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Ophthalmology Jun 2020To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation...
PURPOSE
To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma.
DESIGN
Cohort study.
PARTICIPANTS
Thirty-two children with retinoblastoma.
METHODS
We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing.
MAIN OUTCOME MEASURES
Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features.
RESULTS
Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease.
CONCLUSIONS
Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.
Topics: Child; Child, Preschool; Cohort Studies; DNA Mutational Analysis; DNA, Neoplasm; Eye Enucleation; Female; Gene Silencing; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Infant; Male; Paraffin Embedding; Retinal Neoplasms; Retinoblastoma; Retinoblastoma Binding Proteins; Tissue Fixation; Ubiquitin-Protein Ligases
PubMed: 32139107
DOI: 10.1016/j.ophtha.2019.12.005 -
European Journal of Cancer (Oxford,... Mar 2020High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome. (Clinical Trial)
Clinical Trial
INTRODUCTION
High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome.
METHODS
Here, we report the results of HR (diffuse anaplastic [DA] or blastemal type [BT]) stage IV WT treated patients according to the HR arm in the SIOP2001 prospective study.
RESULTS
From January 2002 to August 2014, 3559 patients with WT were included in the SIOP2001 trial. Among the 525 patients (15%) with metastatic WT, 74 (14%) had stage IV HR-WT. The median age at diagnosis was 5.5 years (range: 1.4-18.3). Thirty-four patients (47%) had BT-WT and 40 (53%) had DA-WT. Five-year event-free survival rates were 44 ± 17% and 28 ± 15% for BT-WT and DA-WT, respectively (p = 0.09). Five-year overall survival rates were 53 ± 17% and 29 ± 16% for BT-WT and DA-WT, respectively (p = 0.03). Metastatic complete response after preoperative treatment was significantly associated with outcome in univariate and multivariate analyses (hazards ratio = 0.3; p = 0.01). Postoperative radiotherapy of metastatic sites might also be beneficial. Forty-three of 74 patients experienced a relapse or progression predominantly in the lungs (80%). The median time to relapse/progression after diagnosis was 7.3 months (range: 1.6-33.3) and 4.9 months (range: 0.7-28.4) for BT-WT and DA-WT, respectively (p = 0.67). This is the first prospective evidence of inferior survival of stage IV BT-WT as compared with historical intermediate-risk WT. Survival of patients with stage IV DA-WT has not improved compared to the previous SIOP93-01 study.
CONCLUSION
These results call for new treatment approaches for patients with HR stage IV WT.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dactinomycin; Disease Progression; Disease-Free Survival; Female; Humans; Infant; Kidney Neoplasms; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Prospective Studies; Survival Rate; Time Factors; Vincristine; Wilms Tumor
PubMed: 32109849
DOI: 10.1016/j.ejca.2020.01.001 -
Modern Pathology : An Official Journal... Jul 2020We describe a morphologically distinct pattern of tumor infarction and associated sarcoma-like changes, mimicking focal anaplasia, in otherwise WHO grade I meningiomas....
We describe a morphologically distinct pattern of tumor infarction and associated sarcoma-like changes, mimicking focal anaplasia, in otherwise WHO grade I meningiomas. The described cases (n = 9) all demonstrated a discrete spindle-cell (pseudosarcomatous) component with brisk mitotic activity (12-14 mitoses/10 HPF), elevated Ki-67 (mean 75.5 ± 25.0%, quantified), absence of PR, SSTR2A, or EMA expression, and potential SMA expression (50%). Despite these high-grade features, all nine patients remained free of progression or recurrence post resection (follow-up mean: 49.8 months). In contrast, among a comparison (control) cohort of consecutive WHO grade II and III meningiomas (n = 16), as expected, progression rate was high (68.8%, P = 0.002, Fisher's exact, average time to progression = 25 months, follow-up mean: 39.8 months). While necrosis was a frequent feature among atypical/anaplastic meningiomas (12/16, 75%), and elevated mitoses and proliferative index were present consistent with histologic grade, a well-defined zonal pattern with pseudosarcomatous component was not present among these tumors. DNA methylation-based analysis readily distinguished meningiomas by copy number profiles and DNA-based methylation meningioma random forest classification analysis (meningioma v2.4 classifier developed at University of Heidelberg); all pseudosarcomatous cases analyzed (4/9) matched with high level calibrated classifier score to "MC benign-1", with isolated loss of chromosome 22q identified as the sole copy number alteration. In contrast, multiple chromosomal losses were detected among the comparison cohort and classifier results demonstrated good concordance with histologic grade. Our findings suggest that pseudosarcomatous alterations represent reactive changes to central meningioma infarction, rather than focal anaplasia, and further support the use of DNA methylation-based analysis as a useful adjunct for predicting meningioma behavior. These indolent tumors should be distinguished from their atypical and anaplastic counterparts.
Topics: Aged; Anaplasia; Biomarkers, Tumor; DNA Methylation; Female; Humans; Infarction; Male; Meningeal Neoplasms; Meningioma; Middle Aged
PubMed: 32047229
DOI: 10.1038/s41379-020-0491-6 -
Intractable & Rare Diseases Research Nov 2019Glioneuronal tumors are usually low-grade and have favorable prognosis. The anaplastic glioneuronal tumor with fusion has not yet been documented. This article reports...
Glioneuronal tumors are usually low-grade and have favorable prognosis. The anaplastic glioneuronal tumor with fusion has not yet been documented. This article reports a case of glioneuronal tumor with anaplasia and fusion to illuminate the importance of fusion in high-grade glioneuronal tumors. A ten-year-old boy presented with one year of headache and three months of blurry vision and proptosis. Ophthalmologic evaluation revealed bilateral papilledema. Magnetic resonance imaging showed a large mixed cystic and solid mass in the left frontal lobe of cerebrum. Histologic analysis demonstrated a neoplasm with pseudopapillary growth pattern, focal necrosis, microcalcification, and brisk mitotic activity with a high Ki67 labeling index of focally up to 20%. Immunohistochemical assessment identified a mixed glial and neuronal neoplastic cell population. Molecular studies revealed a fusion. The histological and molecular changes are consistent with an anaplastic glioneuronal tumor with fusion. In view of the fact that the effective, targeted therapies for the tumors with fusion are available, detection of fusion for high-grade glioneuronal tumors is clinically helpful.
PubMed: 31890457
DOI: 10.5582/irdr.2019.01118 -
Acta Neuropathologica Feb 2020Pilocytic astrocytoma (PA) is the most common pediatric glioma, arising from a single driver MAPK pathway alteration. Classified as a grade I tumor according to the 2016...
Pilocytic astrocytoma (PA) is the most common pediatric glioma, arising from a single driver MAPK pathway alteration. Classified as a grade I tumor according to the 2016 WHO classification, prognosis is excellent with a 10-year survival rate > 95% after surgery. However, rare cases present with anaplastic features, including an unexpected high mitotic/proliferative index, thus posing a diagnostic and therapeutic challenge. Based on small histomolecular series and case reports, such tumors arising at the time of diagnosis or recurrence have been designated by many names including pilocytic astrocytoma with anaplastic features (PAAF). Recent DNA methylation-profiling studies performed mainly on adult cases have revealed that PAAF exhibit a specific methylation signature, thus constituting a distinct methylation class from typical PA [methylation class anaplastic astrocytoma with piloid features-(MC-AAP)]. However, the diagnostic and prognostic significance of MC-AAP remains to be determined in children. We performed an integrative work on the largest pediatric cohort of PAAF, defined according to strict criteria: morphology compatible with the diagnosis of PA, with or without necrosis, ≥ 4 mitoses for 2.3 mm, and MAPK pathway alteration. We subjected 31 tumors to clinical, imaging, morphological and molecular analyses, including DNA methylation profiling. We identified only one tumor belonging to the MC-AAP (3%), the others exhibiting a methylation profile typical for PA (77%), IDH-wild-type glioblastoma (7%), and diffuse leptomeningeal glioneuronal tumor (3%), while three cases (10%) did not match to a known DNA methylation class. No significant outcome differences were observed between PAAF with necrosis versus no necrosis (p = 0.07), or with 4-6 mitoses versus 7 or more mitoses (p = 0.857). Our findings argue that the diagnostic histomolecular criteria established for anaplasia in adult PA are not of diagnostic or prognostic value in a pediatric setting. Further extensive and comprehensive integrative studies are necessary to accurately define this exceptional entity in children.
Topics: Adolescent; Age Factors; Astrocytoma; Brain Neoplasms; Child; Child, Preschool; DNA Methylation; Female; Humans; Infant; Infant, Newborn; Male; Progression-Free Survival; Retrospective Studies; Survival Rate
PubMed: 31677015
DOI: 10.1007/s00401-019-02088-8 -
Pediatric Blood & Cancer Feb 2020As a significant proportion of relapses occurred in the tumor bed or abdomen on patients with the fifth National Wilms Tumor Study stage I anaplastic Wilms tumor (WT),... (Observational Study)
Observational Study
BACKGROUND
As a significant proportion of relapses occurred in the tumor bed or abdomen on patients with the fifth National Wilms Tumor Study stage I anaplastic Wilms tumor (WT), flank radiotherapy was added for stage I anaplastic WT in the subsequent study of the Children's Oncology Group (AREN0321). Preliminary results revealed reduction of relapse rate and improved survival. In cases treated with preoperative chemotherapy, such as in International Society of Pediatric Oncology (SIOP), the value of radiotherapy has never been studied. The aim of this observational study is to describe the pattern of recurrence and survival of patients with stage I diffuse anaplastic WT (DAWT) after induction chemotherapy.
METHODS
Retrospective data analysis of the pattern of relapse and survival of all patients with stage I DAWT were included in recent SIOP, L'Associazone Italiana Ematologica Oncologia Pediatrica (AIEOP), Japan Wilms Tumor Study Group (JWiTS), United Kingdom Children's Cancer Study Group (UKCCSG) renal tumor registries. Postoperative treatment consisted of actinomycin D, vincristine, and doxorubicin for 28 weeks without local irradiation.
RESULTS
One hundred nine cases with stage I DAWT were identified, of which 95 cases received preoperative chemotherapy. Of these, seven patients underwent preoperative true-cut biopsy. Sixteen of the 95 patients relapsed (17%), six locally, four at distant site, and six combined, and all treated according to SIOP 2001 relapse protocol, which resulted in a 5-year overall survival of 93%.
CONCLUSION
Despite 13% locoregional relapse rate, an excellent rescue rate was achieved after salvage treatment, in patients with stage I DAWT whose first-line treatment comprised three-drug chemotherapy (including doxorubicin), without flank irradiation. Therefore, we continue not to advocate the use of radiotherapy in first-line treatment after preoperative chemotherapy in stage I DAWT in the next SIOP protocol.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Dactinomycin; Doxorubicin; Female; Follow-Up Studies; Humans; Infant; Kidney Neoplasms; Male; Prognosis; Prospective Studies; Radiotherapy; Retrospective Studies; Survival Rate; Vincristine; Wilms Tumor
PubMed: 31625685
DOI: 10.1002/pbc.28039 -
The Turkish Journal of Pediatrics 2019Aydın B, Akyüz C, Yalçın B, Ekinci S, Oğuz B, Akçören Z, Yıldız F, Varan A, Kurucu N, Büyükpamukçu M, Kutluk T. Bilateral Wilms tumors: Treatment results...
Aydın B, Akyüz C, Yalçın B, Ekinci S, Oğuz B, Akçören Z, Yıldız F, Varan A, Kurucu N, Büyükpamukçu M, Kutluk T. Bilateral Wilms tumors: Treatment results from a single center. Turk J Pediatr 2019; 61: 44-51. The management of bilateral Wilms tumor (BWT) is challenging, particularly due to its presentation at a younger age, rarity, and difficulty for treatment decisions and surgical evaluation comparing to unilateral WT. In this study, the outcome of BWT patients from a single center who were treated by the Turkish Pediatric Oncology Group (TPOG) Wilms Tumor Regimen were retrospectively reviewed. From 1990 to 2016, 30 patients with synchronous BWT were treated with a preoperative chemotherapy of vincristine and actinomycin-D (VA). Chemotherapy was continued until safe nephron sparing surgery (NSS) could be performed for as long as radiological tumor response continued; otherwise, the chemotherapy was intensified by adding doxorubicin (D) alternating with VA every 6 weeks. The median followup of patients was 59 months (4-297 months). The median duration of preoperative chemotherapy was 81 days and ranged between 14 days and 198 days. Preoperative chemotherapy was modified in seven patients (23%) to the VAD regimen. Twenty-two patients (73%) had a radical nephrectomy on the larger tumor and NSS on the contralateral kidney, and 6 patients (20%) had bilateral NSS. Postoperative tumor stages for stage I, II and III were 60%, 22% and 14%, respectively. The 5-year event free survival (EFS) rates were 100%, 90% and 51% for stages I, II and III (p=0.02), respectively. Unfavorable histology and nephrogenic rests were reported in 20% and 20% of patients, respectively. The 5-year overall survival (OS) and EFS rates were 50% and 25%, respectively, in patients with anaplasia, while the same rates were 96% and 96% in patients with favorable histology tumors (p=0.05 and p < 0.001). The 10-year EFS and OS rates for all patients were 82% and 86%, respectively. Our results are comparable with the literature. VA is effective as initial preoperative treatment of BWT and allows for safe resection.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Child; Child, Preschool; Dactinomycin; Doxorubicin; Female; Follow-Up Studies; Humans; Infant; Kidney Neoplasms; Male; Neoadjuvant Therapy; Neoplasm Staging; Nephrectomy; Retrospective Studies; Survival Analysis; Treatment Outcome; Turkey; Vincristine; Wilms Tumor
PubMed: 31559721
DOI: 10.24953/turkjped.2019.01.008 -
Head and Neck Pathology Sep 2020Human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCC) tend to have good outcomes, however a subset does not share this favourable...
Human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCC) tend to have good outcomes, however a subset does not share this favourable prognosis. The aim of this paper is to investigate the utility of tumour cell anaplasia and multinucleation as prognostic markers in oropharyngeal squamous cell carcinoma. Retrospective review of 104 patients with OPSCC or squamous cell carcinoma of unknown primary site (SCCUP) who underwent primary resection and/or lymph node dissection. Slides of both primary and nodal metastatic disease were assessed for the presence of anaplasia and multinucleation. 53 patients were HPV-positive. Anaplasia was more frequent in males (p = 0.005), smokers (p = 0.003), and HPV-negative disease (p = 0.04). HPV status and > 10 pack-year smoking history were independent predictors of recurrence-free survival (RFS) and disease-specific survival (DSS). Neither anaplasia, nor multinucleation, at the primary site or in cervical metastases, had any significant impact on RFS or DSS. We did not find either anaplasia or multinucleation to have any significant prognostic impact in OPSCC. However, given the small number of adverse events in the HPV-positive cohort, we may have lacked sufficient power to detect significance in what was the subgroup of primary interest. Our study highlights the challenge of identifying markers of poor prognosis in HPV-positive OPSCC.
Topics: Female; Humans; Male; Mouth Neoplasms; Neoplasm Grading; Papillomavirus Infections; Pharyngeal Neoplasms; Prognosis; Retrospective Studies; Squamous Cell Carcinoma of Head and Neck
PubMed: 31552619
DOI: 10.1007/s12105-019-01081-7 -
Modern Pathology : An Official Journal... Jan 2020DICER1 syndrome is a hereditary cancer predisposition syndrome caused by deleterious germline DICER1 mutations. Characteristic "hotspot" somatic mutations of DICER1 have...
DICER1 syndrome is a hereditary cancer predisposition syndrome caused by deleterious germline DICER1 mutations. Characteristic "hotspot" somatic mutations of DICER1 have been identified in DICER1-associated tumors. With the exception of genitourinary embryonal rhabdomyosarcoma and anaplastic sarcoma of the kidney, sarcomas are rarely reported in DICER1 syndrome. Herein, we report the clinical, histopathologic, and molecular findings of a germline DICER1-associated ovarian sarcoma in a 5-year-old female, a somatic DICER1-associated metastatic peritoneal sarcoma in a 16-year-old female, and a somatic DICER1-associated primary intracranial sarcoma in a 4-year-old male. A comprehensive review of the literature, including 83 DICER1-associated sarcomas, illustrates an unequivocal histologic pattern mimicking pleuropulmonary blastoma, regardless of the site of origin. The features include undifferentiated small round blue cells, poorly differentiated spindle cells, and large bizarre pleomorphic cells (anaplasia), often with rhabdomyoblastic and/or chondroid differentiation, and rare bone/osteoid formation. This unique heterogeneous histologic pattern should raise suspicion for pathogenic DICER1 mutation(s) warranting a detailed review of the family history and DICER1 mutation analysis. In addition to expanding the phenotypic spectrum of DICER1-associated conditions, identification of pathogenic DICER1 variants facilitates optimized genetic counseling, caregiver education and judicious imaging-based surveillance.
Topics: Adolescent; Brain Neoplasms; Child, Preschool; DEAD-box RNA Helicases; Female; Genetic Predisposition to Disease; Humans; Male; Mutation; Ovarian Neoplasms; Peritoneal Neoplasms; Ribonuclease III; Sarcoma
PubMed: 31537896
DOI: 10.1038/s41379-019-0366-x -
Therapeutic Advances in Medical Oncology 2019The logic behind the outcome of endocrine therapy in breast cancer has long remained poorly understood. The prognostic role of DNA damage and repair biomarkers (DDR) was...
Prognostic relevance of DNA damage and repair biomarkers in elderly patients with hormone-receptor-positive breast cancer treated with neoadjuvant hormone therapy: evidence from the real-world setting.
BACKGROUND
The logic behind the outcome of endocrine therapy in breast cancer has long remained poorly understood. The prognostic role of DNA damage and repair biomarkers (DDR) was explored in postmenopausal, hormone-receptor-positive breast cancer patients treated with neoadjuvant hormone therapy (NAHT).
METHODS
Data on 55 patients were included. The phosphorylated ataxia-teleangectasia and Rad3-related protein (pATR), phosphorylated ataxia-telangiectasia mutated (ATM) kinase, and phosphorylated H2A Histone Family Member X (γ-H2AX) were evaluated by immunohistochemistry in paired tissues collected at baseline and following NAHT. Biomarkers were considered both singularly and within signatures. Ki-67 percentage change was the primary biomarker endpoint. Classical endpoints were also considered.
RESULTS
The most favorable Ki-67 outcome was associated with the γ-H2AX/pATM signature ( = 0.011). In models of Ki-67 reduction, 'luminal B' subtype, higher grade of anaplasia, and the γ-H2AX/pATM signature tested as significant ( < 0.05 for all). Results were confirmed in multivariate analysis. No association was observed with pathologic response. An increase of ∆γ-H2AX in paired breast tissues was associated with longer event-free survival ( = 0.027) and overall survival ( = 0.042). In Cox models, both survival outcomes were solely affected by grade of anaplasia, with less favorable prognosis in the highest grades ( < 0.05 for both).
CONCLUSIONS
We report novel evidence of the prognostic role of DDR biomarkers on important patient outcomes in postmenopausal hormone-receptor-positive breast cancer patients treated with NAHT. If confirmed in future and adequately sized trials, our results may help inform therapeutic decisions and clarify underlying biological mechanisms.
PubMed: 31452691
DOI: 10.1177/1758835919853192