Atypical Teratoid/Rhabdoid Tumors in Adults: A Case Report and Treatment-Focused Review

Atypical teratoid/rhabdoid tumor is predominantly a childhood tumor and has only been rarely reported in adults; therefore, treatment regimens are often extrapolated from the pediatric experience. Typically, children are treated with craniospinal radiation therapy which is often followed by systemic chemotherapy. Employing pediatric regimens to treat this tumor in adult patients poses a particular risk for myelosuppression, as the prescribed doses in pediatric protocols exceed those tolerated by adults, and conventional craniospinal radiation can be associated with prolonged myelotoxicity and a depletion of the bone marrow reserve in vertebrae of adults. Here we present a case of a woman with a pineal region atypical teratoid/rhabdoid tumor, an unusual adult cancer presenting in an atypical location. This is followed by a review of the disease in adult patients with an emphasis on treatment and suggestions to minimize myelotoxicity

Afatinib and Temozolomide Combination Inhibits Tumorigenesis by Targeting EGFRvIII-cMet Signaling in Glioblastoma Cells

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor with universal recurrence and poor prognosis. The recurrence is largely driven by chemoradiation resistant cancer stem cells (CSCs). Epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are amplified in ~ 60% and ~ 30% of GBM patients, respectively; however, therapies targeting EGFR have failed to improve disease outcome. EGFRvIII-mediated cross-activation of tyrosine kinase receptor, cMET, regulates GBM CSC maintenance and promote tumor recurrence. Here, we evaluated the efficacy of pan-EGFR inhibitor afatinib and Temozolomide (TMZ) combination on GBM in vitro and in vivo. METHODS: We analyzed the effect of afatinib and temozolomide (TMZ) combination on GBM cells U87MG and U251 engineered to express wild type (WT) EGFR, EGFRvIII or EGFRvIII dead kinase, CSCs isolated from U87 and U87EGFRvIII in vitro. The therapeutic utility of the drug combination was investigated on tumor growth and progression using intracranially injected U87EGFRvIII GBM xenografts. RESULTS: Afatinib and TMZ combination synergistically inhibited the proliferation, clonogenic survival, motility, invasion and induced senescence of GBM cells compared to monotherapy. Mechanistically, afatinib decreased U87EGFRvIII GBM cell proliferation and motility/invasion by inhibiting EGFRvIII/AKT, EGFRvIII/JAK2/STAT3, and focal adhesion kinase (FAK) signaling pathways respectively. Interestingly, afatinib specifically inhibited EGFRvIII-cMET crosstalk in CSCs, resulting in decreased expression of Nanog and Oct3/4, and in combination with TMZ significantly decreased their self-renewal property in vitro. More interestingly, afatinib and TMZ combination significantly decreased the xenograft growth and progression compared to single drug alone. CONCLUSION: Our study demonstrated significant inhibition of GBM tumorigenicity, CSC maintenance in vitro, and delayed tumor growth and progression in vivo by combination of afatinib and TMZ. Our results warrant evaluation of this drug combination in EGFR and EGFRvIII amplified GBM patients

Differential Gene Expression-Based Connectivity Mapping Identified Novel Drug Candidate and Improved Temozolomide Efficacy for Glioblastoma

BACKGROUND: Glioblastoma (GBM) has a devastating median survival of only one year. Treatment includes resection, radiation therapy, and temozolomide (TMZ); however, the latter increased median survival by only 2.5 months in the pivotal study. A desperate need remains to find an effective treatment. METHODS: We used the Connectivity Map (CMap) bioinformatic tool to identify candidates for repurposing based on GBM\u27s specific genetic profile. CMap identified histone deacetylase (HDAC) inhibitors as top candidates. In addition, Gene Expression Profiling Interactive Analysis (GEPIA) identified HDAC1 and HDAC2 as the most upregulated and HDAC11 as the most downregulated HDACs. We selected PCI-24781/abexinostat due to its specificity against HDAC1 and HDAC2, but not HDAC11, and blood-brain barrier permeability. RESULTS: We tested PCI-24781 using in vitro human and mouse GBM syngeneic cell lines, an in vivo murine orthograft, and a genetically engineered mouse model for GBM (PEPG - PTEN CONCLUSION: PCI-24781 is a novel GBM-signature specific HDAC inhibitor that works synergistically with TMZ to enhance TMZ efficacy and improve GBM survival. These promising MGMT-agnostic results warrant clinical evaluation

Pancytopenia due to iron deficiency worsened by iron infusion: a case report

<p>Abstract</p> <p>Introduction</p> <p>Iron deficiency anemia is commonly associated with thrombocytosis, although thrombocytopenia has been reported in occasional patients with iron-deficiency anemia. Much less common is the development of thrombocytopenia following replenishment of iron stores.</p> <p>Case Presentation</p> <p>We present the unusual case of a 39 year old African American female Jehovah's Witness who presented with a 10 month history of menorrhagia and pancytopenia. Laboratory investigations confirmed a severe iron deficiency. Since blood transfusion was unacceptable to her, she was started on intravenous iron replacement therapy. This precipitated a sudden drop in both her platelet and white blood cell counts. Histopathological examination of the bone marrow revealed a hypercellular marrow with orderly trilineage hematopoiesis, iron deficiency anemia, granulocytic hyperplasia, and mild megakaryocytic hypoplasia. Both her white blood cell and platelet counts recovered uneventfully with continuing iron supplementation. The possible mechanism for this phenomenon is discussed in this report.</p> <p>Conclusion</p> <p>This case illustrates two rather uncommon associations of a very common problem. Severe iron deficiency anemia may be associated with pancytopenia and iron replacement may cause a transient decline in megakaryopoiesis and leukopoiesis. Severe iron deficiency should be added to the list of conditions leading to thrombocytopenia.</p

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

UNLABELLED Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293

Safety of long-term anticoagulation in patients with brain metastases.

Anticoagulation is thought to be associated with the risk of intracranial hemorrhage (ICH) in patients with brain metastases; however, the data on this topic are limited. This study was conducted to determine the incidence of ICH associated with anticoagulant use in adult patients with brain metastases. Consecutive patients with brain metastases occurring from 2006 to 2014 were identified from a single-institution database. Long-term anticoagulant therapy was defined as outpatient anticoagulation therapy of \u3e 1 month. Chi-square tests and Fisher\u27s exact test were used to compare rates of ICH by groups. This cohort included 125 patients with brain metastases. Of these, 64 had primary of non-small cell lung cancer (51.2%). Of these patients, 12/125 (9.6%) patients developed ICH. Neither the primary tumor site nor the number of brain metastases was associated with the development of ICH. ICH incidence was not associated with the use of anticoagulant therapy, with 8/67 (11.94%) patients on outpatient anticoagulation and 4/58 (6.9%) not on anticoagulation experiencing ICH (p = 0.33). The type of treatment did not significantly influence ICH, although those having combined WBRT and SRS were numerically more likely to experience ICH (4/15; 26.67%) of this cohort. In patients on enoxaparin, there was no difference in the incidence of ICH for daily versus twice-daily dosing (p = 1.0). Long-term anticoagulant use is not associated with an increased incidence of ICH in patients with intracranial metastases

Evaluating survival in subjects with astrocytic brain tumors by dynamic susceptibility-weighted perfusion MR imaging.

PurposeStudies have evaluated the application of perfusion MR for predicting survival in patients with astrocytic brain tumors, but few of them statistically adjust their results to reflect the impact of the variability of treatment administered in the patients. Our aim was to analyze the association between the perfusion values and overall survival time, with adjustment for various clinical factors, including initial treatments and follow-up treatments.Materials and methodsThis study consisted of 51 patients with astrocytic brain tumors who underwent perfusion-weighted MRI with MultiHance® at a dose of 0.1 mmol/kg prior to initial surgery. We measured the mean rCBV, the 5% & 10% maximum rCBV, and the variation of rCBV in the tumors. Comparisons were made between patients with and without 2-year survival using two-sample t-test or Wilcoxon rank-sum test for the continuous data, or chi-square and Fisher exact tests for categorical data. The multivariate cox-proportional hazard regression was fit to evaluate the association between rCBV and overall survival time, with adjustment for clinical factors.ResultsPatients who survived less than 2 years after diagnosis had a higher mean and maximum rCBV and a larger variation of rCBV. After adjusting for clinical factors including therapeutic measures, we found no significant association of overall survival time within 2 years with any of these rCBV values.ConclusionsAlthough patients who survived less than 2 years had a higher mean and maximum rCBV and a larger variation of rCBV, rCBV itself may not be used independently for predicting 2-year survival of patients with astrocytic brain tumors

Post-operative perfusion and diffusion MR imaging and tumor progression in high-grade gliomas.

PURPOSE:Perfusion and diffusion magnetic resonance imaging (MRI) provide important biomarkers for brain tumor analysis. Our aim was to investigate if regions of increased perfusion or tumor with restricted diffusion on the immediate post-operative MRI examination would be predictive of time to tumor progression in patients with high-grade gliomas. MATERIALS AND METHODS:Twenty-three patients with high-grade gliomas were retrospectively analyzed. We measured the perfusion at the resection area and evaluated the presence or absence of the restricted diffusion in residual tumor masses. The associations of the perfusion, diffusion and contrast enhancement (delayed static enhancement (DSE)) characteristics with time to tumor progression were statistically calculated. We also evaluated if the location of the tumor progression was concordant to the areas of the elevated perfusion, tumor type restricted diffusion and enhancement. RESULTS:Patients with >200 days to progression are more likely to have no elevated relative cerebral blood volume (rCBV) ratio (p = 0.0004), no tumor restriction (p = 0.024), and no DSE (p = 0.052). The elevated mean rCBV ratio (p1.5 progressed in 275 days or earlier. Tumors tended to progress at the area where patients with post-operative MRIs showed elevated perfusion (p = 0.006), tumor-type restricted diffusion (p = 0.005) and DSE (p = 0.008). CONCLUSIONS:Post-operative analysis of rCBV, tumor type restricted diffusion and enhancement characteristics are predictive of time to progression, risk of progression and where tumor progression is likely to occur