Publications by authors named "Martin A Weber"

25 Publications

  • Page 1 of 1

Parents' experiences of postmortem tumor donation for high-grade gliomas: benefits and suggested improvements.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab087. Epub 2021 Aug 25.

School of Women's and Children's Health, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia.

Background: Pediatric high-grade glioma is a devastating diagnosis. There has been no improvement in outcomes for several decades, with few children surviving 2 years postdiagnosis. Research progress has been hampered by a lack of tumor samples, which can be used to develop and test novel therapies. Postmortem tumor donations are therefore a valuable opportunity to collect tissue. In this study, we explored Australian parents' experiences of donating their child's tumor for research after their child had died.

Methods: We collected qualitative data from 11 bereaved parents who consented to donate samples of their child's high-grade glioma for research postmortem. We asked parents about their perceived benefits/burdens of the autopsy, recommendations for improving consent discussions, and decision regret.

Results: Parents hoped that their donation would help to find a cure for future children with high-grade glioma. They described feeling comforted knowing that their child's suffering may help others. Some parents also felt that the donation would help them better understand their child's tumor. Although some parents described discomfort about procedures leading up to the autopsy, parents reported minimal regret regarding their decision to donate their child's tumor. Parents provided recommendations to improve consent discussions, such as providing more information about the autopsy logistics and why the donation was needed.

Conclusion: Parents consented to autopsy for altruistic reasons, although donation may also assist parents in their grieving. There is a strong need to improve access to tumor donations for any family who wishes to donate.
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http://dx.doi.org/10.1093/noajnl/vdab087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386242PMC
August 2021

Sarcina in an Adolescent With Repaired Esophageal Atresia: A Pathogen or a Benign Commensal?

J Pediatr Gastroenterol Nutr 2019 08;69(2):e57

Department of Gastroenterology, Sydney Children's Hospital.

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http://dx.doi.org/10.1097/MPG.0000000000002339DOI Listing
August 2019

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Am J Hum Genet 2019 02 10;104(2):213-228. Epub 2019 Jan 10.

Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369446PMC
February 2019

Integration of genomics, high throughput drug screening, and personalized xenograft models as a novel precision medicine paradigm for high risk pediatric cancer.

Cancer Biol Ther 2018 9;19(12):1078-1087. Epub 2018 Oct 9.

a Children's Cancer Institute, Lowy Cancer Research Centre , University of New South Wales , Randwick , New South Wales , Australia.

Pediatric high grade gliomas (HGG) are primary brain malignancies that result in significant morbidity and mortality. One of the challenges in their treatment is inter- and intra-tumoral heterogeneity. Precision medicine approaches have the potential to enhance diagnostic, prognostic and/or therapeutic information. In this case study we describe the molecular characterization of a pediatric HGG and the use of an integrated approach based on genomic, in vitro and in vivo testing to identify actionable targets and treatment options. Molecular analysis based on WGS performed on initial and recurrent tumor biopsies revealed mutations in TP53, TSC1 and CIC genes, focal amplification of MYCN, and copy number gains in SMO and c-MET. Transcriptomic analysis identified increased expression of MYCN, and genes involved in sonic hedgehog signaling proteins (SHH, SMO, GLI1, GLI2) and receptor tyrosine kinase pathways (PLK, AURKA, c-MET). HTS revealed no cytotoxic efficacy of SHH pathway inhibitors while sensitivity was observed to the mTOR inhibitor temsirolimus, the ALK inhibitor ceritinib, and the PLK1 inhibitor BI2536. Based on the integrated approach, temsirolimus, ceritinib, BI2536 and standard therapy temozolomide were selected for further in vivo evaluation. Using the PDX animal model (median survival 28 days) we showed significant in vivo activity for mTOR inhibition by temsirolimus and BI2536 (median survival 109 and 115.5 days respectively) while ceritinib and temozolomide had only a moderate effect (43 and 75.5 days median survival respectively). This case study demonstrates that an integrated approach based on genomic, in vitro and in vivo drug efficacy testing in a PDX model may be useful to guide the management of high risk pediatric brain tumor in a clinically meaningful timeframe.
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http://dx.doi.org/10.1080/15384047.2018.1491498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301829PMC
September 2019

Oral malignant gastrointestinal neuroectodermal tumour with junctional component mimicking mucosal melanoma.

Pathology 2018 Oct 31;50(6):648-653. Epub 2018 Aug 31.

Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Malignant gastrointestinal neuroectodermal tumour (GNET) is a recently characterised rare and aggressive tumour that typically arises in association with the small intestine of adults. We present a novel case of this entity and expand the spectrum of its reported morphological features. The patient was a 5-year-old female, the youngest reported patient affected by the condition, and presented with extra-abdominal disease. The histopathological features included the presence of a junctional component of the palatal tumour, which mimicked mucosal melanoma, a feature that has not been previously reported in GNET. Whole genome and RNA sequencing was performed that demonstrated the EWSR1-ATF1 translocation characteristic of GNET. Knowledge of this entity and its features, together with careful morphological assessment supplemented by judicious immunohistochemical and molecular studies should enable the correct diagnosis to be established.
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http://dx.doi.org/10.1016/j.pathol.2018.07.002DOI Listing
October 2018

A Mutation Outside the Dimerization Domain Causing Atypical STING-Associated Vasculopathy With Onset in Infancy.

Front Immunol 2018 6;9:1535. Epub 2018 Jul 6.

Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

Background: Mutations in the gene encoding stimulator of interferon genes (STING) underlie a type I interferon (IFN) associated disease, STING-associated vasculopathy with onset in infancy (SAVI). Patients suffer cutaneous vasculopathy and interstitial lung disease, but are not known to suffer life-threatening infection.

Case: We describe a child who presented with pneumonia in early life, from which he recovered. He went on to suffer failure to thrive, developmental delay, livedo reticularis, and vesicular rash, but without cutaneous vasculitis, and with normal C-reactive protein and erythrocyte sedimentation rates. At 3 years of age, he developed life-threatening pulmonary hypertension.

Methods: Whole genome sequencing (WGS) was performed using the Illumina HiSeqX10 platform and the Seave platform was used for bioinformatic analysis. mRNA expression of IFN-stimulated genes and inflammatory cytokines from peripheral blood mononuclear cells was determined by quantitative polymerase chain reaction. Luciferase assay was used to model IFNβ and NF-κB activity .

Results: WGS revealed a mutation p.Arg284Ser in STING at an amino acid previously associated with SAVI. Although this mutation did not fall in the dimerization domain (DD), mRNA analysis revealed constitutive IFN-gene activation consistent with an interferonopathy, which correlated to STING activation . The patient was treated with corticosteroids and the JAK inhibitor Ruxolitinib, resulting in a rapid improvement of pulmonary hypertension, general well-being, and resolution of the IFN gene signature. However, he did go on to evolve a nasal septal erosion suggesting incomplete control of disease.

Conclusion: This case provides molecular evidence to support the p.Arg284Ser variant in STING exerting pathogenicity through a gain-of-function mechanism. The lack of cutaneous vasculitis or elevated systemic inflammatory markers, and the occurrence of an opportunistic infection are notable, and raise the possibility that variants outside the STING DD may potentially manifest with an atypical SAVI phenotype. Nevertheless, there was an objective clinical improvement in response to JAK inhibition.
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http://dx.doi.org/10.3389/fimmu.2018.01535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047589PMC
July 2018

"Delayed Villous Maturation" in Placental Reporting: Concordance among Consultant Pediatric Pathologists at a Single Specialist Center.

Pediatr Dev Pathol 2015 Sep-Oct;18(5):375-9

Department of Cellular Pathology, Guy's and St Thomas' Hospital, London, United Kingdom.

Delayed villous maturation (DVM) has been associated with an increased risk of adverse pregnancy outcome, including stillbirth, in the late third trimester, but there are limited published data. Moreover, it is recognized that the assessment of villous maturation is subjective and hampered by both intraobserver and interobserver variability. This audit aims to assess concordance in the reporting of DVM among pediatric pathologists at a single specialist center to improve reproducibility of this potentially important diagnosis. This is a retrospective review of singleton placentas from pregnancies at 35 weeks gestation or greater submitted for histopathologic examination between June 2013 and December 2013. Placental slides were reviewed independently by 4 pediatric pathologists, blinded to the original report, apart from gestational age; villous maturation was assessed as appropriate, accelerated, or delayed for the stated gestational age. A total of 464 placental histopathology reports were reviewed, of which 164 were greater than 35 weeks gestation; of those, 42 (26%) were originally reported as DVM. Following the audit slide review, 38 cases (23%) were assessed to show DVM by at least 1 pathologist. Consensus, with at least 3 pathologists agreeing to a diagnosis of DVM, was achieved in only 14 cases (9% of all cases reviewed; 37% of all cases called DVM). However, the proportion of overall agreement between 2 of the pathologists was 0.92. Concordance for DVM is poor among pathologists and subject to much interobserver variability. Consistency may be improved by consensus histologic review of all the placentas in which the diagnosis of DVM is being considered and stringent application of the published diagnostic criteria.
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http://dx.doi.org/10.2350/12-02-1604-OA.1DOI Listing
February 2016

Clinicopathological features of fatal cardiomyopathy in childhood: an autopsy series.

J Paediatr Child Health 2012 Aug 19;48(8):675-80. Epub 2012 Apr 19.

UCL Institute of Child Health, Department of Paediatric Pathology, Great Ormond Street Hospital for Children, University College London, United Kingdom.

Aim:   Cardiomyopathy, a group of primary myocardial disorders, is an uncommon, but important, cause of death in childhood. This study examines the demographic, clinical and pathological features of fatal cardiomyopathy in childhood with particular reference to its classification and autopsy findings.

Method:   The method of this study was a retrospective structured review of all paediatric autopsies performed at a single specialist centre from 1995 to 2009 inclusive, in order to determine the demographic, clinical and pathological features of fatal cardiomyopathy.

Results:   From a total of 2229 autopsies performed at the centre during the study period on live-born infants and children, 34 confirmed cases of cardiomyopathy were identified (1.5%). More than half (59%) of these cases occurred in infants (less than 1 year of age). Heart weight of cardiomyopathy cases was significantly greater than those with normal hearts (P < 0.001), and 77% had heart weights above the 95th percentile of the normal expected range for age, including all of those over 1 year age. Of cardiomyopathy cases, 50% were primary dilated cardiomyopathy and 27% were primary hypertrophic cardiomyopathy. Twelve of 34 cases (35%) presented as sudden unexpected death, the diagnosis of cardiomyopathy being only made at autopsy.

Conclusion:   Cardiomyopathy is an uncommon cause of death in infancy and childhood. It can present as sudden unexpected death and encompasses a range of aetiologies. Heart weight above the 95th percentile at autopsy is present in most cases but heart weight may be within the normal range in infants.
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http://dx.doi.org/10.1111/j.1440-1754.2012.02450.xDOI Listing
August 2012

Postmortem tandem mass spectrometry profiling for detection of infection in unexpected infant death.

Forensic Sci Med Pathol 2012 Sep 14;8(3):252-8. Epub 2012 Jan 14.

Departments of Paediatric Pathology, Great Ormond Street Hospital for Children, London, UK.

Numerous hypotheses have been suggested to explain the cause of sudden unexpected infant death, including infection. As part of the autopsy, routine ancillary investigations are performed, including blood/bile tandem mass spectrometry (TMS) primarily for detection of metabolic disease. The aim of this study was to evaluate and assess TMS derived acylcarnitine profiles to determine whether infectious deaths were associated with characteristic profiles. As part of a retrospective study including >2,500 pediatric autopsies at a single specialist centre over a 14 year period, acylcarnitine profiles were reviewed. Using multiple linear regression, standardised residuals were prepared and findings compared between different cause of death groups, including unexplained, focal infection, microbiological infection and accidental injuries. 415 blood samples from SUDI autopsies were identified. Statistically significant differences in TMS profiles were identified between those dying of infection and the unexplained SUDI group, including changes in free carnitine, short chain acylcarnitines and octanoylcarnitine. Cases with microbiological infection diagnosed only from postmortem cultures did not show any significant difference from the unexplained group. Postmortem TMS profiling identifies SUDI deaths which are associated with histological evidence of infection, and an acylcarnitine profile suggesting perturbation of oxidative metabolism. Such findings raise the possibility that more comprehensive TMS profiling may offer additional diagnostic clues beyond screening for metabolic disorders, and may contribute to determination of mode of death.
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http://dx.doi.org/10.1007/s12024-011-9308-8DOI Listing
September 2012

Autopsy findings of co-sleeping-associated sudden unexpected deaths in infancy: relationship between pathological features and asphyxial mode of death.

J Paediatr Child Health 2012 Apr 21;48(4):335-41. Epub 2011 Oct 21.

Department of Paediatric Histopathology, Great Ormond Street Hospital for Children, London, UK.

Aim: Co-sleeping is associated with increased risk of sudden unexpected death in infancy (SUDI)/sudden infant death syndrome (SIDS). The aim of this study is to examine autopsy findings from a single U.K. specialist centre to determine the relationship between co-sleeping and cause of death.

Methods: Retrospective analysis of >1500 paediatric autopsies carried out by paediatric pathologists over a 10-year period. SUDI was defined as sudden unexpected death of an infant aged 7-365 days; deaths were categorised into explained SUDI (cause of death was determined) and unexplained SUDI (equivalent to SIDS).

Results: There were 546 SUDI; sleeping arrangements were specifically recorded in 314; of these, 174 (55%) were co-sleeping-associated deaths. Almost two thirds (59%) of unexplained SUDI were co-sleeping compared to 44% explained SUDI (95% confidence interval (CI) 1.0-27.2%, P=0.03); however, this difference remained statistically significant only for the first 5 months of life (95% CI 3.5-33.2%, P=0.01). In unexplained SUDI aged < 6 months, there were no significant differences between co-sleeping and non-co-sleeping deaths with respect to ante-mortem symptoms, intrathoracic petechiae, macroscopic lung appearances, pulmonary haemosiderin-laden macrophages, and isolation of specific bacterial pathogens; however, fresh intra-alveolar haemorrhage was reported more commonly in co-sleeping (54%) than in those that were not (38%; 95% CI 1.4-30.5%, P=0.03).

Conclusions: Co-sleeping is associated with unexplained SUDI/SIDS in infants aged < 6 months, suggesting that co-sleeping is related to the pathogenesis of death in younger infants. The finding that intra-alveolar haemorrhage is more common in co-sleeping suggests that a minority of co-sleeping-associated deaths may be related to an asphyxial process.
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http://dx.doi.org/10.1111/j.1440-1754.2011.02228.xDOI Listing
April 2012

Minimally invasive perinatal autopsies using magnetic resonance imaging and endoscopic postmortem examination ("keyhole autopsy"): feasibility and initial experience.

J Matern Fetal Neonatal Med 2012 May 10;25(5):513-8. Epub 2011 Aug 10.

Department of Paediatric Pathology, Clinical Molecular Genetics, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK.

Objective: Perinatal autopsy provides additional diagnostic information in a significant proportion of cases but parents and relatives frequently decline traditional postmortem (PM) examination, partly due to the unacceptability of the cosmetic effects of large incisions and concerns regarding organ retention. We present a novel minimally invasive autopsy method for fetal and neonatal PMexaminations, which includes PM magnetic resonance imaging (MRI) for assessment of anatomy and endoscopic internal examination to allow direct organ visualization and targeted tissue biopsy.

Methods: Descriptive retrospective feasibility report of the first 10 perinatal cases undergoing endoscopic minimally invasive autopsy.

Results: A minimally invasive autopsy (MIA) approach based on postmortem MRI (PM MRI) and endoscopic autopsy with tissue biopsy is feasible and effective with minimal cosmetic consequences compared to traditional PM examination. Endoscopic examination with tissue biopsy provided additional diagnostic information to PM MRI alone in the majority of cases.

Conclusions: Endoscopic MIA is a feasible and potentially more acceptable approach to perinatal autopsy and provides an additional option for parents who do not agree to a traditional PM examination. This approach could result in increased utilization of investigations after death in this group of patients.
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http://dx.doi.org/10.3109/14767058.2011.601368DOI Listing
May 2012

Difficulties in interpretation of post-mortem microbiology results in unexpected infant death: evidence from a multidisciplinary survey.

J Clin Pathol 2011 Aug 10;64(8):706-10. Epub 2011 May 10.

UCL Institute of Child Health, London, UK.

Background: Post-mortem (PM) microbiological investigations are recommended in cases of sudden unexpected death in infancy (SUDI), and infection is a recognised cause of such deaths, but no current evidence-based guidelines exist for the appropriate interpretation of results.

Aim: To assess interpretive difficulties using a targeted cross-specialty questionnaire.

Methods: 109 consultant specialists involved in infant death management were given a questionnaire providing information on five hypothetical standardised SUDI cases, which differed only in their PM microbiology findings. Participants classified each case into categories: definite bacterial infection, probable bacterial infection, bacterial growth of uncertain significance and PM contamination.

Results: 63 (57%) specialists responded. There was no clinical scenario in which complete concordance in interpretation of PM microbiology results was established among participants. In cases with pure growth of Group 2 pathogens such as Group B β-haemolytic Streptococcus, 96% of respondents agreed upon probable or definite bacterial infection. With mixed growth of Group 2 pathogens, 83% reported probable or definite bacterial infection. Growth of organisms such as Staphylococcus aureus caused the most difficulty, with almost equal numbers of participants interpreting the finding as significant or non-significant. There were no consistent differences in interpretation between different specialist groups.

Conclusions: While there is general agreement in interpretation of PM microbiology findings in some SUDI scenarios, no consensus was achieved for any clinical setting, and variation in the presumed significance between specialists was apparent. In the absence of appropriate evidence-based guidelines, this has practical implications for the management of such deaths in a multidisciplinary setting.
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http://dx.doi.org/10.1136/jclinpath-2011-200056DOI Listing
August 2011

Microbiological findings in sudden unexpected death in infancy: comparison of immediate postmortem sampling in casualty departments and at autopsy.

J Clin Pathol 2011 May 8;64(5):421-5. Epub 2011 Mar 8.

UCL Institute of Child Health, London, UK.

Aim: Sudden unexpected death in infancy (SUDI) represents the commonest presentation of post-neonatal infant death in the UK. This audit reviews current practice in the investigation of SUDI deaths, with particular regard to the practice of microbiological sampling in emergency departments (ED) compared with samples obtained at the time of autopsy for establishing the cause of death, as suggested by current guidelines.

Methods: Coronial autopsies performed for the indication of SUDI over a 4-year period at a single specialist centre were reviewed with particular regard to the findings of microbiological investigations performed in ED compared with those performed at the time of autopsy.

Results: Of 229 SUDI postmortems performed during the period, there were 136 cases in which both bacteriological samples taken in ED and at autopsy were available, including 109 with blood cultures taken at both time points. 66 cases had sterile blood cultures in ED of which 37 (56%) showed positive microbiological growth from autopsy samples including nine (14%) cases with group II pathogens. Group II pathogens were identified from ED samples in six (6%) of the total cases; all but two cases of Staphylococcus aureus were not detected at autopsy.

Conclusion: Blood cultures obtained at autopsy are associated with a significantly higher rate of positive microbial cultures compared with blood samples taken in life. Most represent easily identified postmortem translocation or overgrowth rather than infection as the cause of death. No cases with a final infective cause of death would have been missed if ED sampling had not been performed.
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http://dx.doi.org/10.1136/jcp.2011.089698DOI Listing
May 2011

Variation and uncertainties in the classification of sudden unexpected infant deaths among paediatric pathologists in the UK: findings of a National Delphi Study.

J Clin Pathol 2010 Sep;63(9):796-9

Department of Cellular Pathology, John Radcliffe Hospital, Oxford, UK.

Aims: Presently, pathologists in the UK use diverse terminologies for the classification of sudden unexpected infant deaths, including 'unascertained,' 'sudden unexpected death in infancy' (SUDI) and 'sudden infant death syndrome' (SIDS). This study uses the Delphi method to investigate the views of paediatric pathologists on their use of these terms in order to determine areas of consensus.

Methods: There were three Delphi rounds overall; in the final one, participants were asked to score each statement using a modified Likert scale (0-9). The scores were analysed using non-parametric statistics, and statements in which the median score was or=7 (approximately 70% agreement) were considered to have reached 'consensus agreement.'

Results: Twenty-five of the 36 UK paediatric pathologists who were approached in the initial round contributed to all three rounds. There was consensus that 'SIDS' be used for unexplained sudden unexpected infant deaths that occurred during sleep. 'Infancy' was defined as up to 1 year of age, but there was no consensus regarding the lower age limit of SIDS. There was agreement that 'SUDI' be used for unexplained sudden infant deaths with a history of preceding illness, deaths with minor histological abnormalities of uncertain significance and co-sleeping-associated deaths. Most paediatric pathologists used 'unascertained' for findings suspicious of a non-natural cause of death. There was consensus that co-sleeping-associated deaths should be classified as 'unascertained' if parents had consumed alcohol or used drugs in the preceding 24 h.

Conclusions: The areas of consensus relating to terminology around SUDI and SIDS should guide future use by pathologists. However, there remains a significant lack of agreement, suggesting that acceptable alternative terms be identified for infant deaths which remain unexplained following autopsy in whom there are no suspicious features; the authors propose that 'unexplained SUDI,' followed by a comment, may represent the most factually correct compromise.
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http://dx.doi.org/10.1136/jcp.2010.079715DOI Listing
September 2010

Postmortem MRI of bladder agenesis.

Pediatr Radiol 2011 Jan 6;41(1):110-2. Epub 2010 Aug 6.

Radiology Department, St George's Hospital, Blackshaw Road, London, SW17 0QT, UK.

We report a 35-week preterm neonate with bladder agenesis and bilateral dysplastic kidneys. A suprapubic catheter was inadvertently inserted into one of the larger inferior cysts of the left dysplastic kidney. A postmortem MRI scan was performed with the findings being confirmed on autopsy. We are unaware of another postmortem MRI study demonstrating bladder agenesis.
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http://dx.doi.org/10.1007/s00247-010-1728-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082691PMC
January 2011

Genetics and developmental pathology of twinning.

Semin Fetal Neonatal Med 2010 Dec;15(6):313-8

Department of Paediatric Pathology, Great Ormond Street Hospital for Children, London, UK.

Twin pregnancy is associated with a high risk of congenital malformations. This review covers the risk of such anomalies in both dizygotic and monozygotic twin pregnancies, and discusses current insights into the associations relating to zygosity, chorionicity and genetic factors. The pathological basis of specific malformations unique to the monochorionic twinning process, including conjoined twinning and twin reversed arterial perfusion (TRAP) sequence, is discussed in more detail, and factors contributing to the higher perinatal mortality rate in multiple pregnancies are addressed.
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http://dx.doi.org/10.1016/j.siny.2010.06.002DOI Listing
December 2010

Post-mortem interval and bacteriological culture yield in sudden unexpected death in infancy (SUDI).

Forensic Sci Int 2010 May 11;198(1-3):121-5. Epub 2010 Mar 11.

Department of Paediatric Pathology, Great Ormond Street Hospital for Children and Institute of Child Health, University College London, London, UK.

It has been hypothesised that post-mortem translocation, the migration of micro-organisms from mucosal surfaces into the body after death, leads to microbial overgrowth in post-mortem samples, which is more frequently polymicrobial and which would be detected more frequently with increased post-mortem interval (PMI) from death to autopsy. This study aimed to evaluate the association between PMI and bacteriological yield in post-mortem examinations of sudden unexpected deaths in infancy (SUDI). A retrospective review of all microbiological findings from >500 SUDI autopsies (7-365 days of age) was performed as part of a larger review of >1500 paediatric autopsies over a 10-year period, 1996-2005. All autopsies were carried out in a single specialist centre by a small number of paediatric pathologists. For the 507 SUDI included in the analysis, there were 2079 samples collected for bacteriological culture. The median PMI was 2 days. The proportion of positive cultures decreased from 83% for samples taken within 24h of death, to 67% when taken five or more days after death (chi-square for linear trend=19.99, P<0.0001). Polymicrobial cultures decreased from 61% to 46% (chi-square for linear trend=12.88, P=0.0003), and cultures taken two or more days after death yielded significantly fewer isolates per sample than cultures taken less than 2 days after death (Mann-Whitney U-test, P=0.009). The findings of this study demonstrate that a PMI of several days' duration is neither associated with an increased frequency of positive cultures nor with an increased frequency of mixed-growth episodes as was hypothesised to occur with post-mortem translocation. Indeed, the opposite trend is observed, suggesting that a longer PMI may result in death of micro-organisms. However, these data do not allow assessment of the possibility of significant post-mortem translocation occurring within the first few hours after death. Whilst the interpretation of positive microbiological cultures in SUDI post-mortems remains difficult, a PMI of several days' duration is not associated with an increased risk of post-mortem translocation and routine microbiological sampling is recommended in all SUDI autopsies, even when there is a PMI of several days.
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http://dx.doi.org/10.1016/j.forsciint.2010.02.002DOI Listing
May 2010

Sudden unexpected neonatal death in the first week of life: autopsy findings from a specialist centre.

J Matern Fetal Neonatal Med 2009 May;22(5):398-404

Department of Paediatric Pathology, Great Ormond Street Hospital for Children, London, UK.

Objective: Sudden unexpected early neonatal death (SUEND) in the first week of life shares features with sudden unexpected death in infancy (SUDI) but is not included as SUDI, which is limited to post-perinatal deaths. The aim of this study was to review SUEND autopsies performed in a single specialist centre over a 10-year period, (1996-2005).

Methods: Retrospective analysis of >1500 consecutively performed paediatric autopsies performed by paediatric pathologists at one centre conducted according to a standard protocol including ancillary investigations. SUENDs were identified and autopsy findings reviewed.

Results: Of 1516 post-mortem examinations, 180 were first-week neonatal deaths, 55 (31%) presenting as SUEND. Thirty-two (58%) were explained following autopsy, whilst the remainder were unexplained; most deaths during sleep were associated with adult co-sleeping. Around 40% of explained deaths were associated with undiagnosed congenital abnormalities, mainly congenital heart disease. In addition, there were nine infection-related deaths and three deaths from unsuspected metabolic disease (fatty acid oxidation defects).

Conclusion: There are distinct differences between SUEND and SUDI, with significantly more explained deaths in the former and a much greater proportion due to congenital abnormalities and metabolic disease.
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http://dx.doi.org/10.1080/14767050802406677DOI Listing
May 2009

Rib fractures identified at post-mortem examination in sudden unexpected deaths in infancy (SUDI).

Forensic Sci Int 2009 Aug 23;189(1-3):75-81. Epub 2009 May 23.

Department of Paediatric Pathology, Great Ormond Street Hospital for Children and UCL Institute of Child Health, Great Ormond Street, London WC1N 3JH, UK.

Rib fractures may be associated with non-accidental injury (NAI) in infancy, but the possible significance of fresh rib fractures in relation to resuscitation remains undetermined. Consequently, it is important to detect and confirm the presence of rib fractures when performing a post-mortem examination, particularly in the context of sudden unexpected death in infancy (SUDI). At our centre, it has been local policy to perform routine radiological skeletal surveys and detailed post-mortem examination of the ribs in all SUDI autopsies. The aim of this study is to establish the characteristics of all rib fractures identified at autopsy in the setting of SUDI from a large series of cases examined at a single specialist centre. As part of a larger review of paediatric post-mortem examinations performed at a single specialist institution over a 10-year period (1996-2005), all cases presenting as SUDI (aged 7-365 days) were identified and their anonymised records searched to identify all cases in which rib fractures were recorded. Over the 10-year period, 546 post-mortem examinations were performed for the indication of SUDI, including 94 forensic autopsies. Rib fractures were identified in 24 cases (4%). 15 infants (3% of SUDI) demonstrated healing rib fractures, of which 10 infants (67%) showed additional features suggestive of NAI. The other 9 infants (2% of SUDI) demonstrated fresh rib fractures only with no surrounding tissue reaction histologically; in 7 (78%) of these there were no other injuries and the fresh fractures were interpreted to have been caused by resuscitation-related trauma. All of the resuscitation-related fractures were situated in the anterolateral chest, in contrast to NAI-associated fractures, which were located in the anterolateral and/or posterior chest. Anterior costochondral junction fractures were also seen in a minority of NAI-associated cases, but such fractures were not seen in apparent resuscitation-related cases. Compared to healing rib fractures, which were detected on skeletal survey in 93%, fresh rib fractures were only detected in 22% of skeletal surveys. Rib fractures are uncommon in infancy and may indicate NAI, particularly when healed or healing, posterior or involving the costochondral junction. Fresh rib fractures may be missed on skeletal survey, but can be reliably detected at post-mortem examination following stripping of the pleura and detailed examination of each rib. Fresh anterolateral fractures, which may be multiple, contiguous and even bilateral, are highly likely to be related to resuscitation if there are no other associated injuries.
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http://dx.doi.org/10.1016/j.forsciint.2009.04.015DOI Listing
August 2009

The frequency and significance of alveolar haemosiderin-laden macrophages in sudden infant death.

Forensic Sci Int 2009 May 28;187(1-3):51-7. Epub 2009 Mar 28.

Great Ormond Street Hospital for Children and Institute of Child Health, University College London, London, UK.

Alveolar haemosiderin-laden macrophages (HLMs) in histological sections of the lung represent evidence of previous pulmonary haemorrhage and in infants may be associated with features of non-accidental injury (NAI). The aim of this study is to establish the frequency of alveolar HLMs detected at post-mortem in a large series of sudden unexpected infant deaths, and to determine their clinical significance with particular regard to a possible association with NAI. A search was performed of a database of 1516 anonymised paediatric autopsies to identify all infants (<1 year of age) that died suddenly and unexpectedly in whom HLMs were demonstrated on routine histological examination of lung sections using special iron (Perls') stains. Clinical details and other post-mortem findings were then reviewed. During the study period (1996-2005 inclusive), there were 601 sudden unexpected infant deaths. Of the 536 autopsies in whom histological data regarding HLMs were recorded and slides were available for review, 29 (5%) demonstrated alveolar HLMs in lung sections. In 9 (31%) infants there were additional features of NAI; in 11 (38%) infants, there were features in the clinical history and/or on pathological examination of natural disease sufficient to potentially explain the presence of HLMs, and 9 (31%) represented otherwise unexplained infant deaths with no significant clinical history or other abnormalities. HLMs were present in 9 of the 27 (33%) total infant deaths with other features indicative of NAI, compared to only 9 of the 242 (4%) unexplained infant deaths without any other features of NAI or other contributory pathology (difference 29.6%, 95% CI 14.6-48.6%, p<0.0001; positive likelihood ratio 9.0, 95% CI 3.9-19.8). This association remained even if cases with rib fractures were excluded. Alveolar HLMs may be identified in a significant minority of sudden infant deaths following routine histological examination of the lungs with special stains for iron pigment. In most, there will be features in the clinical history or findings at post-mortem to indicate underlying natural disease which may account for their presence. However, in the absence of such features, alveolar HLMs, whilst not diagnostic, are associated with a significantly increased risk for the detection of other features of NAI; the presence of otherwise unexplained alveolar HLMs at autopsy should therefore prompt a careful exclusion of inflicted injury.
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http://dx.doi.org/10.1016/j.forsciint.2009.02.016DOI Listing
May 2009

Disseminated langerhans cell histiocytosis-related sudden unexpected death in infancy.

Fetal Pediatr Pathol 2009 ;28(1):39-44

Department of Histopathology, Great Ormond Street Hospital for Children, London, United Kingdom.

Sudden unexpected death in infancy (SUDI) is defined as the sudden and unexpected death of an infant aged less than 1 year and comprises a heterogeneous group of deaths; in around one-third of cases a definite cause of death is identified at autopsy, while almost two-thirds of such deaths will remain unexplained despite a careful review of the circumstances of death and a detailed postmortem examination. We report a case of SUDI due to previously undiagnosed disseminated Langerhans cell histiocytosis (LCH) in a 10-month-old male, a disease characterized by a clonal proliferation of dendritic Langerhans cells. The diagnosis was established on histological examination, which revealed extensive infiltration by LCH of the skin, lymph nodes, thymus, spleen, and lungs. Despite a high mortality in disseminated disease, to our knowledge, this is the first reported case in the English-language literature of disseminated multisystem Langerhans cell disease presenting as SUDI. Furthermore, this case demonstrates the importance of routine microscopic tissue sampling in all SUDI, as the diagnosis required histological examination of the organs and might have been missed had histology not been performed.
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http://dx.doi.org/10.1080/15513810802548099DOI Listing
March 2009

Third trimester intrauterine fetal death caused by arterial aneurysm of the umbilical cord.

Pediatr Dev Pathol 2007 Jul-Aug;10(4):305-8

Department of Histopathology, Great Ormond Street Hospital for Children, London, UK.

Umbilical artery aneurysm (UAA) of the umbilical cord is an extremely rare lesion, with only 8 reported cases in the English-language literature; 7 of these were associated with significant fetal morbidity or mortality and 4 were associated with fetal trisomy 18. We report an additional case of UAA with normal karyotype that resulted in intrauterine growth restriction and fetal demise. It has been suggested that these aneurysms cause fetal hypoxia and intrauterine fetal death, either by compression of the umbilical vein or by acute kinking of the umbilical cord. Cytogenetic analysis should be performed in all cases diagnosed with this unusual lesion, and placental mosaicism for trisomy 18 should be excluded.
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http://dx.doi.org/10.2350/06-07-0136.1DOI Listing
September 2007

Co-occurrence of massive perivillous fibrin deposition and chronic intervillositis: case report.

Pediatr Dev Pathol 2006 May-Jun;9(3):234-8

Department of Pathology, Josephine Nefkens Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands, and Department of Histopathology, Guy's and St Thomas' Hospital NHS Trust, London, UK.

Chronic intervillositis (CI) and massive perivillous fibrin deposition (MFD), together with its related entity, maternal floor infarction (MFI), are rare and poorly understood placental lesions. Both MFD/MFI and CI are associated with poor fetal outcome and high risk of recurrence. We report a patient who was found to have both MFD and CI in the same placenta, resulting in severe intrauterine fetal growth restriction and intrauterine fetal death at 37 weeks of gestation. Characteristic histological findings included both very extensive perivillous deposition of fibrinoid material and a heavy infiltrate of CD68-positive macrophages/monocytes in the maternal intervillous space. To our knowledge, this is the first time the co-occurrence of MFD and CI is reported in the literature.
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http://dx.doi.org/10.2350/06-01-0019.1DOI Listing
October 2006

Portopulmonary hypertension in childhood presenting as sudden death.

Pediatr Dev Pathol 2006 Jan-Feb;9(1):65-71. Epub 2006 Apr 4.

Deapartment of Histopathology, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children, Great Ormond Street, London, UK WC1N 3JH.

We present the case of a 9-year-old boy with portal hypertension who died suddenly and unexpectedly due to pulmonary hypertensive crisis during a routine endoscopic procedure. He had known portal hypertension with esophageal varices but had no preceding clinical symptoms suggestive of significant pulmonary hypertensive disease despite postmortem histological evidence of advanced pulmonary vascular changes. Portopulmonary hypertension is a well-described and distinct clinical syndrome that is rare in childhood and is associated with a relatively poor prognosis. Occasional patients with histologically advanced disease may remain asymptomatic but present with pulmonary hypertensive crisis. Children with portopulmonary hypertension should be considered at high risk for surgical procedures, and pulmonary hypertensive complications should be excluded as a cause of death in all children dying suddenly in the setting of portal hypertension.
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http://dx.doi.org/10.2350/08-05-0093.1DOI Listing
July 2006
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