Background
Blue rubber bleb nevus syndrome (BRBNS) is a rare multifocal venous malformation syndrome involving predominantly the skin and gastrointestinal tract. Traditional treatment modalities ...include corticosteroids, interferon‐α, sclerotherapy, and aggressive surgical resection. Sirolimus has been used in several single case reports.
Procedure
We performed a single‐institution retrospective review of four children with BRBNS, who received sirolimus as part of their treatment regimens. A diagnosis of BRBNS was based on clinical, radiologic, and pathologic criteria.
Results
Median age was 6.5 years (range: 2–16 years). Pathologic evaluations revealed a combined malformation with venous and lymphatic components. The novel finding of a lymphatic component was confirmed with PROX‐1 immunostaining. Patients received oral sirolimus with target drug levels between 10 and 13 ng/ml. Responses to treatment were defined as stabilization/decrease in size of lesions; resolution of transfusion requirements; reduction in pain, and improvement in quality of life (QOL). Median time to response was 1.5 months (SD ± 0.96 month, range: 1–3 months). Median follow‐up was 21 months (range: 18–26 months). Lesion size and characteristics improved in all patients. All patients reported decrease in pain and improvement in QOL. All three patients requiring transfusions became transfusion‐independent. One patient had resolution of coagulopathy. Adverse effects of sirolimus consisted of mucositis in three patients and neutropenia in one patient.
Conclusions
Sirolimus is safe and efficient for the treatment of BRBNS. Further prospective studies are needed to evaluate the long‐term effectiveness of this drug. This is the first report that identifies a lymphatic component as part of BRBNS.
Diffuse intrinsic pontine glioma (DIPG) and midline high-grade glioma (mHGG) are lethal childhood brain tumors. Spatial genomic heterogeneity has been well-described in adult HGG but has not been ...comprehensively characterized in pediatric HGG. We performed whole exome sequencing on 38-matched primary, contiguous, and metastatic tumor sites from eight children with DIPG (n = 7) or mHGG (n = 1) collected using a unique MRI-guided autopsy protocol. Validation was performed using Sanger sequencing, Droplet Digital polymerase-chain reaction, immunohistochemistry, and fluorescent in-situ hybridization.
Median age at diagnosis was 6.1 years (range: 2.9-23.3 years). Median overall survival was 13.2 months (range: 11.2-32.2 months). Contiguous tumor infiltration and distant metastases were observed in seven and six patients, respectively, including leptomeningeal dissemination in three DIPGs. Histopathological heterogeneity was evident in seven patients, including intra-pontine heterogeneity in two DIPGs, ranging from World Health Organization grade II to IV astrocytoma. We found conservation of heterozygous K27M mutations in H3F3A (n = 4) or HIST1H3B (n = 3) across all primary, contiguous, and metastatic tumor sites in all DIPGs. ACVR1 (n = 2), PIK3CA (n = 2), FGFR1 (n = 2), and MET (n = 1) were also intra-tumorally conserved. ACVR1 was co-mutated with HIST1H3B (n = 2). In contrast, PDGFRA amplification and mutation were spatially heterogeneous, as were mutations in BCOR (n = 1), ATRX (n = 2), and MYC (n = 1). TP53 aberrations (n = 3 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved.
Spatial conservation of prognostically-relevant and therapeutically-targetable somatic mutations in DIPG and mHGG contrasts the significant heterogeneity of driver mutations seen in adult HGG and supports uniform implementation of diagnostic biopsy in DIPG and mHGG to classify molecular risk groups and guide therapeutic strategy.
Medulloblastoma (MB) is a malignant, heterogenous brain tumor. Advances in molecular profiling have led to identifying four molecular subgroups of MB (WNT, SHH, Group 3, Group 4), each with distinct ...clinical behaviors. We hypothesize that (1) aggressive MB tumors, growing heterogeneously, induce pronounced local structural deformations in the surrounding parenchyma, and (b) these local deformations as captured on Gadolinium (Gd)-enhanced-T1w MRI are independently associated with molecular subgroups, as well as overall survival in MB patients.
In this work, a total of 88 MB studies from 2 institutions were analyzed. Following tumor delineation, Gd-T
scan for every patient was registered to a normal age-specific T
-MRI template via deformable registration. Following patient-atlas registration, local structural deformations in the brain parenchyma were obtained for every patient by computing statistics from deformation magnitudes obtained from every 5mm annular region, 0 < d < 60 mm, where d is the distance from the tumor infiltrating edge.
Multi-class comparison via ANOVA yielded significant differences between deformation magnitudes obtained for Group 3, Group 4, and SHH molecular subgroups, observed up to 60-mm outside the tumor edge. Additionally, Kaplan-Meier survival analysis showed that the local deformation statistics, combined with the current clinical risk-stratification approaches (molecular subgroup information and Chang's classification), could identify significant differences between high-risk and low-risk survival groups, achieving better performance results than using any of these approaches individually.
These preliminary findings suggest there exists significant association of our tumor-induced deformation descriptor with overall survival in MB, and that there could be an added value in using the proposed radiomic descriptor along with the current risk classification approaches, towards more reliable risk assessment in pediatric MB.
Background
Central nervous system tumors are now the most common primary neoplasms seen in children, and radiation therapy is a key component in management. Secondary malignant neoplasms (SMNs) are ...rare, but dreaded complications. Proton beam therapy (PBT) can potentially minimize the risk of SMNs compared to conventional photon radiation therapy (RT), and multiple recent studies with mature data have reported the risk of SMNs after PBT. We performed this systematic review and meta-analysis to characterize and compare the incidence of SMNs after proton and photon-based radiation for pediatric CNS tumors.
Methods
A systematic search of literature on electronic (PubMed, Cochrane Central, and Embase) databases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We included studies reporting the incidence and nature of SMNs in pediatric patients with primary CNS tumors. The crude incidence of SMNs and all secondary neoplasms were separately extracted, and the random-effects model was used for pooled analysis and subgroup comparison was performed between studies using photons vs. protons.
Results
Twenty-four studies were included for analysis. A total of 418 SMNs were seen in 38,163 patients. The most common SMN were gliomas (40.6%) followed by meningiomas (38.7%), sarcomas (4.8%), and thyroid cancers (4.2%). The median follow-up was 8.8 years 3.3–23.2.The median latency to SMN for photons and protons were 11.9 years 5-23 and 5.9 years 5-6.7, respectively. The pooled incidence of SMNs was 1.8% (95% CI: 1.1%–2.6%, I
2
= 94%) with photons and 1.5% (95% CI: 0%–4.5%, I
2
= 81%) with protons. The pooled incidence of all SNs was not different photons: 3.6% (95% CI: 2.5%–4.8%, I
2
= 96%) vs. protons: 1.5% (95% CI: 0–4.5%, I
2
= 80%); p = 0.21.
Conclusion
We observed similar rates of SMN with PBT at 1.5% compared to 1.8% with photon-based RT for pediatric CNS tumors. We observed a shorter latency to SMN with PBT compared to RT. With increasing use of pencil beam scanning PBT and VMAT, further studies are warranted to evaluate the risk of secondary cancers in patients treated with these newer modalities.
Introduction
177
Lu-DOTATATE, a radionuclide therapy that binds somatostatin type-2A receptors (SST2A), has demonstrated efficacy in neuroendocrine tumors and evidence of central nervous system (CNS) ...penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A.
Methods
SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by an experienced pathologist (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (<10%), 2 (10-50%), 3 (51-80%), or 4 (>80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (Range: 0-12).
Results
A total of 120 tumor samples from 114 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean ± SD: 7.5 ± 3.6 n=38) and meningioma (5.7 ± 3.4 n=15), compared to minimal or absent expression in ATRT (0.3 ± 0.6 n=3), ETMR (1.0 ± 0 n=3), ependymoma (grades I-III; 0.2 ± 0.7 n=27), and high-grade glioma (grades III-IV; 0.4 ± 0.7 n=23). Pineoblastoma (3.8 ± 1.5 n=4) and other embryonal tumors (2.0 ± 4.0 n=7) exhibited intermediate, variable expression. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.5 ± 3.1) than SHH (5.0 ± 3.3) molecular subgroups (p=0.033). In a subset of paired primary and recurrent specimens from four patients, SST2A IHC scores remained largely unchanged.
Discussion
High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as
177
Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors.
Rhabdoid tumors (RTs) of the brain (atypical teratoid/rhabdoid tumor; AT/RT) and extracranial sites (most often the kidney; RTK) are malignant tumors predominantly occurring in children, frequently ...those with
SMARCB1
germline alterations. Here we present data from seven RTs from three pediatric patients who all had multi-organ involvement. The tumors were analyzed using a multimodal molecular approach, which included exome sequencing of tumor and germline comparator and RNA sequencing and DNA array-based methylation profiling of tumors.
SMARCB1
germline alterations were identified in all patients and in all tumors. We observed a second hit in
SMARCB1 via
chr22 loss of heterozygosity. By methylation profiling, all tumors were classified as rhabdoid tumors with a corresponding subclassification within the MYC, TYR, or SHH AT/RT subgroups. Using RNA-seq gene expression clustering, we recapitulated the classification of known AT/RT subgroups. Synchronous brain and kidney tumors from the same patient showed different patterns of either copy number variants, single-nucleotide variants, and/or genome-wide DNA methylation, suggestive of non-clonal origin. Furthermore, we demonstrated that a lung and abdominal metastasis from two patients shared overlapping molecular features with the patient’s primary kidney tumor, indicating the likely origin of the metastasis. In addition to the
SMARCB1
events, we identified other whole-chromosome events and single-nucleotide variants in tumors, but none were found to be prognostic, diagnostic, or offer therapeutic potential for rhabdoid tumors. While our findings are of biological interest, there may also be clinical value in comprehensive molecular profiling in patients with multiple rhabdoid tumors, particularly given the potential prognostic and therapeutic implications for different rhabdoid tumor subgroups demonstrated in recent clinical trials and other large cohort studies.
Pediatric high-grade gliomas (pHGGs) are aggressive neoplasms representing approximately 20% of brain tumors in children. Current therapies offer limited disease control, and patients have a poor ...prognosis. Empiric use of targeted therapy, especially at progression, is increasingly practiced despite a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. To study the genetic landscape of pHGGs at recurrence, we performed whole exome and methylation analyses on matched primary and recurrent pHGGs from 16 patients. Tumor mutational profiles identified three distinct subgroups. Group 1 (n = 7) harbored known hotspot mutations in Histone 3 (H3) (K27M or G34V) or IDH1 (H3/IDH1 mutants) and co-occurring TP53 or ACVR1 mutations in tumor pairs across the disease course. Group 2 (n = 7), H3/IDH1 wildtype tumor pairs, harbored novel mutations in chromatin modifiers (ZMYND11, EP300 n = 2), all associated with TP53 alterations, or had BRAF V600E mutations (n = 2) conserved across tumor pairs. Group 3 included 2 tumors with NF1 germline mutations. Pairs from primary and relapsed pHGG samples clustered within the same DNA methylation subgroup. ATRX mutations were clonal and retained in H3G34V and H3/IDH1 wildtype tumors, while different genetic alterations in this gene were observed at diagnosis and recurrence in IDH1 mutant tumors. Mutations in putative drug targets (EGFR, ERBB2, PDGFRA, PI3K) were not always shared between primary and recurrence samples, indicating evolution during progression. Our findings indicate that specific key driver mutations in pHGGs are conserved at recurrence and are prime targets for therapeutic development and clinical trials (e.g. H3 post-translational modifications, IDH1, BRAF V600E). Other actionable mutations are acquired or lost, indicating that re-biopsy at recurrence will provide better guidance for effective targeted therapy of pHGGs.
Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known ...about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs' genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAF
mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031). Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.
Craniospinal irradiation (CSI) is part of the treatment of central nervous system (CNS) tumors and is associated with cardiovascular disease in adults. Global myocardial strain analysis including ...longitudinal peak systolic strain (GLS), circumferential peak systolic strain (GCS), and radial peak systolic strain (GRS) can reveal subclinical cardiac dysfunction.
Retrospective, single-center study in patients managed with CSI vs. age-matched controls. Clinical data and echocardiography, including myocardial strain analysis, were collected at early (< 12 months) and late (≥ 12 months) time points after completion of CSI.
Echocardiograms were available at 20 early and 34 late time points. Patients at the late time point were older (21.7 ± 10.4 vs. 13.3 ± 9.6 years) and further out from CSI (13.1 ± 8.8 vs. 0.2 ± 0.3 years). Standard echocardiographic parameters were normal for both groups. For early, CSI vs. control: GLS was - 16.8 ± 3.6% vs. -21.3 ± 4.0% (p = 0.0002), GCS was - 22.5 ± 5.2% vs. -21.3 ± 3.4% (p = 0.28), and GRS was 21.8 ± 11.0% vs. 26.9 ± 7.7% (p = 0.07). For late, CSI vs. control: GLS was - 16.2 ± 5.4% vs. -21.6 ± 3.7% (p < 0.0001), GCS was - 20.9 ± 6.8% vs. -21.9 ± 3.5% (p = 0.42), and GRS was 22.5 ± 10.0% vs. 27.3 ± 8.3% (p = 0.03). Radiation type (proton vs. photon), and radiation dose (< 30 Gy vs. ≥ 30 Gy) did not impact any parameter, although numbers were small.
Subclinical cardiac systolic dysfunction by GLS is present both early and late after CSI. These results argue for future studies to determine baseline cardiovascular status and the need for early initiation of longitudinal follow-up post CSI.
A possible case of levofloxacin-induced thrombocytopenia is reported.
A 73-year-old Caucasian woman with stage IV squamous cell cancer of the oral cavity arrived at the hospital with a 6-day history ...of epistaxis; petechiae over her arms, legs, and abdomen; and bruises over her forearms. Her comorbidities included hypertension, type 2 diabetes mellitus, and coronary artery disease. Two weeks before arrival at the hospital, the patient had been admitted to the hospital with community-acquired pneumonia (CAP) and given a 10-day course of levofloxacin 500 mg daily, which she completed 4 days before this admission. Her platelet count was 7,000 cells/mm(3) on admission. Her home medications included aspirin 325 mg daily, ranitidine 150 mg twice daily, alprazolam 0.25 mg daily, and methadone 10 mg twice daily. She last received cetuximab six weeks before this hospital admission. No other new medications were recently introduced. She had no known drug allergies and no recent heparin exposure. The patient was given a platelet transfusion and treated empirically with prednisone for possible immune thrombocytopenic purpura, though drug-induced thrombocytopenia (DIT) was also suspected. She was restarted on her home medications except for aspirin. She was discharged with a 7-day course of oral corticosteroids. At discharge, her platelet count was 38,000 cells/mm(3). Corticosteroids were discontinued when DIT was established to be the most likely diagnosis.
A 73-year-old woman with stage IV squamous cell cancer of the oral cavity developed a possible case of levofloxacin-induced thrombocytopenia after receiving the drug for 10 days for treatment of CAP.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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