A 38-year-old man had undergone allogeneic bone marrow transplantation for multiple myeloma, and his clinical course was complicated by chronic graft-vs-host disease, pulmonary aspergillosis, and bronchiolitis obliterans with organizing pneumonia (BOOP), which was treated with high-dose steroids. Approximately 1 year after transplantation, he was admitted with cough productive of blood-tinged sputum, dyspnea, orthostatic hypotension, fever, and leukocytosis. While undergoing placement of a subcutaneous intravenous port, he experienced profound oxygen desaturation requiring mechanical ventilation. Chest radiographs showed prominent infiltrates in bilateral lung fields (Figure 1). A fiberoptic bronchoscopy performed shortly before death obtained bronchoalveolar lavage (BAL) fluid, which was sent for microbiologic analysis. At autopsy, there were bilateral pleural effusions, and both lungs were congested with numerous areas of consolidation (Figure 2). There was microscopic evidence of acute lung injury with numerous hyaline membranes, hemosiderin-laden macrophages, and desquamated reactive pneumocytes (Figure 3). Also noted were several discrete areas of honeycomb-like fibrosis centered on obliterated small airways (consistent with previous BOOP) as well as patchy interstitial lymphocytic infiltrates and focal sloughing of bronchial epithelium. An example of one of the rare intra-alveolar multinucleated giant cells is presented (Figure 4).What is your diagnosis?Rare multinucleated giant cells with eosinophilic cytoplasmic inclusions surrounded by clear halos, characteristic of respiratory syncytial virus cytopathic effect, were seen on routine histologic sections. The presence of the virus was initially documented by a rapid enzyme immunoassay performed on BAL fluid, with subsequent confirmation by both viral culture and direct immunofluorescence stains. All other microbiology studies, including stains and cultures for bacteria, fungus, acid-fast organisms, Pneumocystis organisms, and viruses, were negative.Respiratory syncytial virus (RSV), a paramyxovirus, is a common cause of community-acquired respiratory illness in infants and children. Epidemics tend to occur in the winter months, with clinical manifestations of infection ranging from a mild self-limited illness to bronchiolitis, pneumonia, otitis media, and rarely meningitis, myelitis, and myocarditis.1 The virus targets both pulmonary epithelial cells and alveolar macrophages, with infection typically resulting in epithelial hyperplasia and desquamation, leading to accumulation of abundant cellular debris within the alveoli and small airways.1,2 Syncytial giant cells may be found within and lining alveolar spaces, bronchioles, or bronchi.1Although mortality is generally low in patients with intact immune systems, RSV-associated deaths are being documented with increasing frequency in high risk-individuals, including those with congenital or acquired immunodeficiency syndromes, and recipients of solid organ and bone marrow transplants.3 This latter group appears to be particularly susceptible, with one prospective study documenting isolation of RSV from 50% of bone marrow transplant (BMT) recipients with acute respiratory illness hospitalized between the winter months of November and May.4 The clinical progression of illness in BMT patients infected with RSV is similar to that seen in non immunocompromised persons, with involvement of the upper respiratory tract and sinuses preceding lower respiratory tract infection and acute lung injury.5 In general, preengraftment patients tend to develop pneumonia more frequently than engrafted patients.6 Overall, however, up to 50% of BMT patients succumb to RSV pneumonia within 1 year of transplant.1The treatment of RSV infection in the immunocompromised population remains difficult. In adult BMT recipients, RSV pneumonia treated with aerosolized ribavirin alone has been associated with a 70% mortality rate.7 Therapy with ribavirin and intravenous immunoglobulin7 combined with RSV-immune globulin8 have resulted in more favorable outcomes, and alternate routes of administering ribavirin (oral and intravenous) have been well tolerated.9 In all of these studies, early diagnosis and institution of therapy were stressed, and although still considered the “gold standard” for the detection of RSV, culture is not particularly useful for prompt diagnosis because of the prolonged time required for the production of the diagnostic cytopathic effect. Several groups have therefore turned to the rapid antigen detection method, widely used for diagnosis of infection in the pediatric population.5,10 A recent prospective study evaluated the efficacy of this modality for the documentation of RSV infections in immunocompromised adults and found sensitivities of 15%, 71.4%, and 88.9% for nasal wash–throat swab, endotracheal tube aspirate, and BAL specimens, respectively, with an overall specificity of 97%.10 The insensitivity in upper respiratory tract samples might be attributed to decreased viral load in these sites.10In conclusion, RSV is a major cause of morbidity and mortality in BMT recipients. As in the patient presented, acute lung injury induced by RSV can be rapidly fatal. Diagnostic work-up can be quite challenging given the high rate of concomitant pathologies present in these patients, including graft-vs-host disease and a wide array of opportunistic infections. With primary viral culture requiring several days to yield a positive result, rapid antigen detection methods are becoming the mainstay of early detection. Improved survival in patients with this potentially treatable cause of life-threatening lung injury can be afforded by a heightened clinical awareness, early detection, and institution of one or more of the various therapeutic modalities outlined above.
Craniopharyngiomas represent a rare group of intracranial tumors that often arise in the sellar/suprasellar region of the brain. Adamantinomatous craniopharyngioma is significantly more common than papillary craniopharyngioma. The former most often arises in children whereas the papillary craniopharyngioma is mainly limited to adults. We present the case of a 34-year-old female with visual disturbances and other vague complaints who was found to have a large lobulated sellar mass on neuroimaging studies. She was subsequently diagnosed with an adamantinomatous craniopharyngioma after undergoing transsphenoidal resection. We discuss the patient’s clinical, radiological, and pathological findings in correlation with the current literature and recommendations regarding this type of tumor. Given that adamantinomatous craniopharyngioma rarely presents in adulthood, especially in middle-aged adults, this case is considered rare, and we hope to increase awareness to include adamantinomatous craniopharyngioma in the differential diagnosis for sellar lesions in this age group.
Abstract Purpose Rasmussen encephalitis (RE) is a very rare chronic neurological disorder of unilateral inflammation of the cerebral cortex. Hemispherotomy provides the best chance at achieving seizure freedom in RE patients, but with significant risks and variable long-term outcomes. The goal of this study is to utilize our multicenter pediatric cohort to characterize if differences in pathology and/or imaging characterization of RE may provide a window into postoperative seizure outcomes, which in turn could guide decision making for parents and healthcare providers. Methods This multi-institutional retrospective review of medical record, imaging, and pathology samples was approved by each individual institution’s review board. Data was collected from all known pediatric cases of periinsular functional hemispherotomy from the earliest available electronic medical records. Mean follow up time was 4.9 years. Clinical outcomes were measured by last follow up visit using both Engel and ILAE scoring systems. Relationships between categorical and continuous variables were analyzed with Pearson correlation values. Results 27 patients met study criteria. No statistically significant correlations existed between patient imaging and pathology data. Pathology stage, MRI brain imaging stages, and a combined assessment of pathology and imaging stages showed no statistically significant correlation to post-operative seizure freedom rates. Hemispherectomy Outcome Prediction Scale scoring demonstrated seizure freedom in only 71% of patients receiving a score of 1 and 36% of patients receiving a score of 2 which were substantially lower than predicted. Conclusions Our analysis did not find evidence for either independent or combined analysis of imaging and pathology staging being predictive for post peri-insular hemispherotomy seizure outcomes, prompting the need for other biomarkers to be explored. Our data stands in contrast to the recently proposed Hemispherectomy Outcome Prediction Scale and does not externally validate this metric for an RE cohort.
Infantile myofibromatosis is the most common fibrous disorder of infancy and early childhood. Intracranial involvement is rare, with the majority of lesions being localized to the skull or dura with variable intracranial extension. We present the case of a 19-month-old girl with infantile myofibromatosis and an incidentally discovered, enlarging, calcified, posterior fossa mass. The patient underwent suboccipital craniotomy and resection of the lesion. This is the first report of the surgical removal of an intraparenchymal infantile myofibroma.
Low-grade gliomas represent the most frequent primary brain tumors in children, and are also an important category of brain neoplasms in young adults. They are characterized by slow growth, but often associated with increased morbidity, as well as mortality in the subset that develop histologic progression. Pathologically they correspond to WHO grade I or II and include pilocytic astrocytoma (PA), pilomyxoid astrocytoma variant, angiocentric glioma, diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, and pleomorphic xanthoastrocytoma (PXA). Although all low-grade glioma subtypes may develop in children and adults, and be histologically indistinguishable in these two populations, there are important clinical and molecular differences. As a rule, low-grade gliomas in adults have a greater tendency for histologic progression and more aggressive clinical behavior than those in children. With respect to genetic alterations, activating BRAF alterations and increased MAPK pathway signaling are near universal features of the circumscribed low-grade glioma group (e.g., PA and PXA). Whole exome/genome sequencing efforts and high resolution copy number platforms have also provided important biologic insights in these tumors, with adult low-grade diffuse gliomas containing frequent ATRX, TP53 mutations (astrocytomas), as well as 1p19q co-deletions, CIC, FUBP1 and TERT promoter mutations (oligodendrogliomas). Conversely, alterations in FGFR1, MYB, and MYBL1 are frequent events in pediatric low-grade diffuse gliomas. In this review we summarize our current knowledge of the diagnostic and molecular pathology of these tumors, and explore possible avenues for targeted therapeutics.
Abstract Established in April 2012, the mission of the IDIPGR is to provide secure integrated data sets including clinical, pathologic, radiologic and molecular genomics to the research community to promote hypothesis driven research. Over 600 data points per patient are securely stored on a CCHMC constructed web resource and domain using the open-source data mart development framework Harvest (PMID:24303304) (‘Links’). Genomic data is stored in the cloud-enabled VIVA platform and accessed through cross-platform integration and standardization algorithms for comparison across datasets. Features include source identification, data wrangling, and standardization of molecular and phenotypic data (2017), a web-enabled data mart that provides phenotype-genotype query/exploration, along with raw and processed data file downloads to authorized investigators (Harvest, 2017), additional tools for filtering and analysis of genomic datasets at the level of a phenotype, sample, gene, and variant (VIVA, 2017–2018), and uploaded digitized slides (Aperio, 2019). The IDIPGR Repository stores abstracted datasets for >1020 patients with DIPG/DMG, of whom 366 have tumor tissue available through biopsy and/or autopsy, and centrally reviewed and digitized specimens from 124 patients. The Repository contains >5000 radiology studies from >700 patients, with >550 patients centrally reviewed, and genomics data from 80 patients. Currently 27 IDIPGR approved projects utilize these datasets. The DIPG/DMG Registry constructed a robust database platform and integration system that provides the infrastructure to promote highly collaborative, international, hypothesis-driven research. Broadening collaboration among investigators for hypothesis-driven research studies will lead to better classification and more effective treatment of patients with DIPG and DMG.
<div>Abstract<p>Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatric brain tumor with a median survival of less than 1 year. No effective therapy is currently available, and no therapeutic advances have been made in several decades. We have previously identified BMI-1 as a potential therapeutic target in DIPG and have shown that BMI-1 is highly expressed in DIPG tumors regardless of histone 3 subtype. In the present study, we show that the modulation of BMI-1 leads to DNA damage, M phase cell-cycle arrest, chromosome scattering, and cell death. Interestingly, EZH2 inhibition did not alter these effects. Furthermore, modulation of BMI-1 sensitizes DIPG patient-derived stem-like cells to ionizing radiation (IR). Treatment of DIPG stem-like cells with PTC596, a BMI-1 modulator, and IR impairs the kinetics of DNA damage response (DDR). Both DDR foci formation and resolution were delayed, resulting in further reduction in cell viability compared with either treatment alone. <i>In vivo</i>, treatment of mice bearing DIPG xenografts with PTC596 leads to decreased tumor volume and growth kinetics, increased intratumoral apoptosis, and sustained animal survival benefit. Gene expression analysis indicates that <i>BMI-1</i> expression correlates positively with DIPG stemness and BMI-1 signature. At the single-cell level, the analysis reveals that BMI-1 pathway is upregulated in undifferentiated cells and positively correlates with stemness in DIPG tumors.</p>Implications:<p>Together, our findings indicate that BMI-1 modulation is associated with mitotic abnormalities, impaired DDR, and cell death, supporting the combination of BMI-1 modulation and radiation as a promising novel therapy for children with DIPG.</p></div>
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)