William Mifsud - Academia.edu (original) (raw)

Papers by William Mifsud

Pediatric Blood & Cancer, Oct 15, 2023

Pediatric blood & cancer, Apr 11, 2024

Gastroenterology, May 1, 2022

Forensic Science Medicine and Pathology, Jun 5, 2015

Purpose: To determine the proportion of pediatric deaths investigated by HM Coronial autopsy, whi... more Purpose: To determine the proportion of pediatric deaths investigated by HM Coronial autopsy, which were potentially preventable deaths due to treatable natural disease, and what implications such findings may have for health policy to reduce such deaths. Methods: Retrospective Study of 1,779 autopsies of individuals between 7 days and 14 years of age requested by HM Coroner, taking place in one specialist pediatric autopsy centre. Cases were included if they involved a definite natural disease process, in which appropriate recognition and treatment was likely to have affected outcome. Strict criteria were used and cases were excluded where the individual had any longstanding condition which might have predisposed to, or altered the recognition of, acute illness, or its response to therapy. Results: Almost 8% (134/1779) of this population were potentially preventable deaths as a result of natural disease, the majority below the age of two years. Most individuals reported one to seven days of symptoms before death and the majority had sought medical advice during this period, including from general practitioners within working hours, and hospital emergency departments. Of those who had sought medical attention, around one third had more than once (28%, 15/53). Sepsis and pneumonia accounted for the majority of deaths (46% and 34% respectively), with all infections (sepsis, pneumonia and meningitis) accounting for 110/134 (82%). Conclusion: Around 10% of pediatric deaths referred to HM Coroner are potentially preventable, being the result of treatable natural acute illnesses. In many cases medical advice had been sought during the final illness. The results highlight how autopsy data review can identify findings of potential significance to mortality reduction, and the importance of centralised investigation and reporting of pediatric deaths.

Journal for ImmunoTherapy of Cancer, Nov 1, 2020

Nature Reviews Urology, Oct 25, 2017

Refers to Gadd, S. et al. A Children's Oncology Group and TARGET initiative exploring the genetic... more Refers to Gadd, S. et al. A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor. Nat. Genet.

Ultrasound in Obstetrics & Gynecology, Dec 2, 2015

Congenital cardiac malformations are commonly identified at perinatal autopsy, which can be chall... more Congenital cardiac malformations are commonly identified at perinatal autopsy, which can be challenging in fetuses of early gestation and in macerated fetuses. Our objective was to examine fetal complex congenital heart disease by microcomputed tomography (micro‐CT), using standard autopsy as the gold standard.

Genes & Development, Apr 14, 2014

Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differ... more Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis.

European Journal of Cancer, May 1, 2022

Background: Anaplasia is an unfavorable prognostic histologic feature in Wilms tumor (WT). Patien... more Background: Anaplasia is an unfavorable prognostic histologic feature in Wilms tumor (WT). Patients with stage I anaplastic WT (AWT) typically achieve good outcomes, albeit with more treatment than for stage I non-anaplastic WT. Since the SIOP-WT-2001 study, patients with focal AWT (FAWT) have been classified as intermediate-risk and received less intense treatment than patients with diffuse AWT (DAWT). The aim of the study was to analyze outcome in these patients. Patients and Methods: Retrospective analysis of clinico-pathologic features and outcomes of 59 patients with stage I AWT (19 FAWT, 40 DAWT) from the SIOP-WT-2001 GPOH and UK-CCLG groups. The patients with FAWT were treated as intermediate-risk WT, with eight weeks of vincristine and actinomycin D (four weeks pre-operatively, and four weeks post-operatively). For comparison, we also assessed outcomes in 818 patients with stage I intermediate-risk non-anaplastic WT (IR-non-AWT). The patients with DAWT were treated with vincristine, actinomycin D and doxorubicin for 31 weeks. No group received radiotherapy. Results: Median follow-up was 67.6 months. 4-year EFS and OS in the FAWT group were 87% (95% CI 72-100) and 100%, respectively, in the DAWT group 85% (95% CI 74-98) and 93% (95% CI 85-100), respectively, and in the IR-non-AWT group 91% (95% CI 89-93) and 98% (95% CI 97-99), respectively. Conclusions: Outcomes for patients with stage I FAWT were comparable with those of other, identically treated, patients with stage I IR-non-AWT. Patients with stage I DAWT 4 also showed good outcomes, albeit with more intensive chemotherapy than IR-non-AWT, but without radiotherapy.

Cancer, Feb 4, 2022

BackgroundSince the International Society of Paediatric Oncology Wilms' Tumour 2001 (SIOP‐WT‐... more BackgroundSince the International Society of Paediatric Oncology Wilms' Tumour 2001 (SIOP‐WT‐2001) study, focal anaplastic Wilms tumors (FAWTs) have been treated as intermediate‐risk Wilms tumors (WTs), and diffuse anaplastic Wilms tumors (DAWTs) have been treated as high‐risk tumors.MethodsThe authors performed a retrospective analysis of preoperatively treated patients with FAWT or DAWT recruited in 2 consecutive UK Children's Cancer and Leukaemia Group WT studies.ResultsOne hundred twenty‐one of 1237 patients (10%) had an anaplastic WT confirmed by central pathology review (CPR): 93 (77%) had DAWT, and 28 (23%) had FAWT. The 4‐year event‐free survival (EFS) was 51% (95% confidence interval [CI], 41%‐63%) for DAWT, 88% (95% CI, 76%‐100%) for FAWT, and 84% (95% CI, 82%‐87%) for intermediate‐risk nonanaplastic Wilms tumor (IR‐non‐AWT). Overall survival (OS) was 58% (95% CI, 48%‐70%) for DAWT, 95% (95% CI, 86%‐100%) for FAWT, and 95% (95% CI, 93%‐96%) for IR‐non‐AWT. In a multivariate analysis, the presence of DAWT was a significant prognostic factor for both EFS and OS in stages II, III, and IV. In a multivariate analysis of unilateral DAWT, stages III and IV remained the only significant prognostic factors for both EFS and OS. In 28% of the cases, there were discrepancies affecting the recognition of anaplasia, classification (DAWT vs FAWT), or the local pathologic stage.ConclusionsPreoperatively treated patients with FAWT had excellent outcomes in comparison with those with identically treated IR‐non‐AWT, whereas patients with DAWT showed significantly worse outcomes. All patients with stage I disease had comparable good outcomes, regardless of the presence/absence of anaplasia. In contrast, the presence of DAWT was associated with significantly worse outcomes for patients with stage II to V disease. Finally, significant diagnostic discrepancies emphasize the value of CPR.Lay Summary Anaplasia is an unfavorable feature in Wilms tumor (WT), and it is classified as focal (focal anaplastic Wilms tumor [FAWT]) or diffuse (diffuse anaplastic Wilms tumor [DAWT]). This study reports the outcomes of patients with FAWT and DAWT who were, for the first time, treated differently. Patients with FAWT received less intensive treatment, and their outcomes were comparable to the outcomes of patients with identically treated nonanaplastic WT. Patients with stage I DAWT also had good outcomes when they were treated without radiotherapy, whereas patients with stage II to V DAWT had poor outcomes despite more intensive treatment.

Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuc... more Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm and the mitochondrial double membrane. Despite these physical barriers we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements and the features of the fusion fragments indicate that non-homologous end joining and/or replication-dependent DNA double strand break repair are the dominant mechanism involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells. Citation Format: Young Seok Ju, Jose Tubio, William Mifsud, Beiyuan Fu, ICGC Prostate Cancer, Bone Cancer, Breast Cancer Working Groups, Fengtang Yang, Peter Campbell, Michael Stratton. Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-161. doi:10.1158/1538-7445.AM2015-LB-161

Genome Research, May 1, 2016

The corrected sentence should read as follows: "our inference method rejects the hypothesis that ... more The corrected sentence should read as follows: "our inference method rejects the hypothesis that the ancestors of AMH were genetically isolated in Africa, thus providing model-based whole genome-level evidence of African archaic admixture." In addition, they also would like to make a change in the last sentence in the Introduction, and the corrected sentence should read as follows: "Together, our results provide a model-based whole-genome perspective on archaic introgression in Africa." The article has already been corrected in both the PDF and full-text HTML files online.

Translational Oncology, Dec 1, 2018

BACKGROUND: Diffuse anaplastic Wilms tumor (DAWT) is a rare, high-risk subtype that is often miss... more BACKGROUND: Diffuse anaplastic Wilms tumor (DAWT) is a rare, high-risk subtype that is often missed on diagnostic needle biopsy. Somatic mutations in TP53 are associated with the development of anaplasia and with poorer survival, particularly in advanced-stage disease. Early identification of DAWT harboring TP53 abnormalities could improve risk stratification of initial therapy and monitoring for recurrence. METHODS: Droplet digital polymerase chain reaction (ddPCR) was used to evaluate 21 samples from 4 patients with DAWT. For each patient, we assessed TP53 status in frozen tumor, matched germline DNA, and circulating tumor DNA (ctDNA) from plasma, serum, and urine collected throughout treatment. RESULTS: Mutant TP53 was detectable in ctDNA from plasma and serum in all patients. We did not detect variant TP53 in the same volume (200 μl) of urine. One patient displayed heterogeneity of TP53 in the tumor despite both histological sections displaying anaplasia. Concentration of ctDNA from plasma/serum taken prenephrectomy varied significantly between patients, ranging from 0.44 (0.05-0.90) to 125.25 (109.75-140.25) copies/μl. We observed variation in ctDNA throughout treatment, and in all but one patient, ctDNA levels fell significantly following nephrectomy. CONCLUSION: We demonstrate for the first time that ddPCR is an effective method for detection of mutant TP53 in ctDNA from children with DAWT even when there is intratumoral somatic heterogeneity. This should be further explored in a larger cohort of patients, as early detection of circulating variant TP53 may have significant clinical impact on future risk stratification and surveillance.

Acta Neuropathologica, Oct 20, 2017

by interrogating our expression data, we were able to show that each molecular group possessed ex... more by interrogating our expression data, we were able to show that each molecular group possessed expression phenotypes suggesting different cellular differentiation: astrocytic in one group and oligodendroglial in the second. Informed by this, we were able to identify CCND1, CSPG4, and PDGFRA as immunohistochemical targets which could distinguish between molecular groups. Our data suggest that the current histological classification of glioneuronal tumours does not adequately represent their underlying biology. Instead, we show that there are two molecular groups within glioneuronal tumours. The first of these displays astrocytic differentiation and is driven by BRAF mutations, while the second displays oligodendroglial differentiation and is driven by FGFR1 mutations.

Nature Communications, Jun 23, 2017

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present t... more Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.

Springer eBooks, 2015

A basic requirement of the perinatal autopsy is to document the fetal sex. When this is discordan... more A basic requirement of the perinatal autopsy is to document the fetal sex. When this is discordant with the sex documented by the clinical team, it should be communicated rapidly. Occasionally, a disorder of sex development (DSD) may be present, and this should be studied carefully so that the parents may be adequately counseled. Well-documented DSDs, when properly investigated, may also shed new light on our understanding of human reproductive system development. Reproductive tract anomalies can also be associated with complex malformations involving other organs; occasionally a DSD may be the cause of fetal or neonatal demise, such as in cases of pulmonary hypoplasia secondary to hydrometrocolpos.

Journal of Clinical Pathology, Dec 4, 2014

Diffuse lung disease (DLD) of infancy has multiple aetiologies and the spectrum of disease is sub... more Diffuse lung disease (DLD) of infancy has multiple aetiologies and the spectrum of disease is substantially different from that seen in older children and adults. In many cases, a specific diagnosis renders a dire prognosis for the infant, with profound management implications. Two recently published series of DLD of infancy, collated from the archives of specialist centres, indicate that the majority of their cases were referred, implying that the majority of biopsies taken for DLD of infancy are first received by less experienced pathologists. The current literature describing DLD of infancy takes a predominantly aetiological approach to classification. We present an algorithmic, histological, pattern-based approach to diagnosis of DLD of infancy, which, with the aid of appropriate multidisciplinary input, including clinical and radiological expertise and ancillary diagnostic studies, may lead to an accurate and useful interim report, with timely exclusion of inappropriate diagnoses. Subsequent referral to a specialist centre for confirmatory diagnosis will be dependent on the individual case and the decision of the multidisciplinary team.