Gordan Vujanic | Cardiff University (original) (raw)
Papers by Gordan Vujanic
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 18, 2016
Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International... more Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95...
The American Journal of Surgical Pathology, Nov 1, 2007
We report 20 cases of a distinct, previously unrecognized renal neoplasm, anaplastic sarcoma of t... more We report 20 cases of a distinct, previously unrecognized renal neoplasm, anaplastic sarcoma of the kidney with polyphenotypic features. The tumors were identified by rereviewing tumors with unusual anaplastic features from the National Wilms Tumor Study Pathology Center, the Interna-
In the International Society of Paediatric Oncology renal tumour trials, preoperative chemotherap... more In the International Society of Paediatric Oncology renal tumour trials, preoperative chemotherapy has been successfully applied with resulting reduction of tumour rupture and increased favourable stage distribution of nephroblastoma. Postoperative treatment includes chemotherapy and sometimes radiotherapy in a riskadapted approach based on histological sub-classification and stage of the tumour. However, preoperative chemotherapy alters the tumour's histological features and distribution of subtypes, and makes staging more difficult. The paper highlights the most common practical diagnostic difficulties that a pathologist is faced with in dealing with pretreated nephroblastomas. It emphasises the importance of a systematic, step-by-step analysis based on adequately sampled material, in order to accurately sub-classify a nephroblastoma as a low, intermediate or high risk tumour and assign its genuine stage. Finally, it outlines the standard operating procedure for submission of renal tumours for rapid central pathology review which allows the treating oncologists to apply the optimal treatment protocol.
Fifty-eight human thyroid glands obtained at autopsy from fetuses with proven retrosternal thymus... more Fifty-eight human thyroid glands obtained at autopsy from fetuses with proven retrosternal thymus were systematically studied for the presence of intrathyroidal thymic tissue. The latter was found in one thyroid lobe in each of three fetuses (5.1%). It was located in a subcapsular position in two cases (3.4%) and lying deep in thyroid tissue in one (1.7%). Our findings would support a IV-V pharyngeal pouch origin for some accessory thymic tissue and would provide an explanation of the histogenesis of intrathyroid thymomas.
Plos One 8 Article E53417, Jan 7, 2013
The current SIOP treatment protocol for Wilms' tumor involves pre-operative chemotherapy followed... more The current SIOP treatment protocol for Wilms' tumor involves pre-operative chemotherapy followed by nephrectomy. Not all patients benefit equally from such chemotherapy. The aim of this study was to generate a miRNA profile of chemo resistant blastemal cells in high risk Wilms' tumors which might serve as predictive markers of therapeutic response at the pre-treatment biopsy stage. We have shown here that unsupervised hierarchical clustering of genome-wide miRNA expression profiles can clearly separate intermediate risk tumors from high risk tumors. A total of 29 miRNAs were significantly differentially expressed between post-treatment intermediate risk and high risk groups, including miRNAs that have been previously linked to chemo resistance in other cancer types. Furthermore, 7 of these 29 miRNAs were already at the pre-treatment biopsy stage differentially expressed between cases ultimately deemed intermediate risk compared to high risk. These miRNA alterations include down-regulation in high risk cases of miR-193a.5p, miR-27a and the up-regulation of miR-483.5p, miR-628.5p, miR-590.5p, miR-302a and miR-367. The demonstration of such miRNA markers at the pretreatment biopsy stage could permit stratification of patients to more tailored treatment regimens.
Fetal & Pediatric Pathology, 1991
A unilateral teratoid Wilms' tumor was removed 2.5 weeks after the institution of chemoth... more A unilateral teratoid Wilms' tumor was removed 2.5 weeks after the institution of chemotherapy. Teratoid Wilms' tumor is an extremely rare renal tumor, and only four cases, all bilateral, have been reported. Because of the finding of deep cortical intralobar nephroblastomatosis, strongly associated with bilateral Wilms' tumors, the patient has been closely followed since surgery without evidence of tumor in the remaining kidney at 2 years.
Forensic Science International, Jun 10, 1994
the variation with age of the nerve tibre content of the cardiac conduction system (CCS), using a... more the variation with age of the nerve tibre content of the cardiac conduction system (CCS), using an immunocytochemical approach, it became evident that in two sudden infant death syndrome (SIDS) cases there was a selective lack of SlOO positive nerve fibres in the atrioventricular (AV) node and His bundle. In the present study therefore, the examination of CCS with SlOO was extended to a further live SIDS cases and three cases of sudden explained death. Also, in addition to St00 -which selectively marks Schwann cells associated with both myehnated and non-myelinated nerves ~ PGP 9.5 (protein gene product) was used to reveal the presence of nerve axonal elements associated with the CCS. The results showed a uniform presence of SlOO and PGP 9.5 positive nerve fibres in the sinoatrial (SA) node. the AV node and His bundle tissue of all three control cases. In contrast, five out of seven SIDS cases showed a uniform lack of staining with these markers in the AV node and His bundle tissue, whilst in the two remaining cases it was present in greatly diminished amounts. Staining in the SA node, although present in all seven cases, was reduced when compared with the control cases. This is the first time the CCS of SIDS cases has been studied with immunocyto-* Corresponding author,
Pediatr Blood Cancer 56 744 748, May 1, 2011
Annals of Oncology
Background: Recent Wilms' tumor (WT) trials and studies have tried to determine the minimal thera... more Background: Recent Wilms' tumor (WT) trials and studies have tried to determine the minimal therapy needed for cure. The goal was survival without morbidity.
Genes, chromosomes & cancer, Jan 6, 2015
Clear cell sarcoma of the kidney (CCSK) although uncommon, is the second most frequent renal mali... more Clear cell sarcoma of the kidney (CCSK) although uncommon, is the second most frequent renal malignancy of childhood. Until now, the sole recurrent genetic aberration identified in CCSKs is t(10;17)(q22;p13), which gives rise to a fusion transcript of YWHAE and NUTM2B/E. So far, the clinical relevance of this fusion transcript is unknown. The aim of this descriptive study was to determine the clinical phenotype of t(10;17)(q22;p13) positive CCSKs. Snap-frozen tissues, formalin-fixed paraffin-embedded tissues or RNA previously extracted from CCSK samples throughout European, North-American and Japanese study groups were screened by RT-PCR for the YWHAE-NUTM2B/E transcript. Clinical characteristics, tumor characteristics, and outcome of patients with and without the fusion transcript were studied. The cohort comprised 51 previously published cases to which were added 139 internationally collected CCSK samples. RNA from 57 of these additionally collected cases was of sufficient quality...
Srpski arhiv za celokupno lekarstvo
Stridor is the major clinical sign of upper airways obstruction in children and is usually caused... more Stridor is the major clinical sign of upper airways obstruction in children and is usually caused by various inflammatory and structural lesions of the pharynx, larynx and subglottic trachea. Rarely, this obstruction can be produced by growth of a tumour. We present a three-month-old infant with upper airways obstruction caused by thyroid teratoma. Teratomas represent 3-5% of all tumours in childhood. The main sites of these tumours are the gonads, the sacrococcygeal region and the anterior mediastinum. The neck is one of the least common sites, accounting for only about 5% of all teratomas. As opposed to adults in whom prognosis depends primarily on histologic type of the tumour, the most important prognostic factors in children are the age of the patient, localization and histologic type of the tumour. In about 30% of cases neck teratomas are associated with polyhydramnios which can be easily detected by routine ultrasound examination in pregnancy. Surgery is the treatment of choice in young children and usually no further radio- or chemotherapy is needed. Clinical diagnosis, histologic features, prognosis, management, follow-up and prenatal detection of thyroid teratoma in children are discussed in the paper.
Lancet (London, England), Jan 8, 2015
Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms... more Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randoml...
Srpski arhiv za celokupno lekarstvo, 2008
There have been only few studies of immunoexpression of p53 in Wilms tumour (WT), and their resul... more There have been only few studies of immunoexpression of p53 in Wilms tumour (WT), and their results are somewhat contradictory. The aim of the study was to determine p53 immunohistochemical expression in WT in relation to its histological components, histological prognostic types classified according to the SIOP Working Classification of Renal Tumours of Childhood (2001), and influence of preoperative chemotherapy. The analyses are based on 79 primary WTs treated in single institution according to SIOP protocols between 1983-2001. For the immunohistochemical detection of p53, the monoclonal p53 antibody (DO-7, DAKO) was used. Semiquantitative grading of nuclear staining was done. The immunoexpression of p53 was significantly higher in the blastemal and epithelial than in the stromal component (p < 0.001). It was significantly correlated to WT histological prognostic types (p = 0.039).The exensivity of p53 immunoexpression was higher in anaplastic components but a difference betwe...
Srpski arhiv za celokupno lekarstvo, 2008
Renal tumours of childhood represent a fascinating group of tumours in which very significant dis... more Renal tumours of childhood represent a fascinating group of tumours in which very significant discoveries have been made in the last 100 years, leading to better understanding of these not only tumours but also tumour in general. By studying a large series of renal tumours of childhood collected through international multicentre trials, their clinico-pathological features have been better recognised resulting in more appropriate treatment and better prognosis, numerous new tumour entities have been identified, and thank to new molecular biology studies and techniques, many tumour genes and genetic abnormalities which are important in tumorigenesis have been found. The most common renal tumour of childhood is Wilms&amp;amp;amp;amp;amp;#39; tumour, which is now regarded as the most treatable tumour in children with overall survival of 90%. New multicentre trials are focused on reduction of treatment in order to avoid long-term sequalae of treatment, but without jeopardising these excellent survival results. Histopathological studies are searching for subtypes of Wilms&amp;amp;amp;amp;amp;#39; tumour, which could be treated with milder therapy, and in a recently launched trial patients will be stratified in different treatment groups on the basis of molecular features of their tumours. Molecular biology studies have helped us recognising that some renal tumours are identical to tumours of other sites (such as cellular mesoblastic nephroma and infantile fibrosarcoma of soft tissue, renal and extra-renal rhabdoid tumour), as well as that some tumours of other sites may also occur in the kidney (primitive neuroectodermal tumour, desmoplastic small round cell tumour, synovial sarcoma). Finally, some new, kidney-specific entities have been recognised too (metanephric stromal tumour, metanephric adenofibroma, anaplastic sarcoma of the kidney). It is very likely that new advances in molecular biology will result in identification of features, which are going to be even more important in predicting tumour behaviour, response to treatment and prognosis.
Medical and Pediatric Oncology, 1999
Background. Unlike the original definitions of focal (FA) and diffuse anaplasia (DA) in Wilms tum... more Background. Unlike the original definitions of focal (FA) and diffuse anaplasia (DA) in Wilms tumor (WT), recently redefined FA and DA proved to be of prognostic significance. The aim of the study was to analyze WT from the SIOP file, the majority of which were treated with preoperative chemotherapy, in order to investigate whether chemotherapy influenced the presence of anaplasia, whether the new definitions were applicable to these tumors, and whether they were of prognostic significance. Procedure. The unilateral anaplastic WT of children up to 16 years of age from the SIOP 6 and 9 nephroblastoma trials and studies were first classified according to the original definitions and analyzed. Then they were reclassified and analyzed according to the new definitions. Results. Anaplasia was diagnosed in 86 (5.5%) of 1,554 unilateral WT. The age at diagnosis ranged from 9 to 175 months (median, 63) and more than half of children were over 5 years of age. From 15% to 85% of the tumor mass showed chemotherapy-induced changes. Blastemal anaplasia was seen in 74, stromal in 23, and epithelial in 22 cases. According to the original definitions, FA was diagnosed in 55 (64%) and DA in 31 (36%) cases. In total, 48% children were alive and well, including 53% with FA and 39% with DA (P = 0.23). When reclassified, 39 old FA cases were moved to the new DA group, resulting in 70 (81%) DA and 16 (19%) FA cases. The female-to-male ratio for FA changed from 1.9:1 to 1:1 while remained unchanged for DA. The percentage of FA stage I cases increased from 31% to 44%, while it decreased from 25% to 6% for stage III. For other stages it remained virtually unchanged. The overall 4-year actual survival was 75% for FA and 41% for DA (P = 0.03). Conclusions. Preoperative chemotherapy did not obliterate or produce anaplasia. The new definitions were applicable to pretreated cases and they were of prognostic significance. Med. Pediatr. Oncol. 32:317-323, 1999.
Oncotarget, 2012
Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicat... more Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicated in Wilms tumor, the commonest childhood kidney cancer. In this study we analysed all five loci in 120 Wilms tumors. We identified epigenetic 11p15 abnormalities in 69% of tumors, 37% were H19 epimutations and 32% were paternal uniparental disomy (pUPD). We identified mutations of WTX in 32%, CTNNB1 in 15%, WT1 in 12% and TP53 in 5% of tumors. We identified several significant associations: between 11p15 and WTX (P=0.007), between WT1 and CTNNB1 (P less than 0.001), between WT1 and pUPD 11p15 (P=0.01), and a strong negative association between WT1 and H19 epimutation (P less than 0.001). We next used these data to stratify Wilms tumor into three molecular Groups, based on the status at 11p15 and WT1. Group 1 tumors (63%) were defined as 11p15-mutant and WT1-normal; a third also had WTX mutations. Group 2 tumors (13%) were WT1-mutant. They either had 11p15 pUPD or were 11p15-normal. Alm...
European Journal of Cancer, 2015
Rationale: The UKW3 trial compared biopsy/pre-operative chemotherapy versus immediate nephrectomy... more Rationale: The UKW3 trial compared biopsy/pre-operative chemotherapy versus immediate nephrectomy and afforded the opportunity to examine the influence of percutaneous retroperitoneal biopsy and other factors on local and distant relapse of Wilms tumour (WT). Methods: Patients with unilateral WT (stages I-IV) excluding metachronous relapse or early progressive disease were eligible. Metastatic and 'inoperable' tumours were biopsied electively. 'Local' was defined as relapse within the abdomen, except for liver metastases considered as 'distant' relapse, together with other haematogenous routes. Uni-and multivariable analyses estimated the risk factors for relapse. Results: Overall, 285/635 (44.9%) patients had a biopsy. With a median follow-up of 10.1 years, 35 (5.5%) patients experienced a 'local', 15 a combined (2.4%) and 60 (9.4%) a 'distant' relapse. On univariate analysis, biopsy, anaplasia and tumour size were associated with an increased risk of local relapse. On multivariable analysis, anaplasia and tumour size remained significant for local relapse whereas the elevated risk of biopsy (hazards ratio http://dx.
Current Diagnostic Pathology, 2002
This article outlines a number of cystic lesions that may either cause diagnostic problems or in ... more This article outlines a number of cystic lesions that may either cause diagnostic problems or in which there has been recent interest. The pathologist is usually faced with solitary cystic lesions following a radical or partial nephrectomy for a suspected tumour. Diagnosis can rarely be made preoperatively, however, some occur almost exclusively in infants and children while others are found
Plos One, 2013
The current SIOP treatment protocol for Wilms' tumor involves pre-operative chemotherapy followed... more The current SIOP treatment protocol for Wilms' tumor involves pre-operative chemotherapy followed by nephrectomy. Not all patients benefit equally from such chemotherapy. The aim of this study was to generate a miRNA profile of chemo resistant blastemal cells in high risk Wilms' tumors which might serve as predictive markers of therapeutic response at the pre-treatment biopsy stage. We have shown here that unsupervised hierarchical clustering of genome-wide miRNA expression profiles can clearly separate intermediate risk tumors from high risk tumors. A total of 29 miRNAs were significantly differentially expressed between post-treatment intermediate risk and high risk groups, including miRNAs that have been previously linked to chemo resistance in other cancer types. Furthermore, 7 of these 29 miRNAs were already at the pre-treatment biopsy stage differentially expressed between cases ultimately deemed intermediate risk compared to high risk. These miRNA alterations include down-regulation in high risk cases of miR-193a.5p, miR-27a and the up-regulation of miR-483.5p, miR-628.5p, miR-590.5p, miR-302a and miR-367. The demonstration of such miRNA markers at the pretreatment biopsy stage could permit stratification of patients to more tailored treatment regimens.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 18, 2016
Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International... more Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95...
The American Journal of Surgical Pathology, Nov 1, 2007
We report 20 cases of a distinct, previously unrecognized renal neoplasm, anaplastic sarcoma of t... more We report 20 cases of a distinct, previously unrecognized renal neoplasm, anaplastic sarcoma of the kidney with polyphenotypic features. The tumors were identified by rereviewing tumors with unusual anaplastic features from the National Wilms Tumor Study Pathology Center, the Interna-
In the International Society of Paediatric Oncology renal tumour trials, preoperative chemotherap... more In the International Society of Paediatric Oncology renal tumour trials, preoperative chemotherapy has been successfully applied with resulting reduction of tumour rupture and increased favourable stage distribution of nephroblastoma. Postoperative treatment includes chemotherapy and sometimes radiotherapy in a riskadapted approach based on histological sub-classification and stage of the tumour. However, preoperative chemotherapy alters the tumour's histological features and distribution of subtypes, and makes staging more difficult. The paper highlights the most common practical diagnostic difficulties that a pathologist is faced with in dealing with pretreated nephroblastomas. It emphasises the importance of a systematic, step-by-step analysis based on adequately sampled material, in order to accurately sub-classify a nephroblastoma as a low, intermediate or high risk tumour and assign its genuine stage. Finally, it outlines the standard operating procedure for submission of renal tumours for rapid central pathology review which allows the treating oncologists to apply the optimal treatment protocol.
Fifty-eight human thyroid glands obtained at autopsy from fetuses with proven retrosternal thymus... more Fifty-eight human thyroid glands obtained at autopsy from fetuses with proven retrosternal thymus were systematically studied for the presence of intrathyroidal thymic tissue. The latter was found in one thyroid lobe in each of three fetuses (5.1%). It was located in a subcapsular position in two cases (3.4%) and lying deep in thyroid tissue in one (1.7%). Our findings would support a IV-V pharyngeal pouch origin for some accessory thymic tissue and would provide an explanation of the histogenesis of intrathyroid thymomas.
Plos One 8 Article E53417, Jan 7, 2013
The current SIOP treatment protocol for Wilms' tumor involves pre-operative chemotherapy followed... more The current SIOP treatment protocol for Wilms' tumor involves pre-operative chemotherapy followed by nephrectomy. Not all patients benefit equally from such chemotherapy. The aim of this study was to generate a miRNA profile of chemo resistant blastemal cells in high risk Wilms' tumors which might serve as predictive markers of therapeutic response at the pre-treatment biopsy stage. We have shown here that unsupervised hierarchical clustering of genome-wide miRNA expression profiles can clearly separate intermediate risk tumors from high risk tumors. A total of 29 miRNAs were significantly differentially expressed between post-treatment intermediate risk and high risk groups, including miRNAs that have been previously linked to chemo resistance in other cancer types. Furthermore, 7 of these 29 miRNAs were already at the pre-treatment biopsy stage differentially expressed between cases ultimately deemed intermediate risk compared to high risk. These miRNA alterations include down-regulation in high risk cases of miR-193a.5p, miR-27a and the up-regulation of miR-483.5p, miR-628.5p, miR-590.5p, miR-302a and miR-367. The demonstration of such miRNA markers at the pretreatment biopsy stage could permit stratification of patients to more tailored treatment regimens.
Fetal & Pediatric Pathology, 1991
A unilateral teratoid Wilms' tumor was removed 2.5 weeks after the institution of chemoth... more A unilateral teratoid Wilms' tumor was removed 2.5 weeks after the institution of chemotherapy. Teratoid Wilms' tumor is an extremely rare renal tumor, and only four cases, all bilateral, have been reported. Because of the finding of deep cortical intralobar nephroblastomatosis, strongly associated with bilateral Wilms' tumors, the patient has been closely followed since surgery without evidence of tumor in the remaining kidney at 2 years.
Forensic Science International, Jun 10, 1994
the variation with age of the nerve tibre content of the cardiac conduction system (CCS), using a... more the variation with age of the nerve tibre content of the cardiac conduction system (CCS), using an immunocytochemical approach, it became evident that in two sudden infant death syndrome (SIDS) cases there was a selective lack of SlOO positive nerve fibres in the atrioventricular (AV) node and His bundle. In the present study therefore, the examination of CCS with SlOO was extended to a further live SIDS cases and three cases of sudden explained death. Also, in addition to St00 -which selectively marks Schwann cells associated with both myehnated and non-myelinated nerves ~ PGP 9.5 (protein gene product) was used to reveal the presence of nerve axonal elements associated with the CCS. The results showed a uniform presence of SlOO and PGP 9.5 positive nerve fibres in the sinoatrial (SA) node. the AV node and His bundle tissue of all three control cases. In contrast, five out of seven SIDS cases showed a uniform lack of staining with these markers in the AV node and His bundle tissue, whilst in the two remaining cases it was present in greatly diminished amounts. Staining in the SA node, although present in all seven cases, was reduced when compared with the control cases. This is the first time the CCS of SIDS cases has been studied with immunocyto-* Corresponding author,
Pediatr Blood Cancer 56 744 748, May 1, 2011
Annals of Oncology
Background: Recent Wilms' tumor (WT) trials and studies have tried to determine the minimal thera... more Background: Recent Wilms' tumor (WT) trials and studies have tried to determine the minimal therapy needed for cure. The goal was survival without morbidity.
Genes, chromosomes & cancer, Jan 6, 2015
Clear cell sarcoma of the kidney (CCSK) although uncommon, is the second most frequent renal mali... more Clear cell sarcoma of the kidney (CCSK) although uncommon, is the second most frequent renal malignancy of childhood. Until now, the sole recurrent genetic aberration identified in CCSKs is t(10;17)(q22;p13), which gives rise to a fusion transcript of YWHAE and NUTM2B/E. So far, the clinical relevance of this fusion transcript is unknown. The aim of this descriptive study was to determine the clinical phenotype of t(10;17)(q22;p13) positive CCSKs. Snap-frozen tissues, formalin-fixed paraffin-embedded tissues or RNA previously extracted from CCSK samples throughout European, North-American and Japanese study groups were screened by RT-PCR for the YWHAE-NUTM2B/E transcript. Clinical characteristics, tumor characteristics, and outcome of patients with and without the fusion transcript were studied. The cohort comprised 51 previously published cases to which were added 139 internationally collected CCSK samples. RNA from 57 of these additionally collected cases was of sufficient quality...
Srpski arhiv za celokupno lekarstvo
Stridor is the major clinical sign of upper airways obstruction in children and is usually caused... more Stridor is the major clinical sign of upper airways obstruction in children and is usually caused by various inflammatory and structural lesions of the pharynx, larynx and subglottic trachea. Rarely, this obstruction can be produced by growth of a tumour. We present a three-month-old infant with upper airways obstruction caused by thyroid teratoma. Teratomas represent 3-5% of all tumours in childhood. The main sites of these tumours are the gonads, the sacrococcygeal region and the anterior mediastinum. The neck is one of the least common sites, accounting for only about 5% of all teratomas. As opposed to adults in whom prognosis depends primarily on histologic type of the tumour, the most important prognostic factors in children are the age of the patient, localization and histologic type of the tumour. In about 30% of cases neck teratomas are associated with polyhydramnios which can be easily detected by routine ultrasound examination in pregnancy. Surgery is the treatment of choice in young children and usually no further radio- or chemotherapy is needed. Clinical diagnosis, histologic features, prognosis, management, follow-up and prenatal detection of thyroid teratoma in children are discussed in the paper.
Lancet (London, England), Jan 8, 2015
Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms... more Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randoml...
Srpski arhiv za celokupno lekarstvo, 2008
There have been only few studies of immunoexpression of p53 in Wilms tumour (WT), and their resul... more There have been only few studies of immunoexpression of p53 in Wilms tumour (WT), and their results are somewhat contradictory. The aim of the study was to determine p53 immunohistochemical expression in WT in relation to its histological components, histological prognostic types classified according to the SIOP Working Classification of Renal Tumours of Childhood (2001), and influence of preoperative chemotherapy. The analyses are based on 79 primary WTs treated in single institution according to SIOP protocols between 1983-2001. For the immunohistochemical detection of p53, the monoclonal p53 antibody (DO-7, DAKO) was used. Semiquantitative grading of nuclear staining was done. The immunoexpression of p53 was significantly higher in the blastemal and epithelial than in the stromal component (p < 0.001). It was significantly correlated to WT histological prognostic types (p = 0.039).The exensivity of p53 immunoexpression was higher in anaplastic components but a difference betwe...
Srpski arhiv za celokupno lekarstvo, 2008
Renal tumours of childhood represent a fascinating group of tumours in which very significant dis... more Renal tumours of childhood represent a fascinating group of tumours in which very significant discoveries have been made in the last 100 years, leading to better understanding of these not only tumours but also tumour in general. By studying a large series of renal tumours of childhood collected through international multicentre trials, their clinico-pathological features have been better recognised resulting in more appropriate treatment and better prognosis, numerous new tumour entities have been identified, and thank to new molecular biology studies and techniques, many tumour genes and genetic abnormalities which are important in tumorigenesis have been found. The most common renal tumour of childhood is Wilms&amp;amp;amp;amp;amp;#39; tumour, which is now regarded as the most treatable tumour in children with overall survival of 90%. New multicentre trials are focused on reduction of treatment in order to avoid long-term sequalae of treatment, but without jeopardising these excellent survival results. Histopathological studies are searching for subtypes of Wilms&amp;amp;amp;amp;amp;#39; tumour, which could be treated with milder therapy, and in a recently launched trial patients will be stratified in different treatment groups on the basis of molecular features of their tumours. Molecular biology studies have helped us recognising that some renal tumours are identical to tumours of other sites (such as cellular mesoblastic nephroma and infantile fibrosarcoma of soft tissue, renal and extra-renal rhabdoid tumour), as well as that some tumours of other sites may also occur in the kidney (primitive neuroectodermal tumour, desmoplastic small round cell tumour, synovial sarcoma). Finally, some new, kidney-specific entities have been recognised too (metanephric stromal tumour, metanephric adenofibroma, anaplastic sarcoma of the kidney). It is very likely that new advances in molecular biology will result in identification of features, which are going to be even more important in predicting tumour behaviour, response to treatment and prognosis.
Medical and Pediatric Oncology, 1999
Background. Unlike the original definitions of focal (FA) and diffuse anaplasia (DA) in Wilms tum... more Background. Unlike the original definitions of focal (FA) and diffuse anaplasia (DA) in Wilms tumor (WT), recently redefined FA and DA proved to be of prognostic significance. The aim of the study was to analyze WT from the SIOP file, the majority of which were treated with preoperative chemotherapy, in order to investigate whether chemotherapy influenced the presence of anaplasia, whether the new definitions were applicable to these tumors, and whether they were of prognostic significance. Procedure. The unilateral anaplastic WT of children up to 16 years of age from the SIOP 6 and 9 nephroblastoma trials and studies were first classified according to the original definitions and analyzed. Then they were reclassified and analyzed according to the new definitions. Results. Anaplasia was diagnosed in 86 (5.5%) of 1,554 unilateral WT. The age at diagnosis ranged from 9 to 175 months (median, 63) and more than half of children were over 5 years of age. From 15% to 85% of the tumor mass showed chemotherapy-induced changes. Blastemal anaplasia was seen in 74, stromal in 23, and epithelial in 22 cases. According to the original definitions, FA was diagnosed in 55 (64%) and DA in 31 (36%) cases. In total, 48% children were alive and well, including 53% with FA and 39% with DA (P = 0.23). When reclassified, 39 old FA cases were moved to the new DA group, resulting in 70 (81%) DA and 16 (19%) FA cases. The female-to-male ratio for FA changed from 1.9:1 to 1:1 while remained unchanged for DA. The percentage of FA stage I cases increased from 31% to 44%, while it decreased from 25% to 6% for stage III. For other stages it remained virtually unchanged. The overall 4-year actual survival was 75% for FA and 41% for DA (P = 0.03). Conclusions. Preoperative chemotherapy did not obliterate or produce anaplasia. The new definitions were applicable to pretreated cases and they were of prognostic significance. Med. Pediatr. Oncol. 32:317-323, 1999.
Oncotarget, 2012
Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicat... more Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicated in Wilms tumor, the commonest childhood kidney cancer. In this study we analysed all five loci in 120 Wilms tumors. We identified epigenetic 11p15 abnormalities in 69% of tumors, 37% were H19 epimutations and 32% were paternal uniparental disomy (pUPD). We identified mutations of WTX in 32%, CTNNB1 in 15%, WT1 in 12% and TP53 in 5% of tumors. We identified several significant associations: between 11p15 and WTX (P=0.007), between WT1 and CTNNB1 (P less than 0.001), between WT1 and pUPD 11p15 (P=0.01), and a strong negative association between WT1 and H19 epimutation (P less than 0.001). We next used these data to stratify Wilms tumor into three molecular Groups, based on the status at 11p15 and WT1. Group 1 tumors (63%) were defined as 11p15-mutant and WT1-normal; a third also had WTX mutations. Group 2 tumors (13%) were WT1-mutant. They either had 11p15 pUPD or were 11p15-normal. Alm...
European Journal of Cancer, 2015
Rationale: The UKW3 trial compared biopsy/pre-operative chemotherapy versus immediate nephrectomy... more Rationale: The UKW3 trial compared biopsy/pre-operative chemotherapy versus immediate nephrectomy and afforded the opportunity to examine the influence of percutaneous retroperitoneal biopsy and other factors on local and distant relapse of Wilms tumour (WT). Methods: Patients with unilateral WT (stages I-IV) excluding metachronous relapse or early progressive disease were eligible. Metastatic and 'inoperable' tumours were biopsied electively. 'Local' was defined as relapse within the abdomen, except for liver metastases considered as 'distant' relapse, together with other haematogenous routes. Uni-and multivariable analyses estimated the risk factors for relapse. Results: Overall, 285/635 (44.9%) patients had a biopsy. With a median follow-up of 10.1 years, 35 (5.5%) patients experienced a 'local', 15 a combined (2.4%) and 60 (9.4%) a 'distant' relapse. On univariate analysis, biopsy, anaplasia and tumour size were associated with an increased risk of local relapse. On multivariable analysis, anaplasia and tumour size remained significant for local relapse whereas the elevated risk of biopsy (hazards ratio http://dx.
Current Diagnostic Pathology, 2002
This article outlines a number of cystic lesions that may either cause diagnostic problems or in ... more This article outlines a number of cystic lesions that may either cause diagnostic problems or in which there has been recent interest. The pathologist is usually faced with solitary cystic lesions following a radical or partial nephrectomy for a suspected tumour. Diagnosis can rarely be made preoperatively, however, some occur almost exclusively in infants and children while others are found
Plos One, 2013
The current SIOP treatment protocol for Wilms' tumor involves pre-operative chemotherapy followed... more The current SIOP treatment protocol for Wilms' tumor involves pre-operative chemotherapy followed by nephrectomy. Not all patients benefit equally from such chemotherapy. The aim of this study was to generate a miRNA profile of chemo resistant blastemal cells in high risk Wilms' tumors which might serve as predictive markers of therapeutic response at the pre-treatment biopsy stage. We have shown here that unsupervised hierarchical clustering of genome-wide miRNA expression profiles can clearly separate intermediate risk tumors from high risk tumors. A total of 29 miRNAs were significantly differentially expressed between post-treatment intermediate risk and high risk groups, including miRNAs that have been previously linked to chemo resistance in other cancer types. Furthermore, 7 of these 29 miRNAs were already at the pre-treatment biopsy stage differentially expressed between cases ultimately deemed intermediate risk compared to high risk. These miRNA alterations include down-regulation in high risk cases of miR-193a.5p, miR-27a and the up-regulation of miR-483.5p, miR-628.5p, miR-590.5p, miR-302a and miR-367. The demonstration of such miRNA markers at the pretreatment biopsy stage could permit stratification of patients to more tailored treatment regimens.