic cell differentiation, especially during ovarian development. These findings may pave the way for future studies on human ovarian differentiation and development.

Measurable residual disease assessment prior to allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndromes: a 20-year monocentric study.

Patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) who undergo allogeneic hematopoietic stem-cell transplantation (alloHSCT) can have divergent survival outcomes while all in morphological complete remission (CR). Techniques of measurable residual disease (MRD) have allowed us to refine their prognosis in two categories: MRD-positive and MRD-negative patients. We conducted a monocentric retrospective study (01/2000-12/2020) to assess the prognosis of pretransplant MRD status measured by multiparametric flow cytometry (MFC) and molecular biology assessed by PCR. 192 patients were included. The median follow-up period was 77 months. Among patients undergoing alloHSCT in CR, overall survival (median-OS: 130.6 vs. 16.0 months, P < 0.001), disease-free survival (median-DFS: 109.6 vs. 7.1 months, P < 0.001) and cumulative incidence of relapse (12-month CIR: 7.3% vs. 33.7%, P < 0.0001) were significantly different between MRD-negative and MRD-positive patients. Patients with discordant intermethod results had intermediate DFS. MRD-negative patients according to molecular PCR-based techniques, WT1 overexpression and MFC had longer median-DFS, compared to MRD-positive patients (P = 0.001, P < 0.001, P < 0.001, respectively). Looking into subgroups, MRD-positive patients among the ELN2017 adverse-category (P < 0.0001), myeloablative and reduced-intensity conditioning regimens (P < 0.0001, P = 0.005), < 60-year patients (P < 0.001) and AML patients (P < 0.001) were associated with lower DFS. This difference was not found in ≥ 60-year patients (P = 0.27) and MDS patients (P = 0.70). MRD-positive patients within the favorable/intermediate ELN2017 category trended toward lower DFS (P = 0.05). We confirmed that MRD status prior to alloHSCT is a strong prognostic factor for OS, DFS and CIR. Combining MFC and molecular-PCR techniques to assess MRD seems primordial as inter-method discordance can be consequential.

Modeling high-risk Wilms tumors enables the discovery of therapeutic vulnerability.

Wilms tumor (WT) is the most common pediatric kidney cancer treated with standard chemotherapy. However, less-differentiated blastemal type of WT often relapses. To model the high-risk WT for therapeutic intervention, we introduce pluripotency factors into WiT49, a mixed-type WT cell line, to generate partially reprogrammed cells, namely WiT49-PRCs. When implanted into the kidney capsule in mice, WiT49-PRCs form kidney tumors and develop both liver and lung metastases, whereas WiT49 tumors do not metastasize. Histological characterization and gene expression signatures demonstrate that WiT49-PRCs recapitulate blastemal-predominant WTs. Moreover, drug screening in isogeneic WiT49 and WiT49-PRCs leads to the identification of epithelial- or blastemal-predominant WT-sensitive drugs, whose selectivity is validated in patient-derived xenografts (PDXs). Histone deacetylase (HDAC) inhibitors (e.g., panobinostat and romidepsin) are found universally effective across different WT and more potent than doxorubicin in PDXs. Taken together, WiT49-PRCs serve as a blastemal-predominant WT model for therapeutic intervention to treat patients with high-risk WT.

Surgical management and outcomes of renal tumors with inferior vena cava extension among children: a single center retrospective study from Pakistan.

OBJECTIVE: The aim of this study was to assess management and determine outcomes of renal tumors with inferior vena cava (IVC) and intracardiac (IC) extension in a tertiary care center in Pakistan. METHODS: A retrospective chart review was conducted at the Aga Khan University Hospital, Karachi, Pakistan. All patients from 1 to 18 years of age with renal tumors with intravascular extensions, surgically managed from January 1988 till June 2016, were included. Data was extracted by reviewing medical records, and the tumor details, treatment and outcomes were analyzed. RESULTS: A total of 18 patients out of the total 61 patients with renal tumors, presented with IVC and/or IC extension, with the majority involving the right kidney. Mean age was 5.9 (SD:4.9) and a female preponderance (56%) was seen. Wilms tumor (77%) was the most common tumor type, with the level of tumor extension into IVC predominantly being below the diaphragm (55.5%). Fourteen patients received preoperative chemotherapy, with tumor regression, seen in 10. Most patients underwent thrombectomy through the renal vein (56%). Regarding outcomes, frequency of mortality and morbidity was 1 and 2, respectively, with 7 patients having no recurrent 5 years post-surgery. CONCLUSION: A greater incidence (29.5%) of IVC and or IC Tumor extension was found compared to existing literature, which could likely be due to a higher referral rate to the center. Moreover, this is a single-center study and so a multi-center study is crucial to form an assessment of surgical management in resource-limited settings. Our study is the first from Pakistan on this particular renal tumor presentation. Considering the varying case presentations and surgical techniques used, further studies are needed to standardize surgical management and optimize patient outcomes.

Assessment of the Circulating PD-1 and PD-L1 Levels and P53 Expression as a Predictor of Relapse in Pediatric Patients with Wilms Tumor and Hypernephroma.

Background/Objectives: Wilms tumor (WT) is the most common form of pediatric renal tumor, accounting for over 90% of cases followed by hypernephroma. Some pediatric patients with WT (10%) experience relapse or metastasis and have poor survival rates. PD-L1 assists cancer cells in escaping damage from the immune system. P53 mutations are found in relapsed WT tumor samples. We hypothesized that testing circulating PD-1 and PD-L1 and P53 expression levels could offer a simple method to predict patient relapse and explore novel treatments for pediatric WTs and hypernephroma. Methods: Flow cytometric detection of cPD-1, cPD-L1, and P53 expression in relapsed and in-remission WT and hypernephroma before and after one year of chemotherapy was performed. Results: Our data shows increased levels of cPD-L1 in relapsed pediatric patients with WT or hypernephroma before and after chemotherapy. There were also slight and significant increases in cPD-1 levels in relapsed groups before chemotherapy. Additionally, we observed significant decreases in P53 expression after one year of chemotherapy in relapsed pediatric patients. Conclusions: Our study found that circulating PD-L1 can be used as a predictor marker for WT and hypernephroma relapse. In conclusion, these circulating markers can assist in monitoring relapse in WT and hypernephroma patients without the need for several biopsies.

Novel CTR9 germline pathogenic splice site variant in siblings with Wilms tumor from Tanzania.

Wilms tumor is the most common childhood renal malignancy. Though mostly non-genetic, it can be syndromic with the involvement of many Wilms tumor predisposing genes and non-syndromic with the involvement of four genes: WT1, REST, TRIM28, and CTR9. Familial and bilateral Wilms tumors do occur, but these are rare. So far, four Wilms tumor families with pathogenic variants in the CTR9 gene have been described, all (presumably) inherited from unaffected fathers, and three leading to deletion of exon 9. We are reporting female siblings, of whom one has a bilateral Wilms tumor, with a novel pathogenic splice site variant in the CTR9 gene, leading to deletion of exon 9, and inherited from their asymptomatic father. The loss of heterozygosity in the tumor was confirmed. In conclusion, CTR9 pathogenic variants are a very rare cause of Wilms tumors and typically result in familial Wilms tumors.

Secondary TFE3-Rearranged Renal Cell Carcinoma in a Chinese Girl Treated for Wilms Tumor: Case Report and Literature Review.

Background: With the development of modern medicine and the application of multimodal treatment strategies, the survival rate after childhood malignant tumors as well as the incidence of Secondary malignant neoplasm (SMN) have increased. Case report: Patient is a Chinese girl. Initially diagnosed with Wilms tumor affecting her left kidney at the age of 6, she was later found to have TFE3-rearranged renal cell carcinoma (rRCC) affecting her right kidney at the age of 12. Employing NGS technology on specimens obtained from the TFE3-rRCC, we uncovered a significant somatic mutation within PRSS8 gene. This discovery sheds new light on the intricate genetic landscape underlying her condition, paving the way for further exploration and personalized treatment strategies. Conclusion: We consider that the etiology of SMN may be the result of chemoradiotherapy.

Inter-Ethnic Variations in the Clinical, Pathological, and Molecular Characteristics of Wilms Tumor.

Wilms tumor is the commonest primary renal malignancy in children and demonstrates substantial inter-ethnic variation in clinical, pathological, and molecular characteristics. Wilms tumor occurs at a lower incidence and at a younger age in Asians compared to Caucasians and Africans. Asians also present at an earlier stage of disease, with a higher incidence of favorable histology tumors and a lower incidence of perilobar nephrogenic rests compared to Caucasians, while African children present with more advanced disease. Studies have implicated population differences in the incidence of WT1 mutations, loss of imprinting of the IGF2 locus, and loss of heterozygosity of 1p/16q, or 1q gain as possible bases for epidemiological differences in the disease profile of Wilms tumors in various ethnic groups. Yet, evidence to support these associations is confounded by differences in treatment protocols and inequalities in the availability of treatment resources and remains limited by the quality of population-based data, especially in resource-limited settings.

WT1 Expression Is Associated with Poor Overall Survival after Azacytidine and DLI in a Cohort of Adult AML and MDS Patients.

Introduction: Post-transplant relapse of acute myeloid leukemia and myelodysplastic syndrome faces restricted effective salvage regimens. We retrospectively analyzed the use of Azacitidine-donor lymphocyte infusion (AZA/DLI) in this setting. Furthermore, data on bone marrow Wilms tumor gene 1 (WT1) expression were collected. Methods: A Cox proportional hazards model, an outcome-oriented approach for the lowest smoothed plot of the martingale residuals, was performed for the cut-point determination of the respective WT1 expression levels. Finally, a Cox proportional hazards model investigated the association of overall survival (OS) with predictors. Results: An overall response of 41.4% with a median duration of 11.9 months for stable disease and 19.5 months for complete response (CR) patients was achieved. The disease risk index (DRI) high-/very high-risk patients had a shorter OS of 4.4 months than intermediate-risk patients, with 14.5 months, p = 0.007. At transplant, WT1-overexpressing patients (>150 copies) had a shorter median OS of 5.3 months than low-WT1-expressing ones, with 13.5 months, p = 0.024. Furthermore, patients with ≤1000 WT1 copies at relapse had a significantly longer OS with 15.3 months than patients overexpressing WT1, with 4.4 months, p = 0.0002. Conclusions: DRI and WT1 expression associate significantly with OS after AZA/DLI. Hence, WT1 may represent an MRD marker, especially in CR patients at high risk.

Cancer immunotherapy of Wilms tumor: a narrative review.

Wilms tumor (WT) is the most common malignant tumor of the urinary system in children. Though the traditional treatment of surgery plus radiotherapy and chemotherapy achieves exciting clinical efficacy, in relapsed and refractory cases, the long-term overall survival rates are poor. Besides, chemotherapy and radiation have serious long-term toxic side effects on children. Cancer immunotherapy is a new tumor therapy that works by activating the body's immune system to allow immune cells to kill tumor cells more efficiently. Currently, cancer immunotherapy has been tested in clinical trials or basic studies in WT. This article reviews the current status of clinical trials and basic research of cancer immunotherapy in WT to promote the application of cancer immunotherapy in WT patients.

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Role of WT1 in Measurable Residual Disease Follow-Up in the Post Allogeneic Stem Cell Transplant Setting.

Objectives: The Wilms' tumor gene 1 (WT1) plays a critical role in cell development and the regulation of essential genes involved in cell growth and metabolism. In the context of hematopoietic tumors, including acute myeloid leukemia (AML), WT1 has been identified as a potential marker for measurable residual disease (MRD) assessment. Relapse after allogeneic hematopoietic stem cell transplantation (allo-SCT) remains a significant challenge in AML treatment, highlighting the importance of MRD monitoring for risk stratification and treatment decisions. This study aimed to investigate the clinical significance of WT1 as a molecular marker for MRD and its correlation with chimerism in AML patients post-allo-SCT setting. Methods: We have included 58 patients with WT1-expression-positive acute myeloid leukemia (AML) who received allo-SCT in our center between 2016-2022. The exclusion criteria are as follows: not having WT1 polymerase chain reaction (PCR) measurement at diagnosis, not receiving allo-SCT, and not having a serial measurement of WT1 post-transplant. Pre- and post-transplant assessments were made with flow cytometry, WT1 PCR, and bone marrow morphological evaluations. Statistical analyses were carried out to explore correlations between WT1 levels, MRD markers, and chimerism post-transplantation. Results: We found that WT1 had a significant correlation with flow cytometry and bone marrow morphological evaluation, but not with chimerism. Interestingly, high WT1 expressors exhibited a more robust correlation with chimerism compared to the general cohort. The negative predictive value for post-allo-SCT relapse was 91.8% for the whole WT1 cohort; for high WT1 expressors, it was similar, at 87.5%. The negative predictive value for post-allo-SCT relapse was high for the whole WT1 cohort; for high WT1 expressors, it was similar. The WT1 MRD assay showed a high negative predictive value for post-allo-SCT relapse, consistent across both the entire cohort (91.8%) and high WT1 expressors (87.5%). Conclusions: WT1 expression levels may serve as a valuable ancillary marker in MRD assessment and relapse prediction post-allo-SCT in AML patients, particularly for those lacking specific fusion genes or mutations. However, further large-scale, controlled studies are needed to standardize WT1 MRD assays and establish clear guidelines for their clinical application.

Case report: Metastatic BRAF V600E-mutated adult Wilms' tumor with robust response to BRAF/MEK inhibitor therapy.

Nephroblastoma or Wilms' tumor (WT) is the most common pediatric renal malignancy but rare in adults. Treatment protocols for adults are typically extrapolated from pediatric guidelines, but there are no standard guidelines for adults due to the rarity of the disease. However, next-generation sequencing has led to new therapeutic options for adult WT patients. We present the first case to our knowledge of a recurrent adult WT treated with dual BRAF/MEK-targeted therapy, which showed initial robust clinical response and was well tolerated.

Laparoscopic Treatment of Wilms' Tumor: Criteria of SIOP-UMBRELLA Protocol may be Updated.

INTRODUCTION: Total nephrectomies for the treatment of Wilms' tumor (WT) are more and more performed by laparoscopy, although indications for this approach following the UMBRELLA guidelines are currently very restrictive. The purpose of this study was to assess the compliance to the criteria of the UMBRELLA protocol for minimally invasive approach of WT. METHODS: This retrospective multicenter study included children operated on by laparoscopic total nephrectomy for suspected WT before 2020. Imaging was reviewed centrally. RESULTS: Fifty-six patients (50 WT and 6 nephrogenic rests) were operated on at a median age of 3.3 ± 2.6 years. Thirteen (23%) patients had metastasis at diagnosis. The mean operative time was 213 ± 84 min. There were eight (14.3%) conversions and five peroperative complications. A local stage III was confirmed in seven (12.5%) cases, including two for tumor rupture. Only one (1.8%) of the procedures followed the SIOP-UMBRELLA indications for laparoscopy. The criterion "ring of normal parenchyma" was met only once. Conservative surgery seemed possible in ten (17.9%) cases. The extension of the tumor beyond the ipsilateral edge of the vertebra after chemotherapy and a volume over 200 mL were associated with an increased risk of conversion (p = 0.0004 and p = 0.001 respectively). After a mean follow-up of 5.2 ± 4.0 years, although there was no local recurrence, one death occurred due to metastatic progression at 15 months postoperatively. CONCLUSIONS: The laparoscopic approach of WT beyond the UMBRELLA recommendations was feasible with low risk of local recurrence. Its indications may be updated and validated.

Horseshoe kidney with teratoid type of Wilms tumor: a rare case report.

BACKGROUND: Horseshoe kidney is the most common renal fusion anomaly, and Wilms tumor is the most frequent renal malignancy in children. The occurrence of Wilms tumor in association with horseshoe kidney is a scarce anomaly. However, the arising of a teratoid type, which is a rare variant of Wilms tumor in a horseshoe kidney, is exceptionally unique. CASE PRESENTATION: This report presents a 5-year-old male admitted with horseshoe kidney involved by a large heterogeneous calcified mass that was diagnose on biopsy as Wilms tumor blastemal dominant. According to the local and regional extension and metastatic tumor in the lungs, the patient underwent neoadjuvant chemotherapy and then surgery. Post-operative pathologic findings confirmed the diagnosis of teratoid Wilms tumor. CONCLUSIONS: The occurrence of renal anomalies associated with a malignancy might be more frequent in the clinical environment. There are numerous differential diagnoses for renal tumors and masses, but the possibility of exceptional anomalies should not be denied, and clinicians should be prepared for these occasions. Although studies propose that chemotherapy has a trivial effect on teratoid Wilms tumors, it is essential to evaluate the tumor for any possibility of regression in non-teratoid regions before proceeding to upfront tumoral resection.

Construction of a Cancer Stem Cell Marker Genes-Related 22-Gene Signature for Overall Survival Prediction in High-Risk Wilms' Tumor.

Background: This study aimed to investigate the comprehensive expression profile of cancer stem cell (CSC)-related genes and construct a prognostic signature for overall survival (OS) prediction in high-risk Wilms' tumor (WT). Materials and methods: Gene expression and survival data from 120 high-risk WT cases in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-WT were used. Results: In total, 229 CSC-related genes were found to be significantly dysregulated in WT compared to tumor-adjacent normal tissues, among which 34 were associated with OS. Using LASSO regression, a 22-gene signature was developed, which exhibited excellent performance in 3-, 5-, and 10-year OS predictions (AUC > 0.86). The high-risk score group showed markedly poorer OS compared to the low-risk score group (median separation, HR = 6.41, 95% CI: 3.18-12.92, p = 3.2e - 9). The 22-gene signature was an independent prognostic factor for OS (HR = 5.086, 95% CI: 3.019-8.568, p < 0.001). Conclusion: This study identified a robust prognostic signature that can effectively support OS prediction.

Concomitant Wilms tumor and autosomal dominant polycystic kidney disease.

BACKGROUND: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described. PROCEDURE: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. RESULTS: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT. CONCLUSION: Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies.

Wilms Tumor with Vena Caval Intravascular Extension: A Surgical Perspective.

Wilms tumor (WT) is the most common kidney tumor in pediatric patients. Intravascular extension of WT above the level of the renal veins is a rare manifestation that complicates surgical management. Patients with intravascular extension are frequently asymptomatic at diagnosis, and tumor thrombus extension is usually diagnosed by imaging. Neoadjuvant chemotherapy is indicated for thrombus extension above the level of the hepatic veins and often leads to thrombus regression, obviating the need for cardiopulmonary bypass in cases of cardiac thrombus at diagnosis. In cases of tumor extension to the retrohepatic cava, neoadjuvant therapy is not strictly indicated, but it may facilitate the regression of tumor thrombi, making resection safer. Hepatic vascular isolation and cardiopulmonary bypass increase the risk of bleeding and other complications when utilized for tumor thrombectomy. Fortunately, WT patients with vena caval with or with intracardiac extension have similar overall and event-free survival when compared to patients with WT without intravascular extension when thrombectomy is successfully performed. Still, patients with metastatic disease at presentation or unfavorable histology suffer relatively poor outcomes. Dedicated pediatric surgical oncology and pediatric cardiothoracic surgery teams, in conjunction with multimodal therapy directed by a multidisciplinary team, are preferred for optimized outcomes in this patient population.

Worse Wilms' Tumor Outcomes Associated With Chemical Complementarity for Multiple T-Cell Receptor CDR3-CMV Epitope Pairs.

BACKGROUND/AIM: Wilms' tumors are pediatric renal tumors that generally have a good prognosis and outcomes. Viral illnesses have been linked to development of neoplasms and should be considered as a factor that could modulate overall survival. MATERIALS AND METHODS: We considered recently developed adaptive immune receptor, genomics and bioinformatics approaches to assess the potential impact of cytomegalovirus (CMV) infections in Wilms' tumor. RESULTS: T-cell receptor (TCR) complementarity determining region-3 (CDR3) amino acid sequences from Wilms' tumor specimens represented by the Therapeutically Applicable Research to Generate Effective Treatments dataset were compared with known anti-CMV TCR CDR3s, indicating that cases representing the anti-CMV TCR CDR3s had worse outcomes. Then, a chemical complementarity scoring approach for the Wilms' tumor, TCR CDR3s and a series of CMV antigens further indicated that cases representing a higher chemical complementarity to the CMV antigens had worse outcomes. CONCLUSION: Overall, we present a potentially novel method to assess CMV infections and identify patients who could benefit from therapies that address such infections.