Unfavorable Clinical Course Research Articles

Developmental DNA Methylation Subtype Predicts Progression to Treatment and Survival in High-Count Monoclonal B Lymphocytosis

Developmental DNA Methylation Subtype Predicts Progression to Treatment and Survival in High-Count Monoclonal B Lymphocytosis

Long-term Outcomes After Intraprocedural Aneurysm Rupture During Coil Embolization of Unruptured Intracranial Aneurysms

The long-term outcomes of patients with intraprocedural aneurysm rupture (IPR) during endovascular coiling of unruptured intracranial aneurysms (UIAs) remain unclear. We investigated the long-term outcomes and predictors of neurological outcomes in patients who sustained IPR during coil embolization of UIAs. We retrospectively analyzed the medical record of 312 untreated UIAs in 284 patients who underwent endovascular coiling between April 2013 and July2018. The mean follow-up period for the entire cohort was 25.6 months. Twelve patients (3.8%) experienced IPR. The mean aneurysm size in the IPR cohort was significantly smaller than that in the no-IPR cohort (P= 0.045). The IPR cohort had a higher percentage of earlier subarachnoid hemorrhage from another aneurysm (P= 0.019), anterior communicating artery (AComA) aneurysm (P < 0.001), and basilar artery (BA) aneurysm (P= 0.022) than the no-IPR cohort. Neurologic deterioration was observed in 3 patients. The morbidity and mortality rates of the IPR cohort were 25% and 8.3%, respectively. Patients with IPR during coil embolization for AComA aneurysm did not develop neurological deterioration. Two of the 3 patients (66.7%) with a BA aneurysm had neurological deterioration. The proportion of patients with an mRS score of 0-2 at the last follow-up did not differ between the 2 cohorts (P= 0.608). The proportion of functionally independent patients did not differ between patients with and without IPR. Patients with BA aneurysms who developed an IPR tended to exhibit more unfavorable clinical courses than patients with AcomA aneurysms.

The fifth vital sign? Nurse worry predicts inpatient deterioration within 24 hours.

IntroductionIdentification of hospitalized patients with suddenly unfavorable clinical course remains challenging. Models using objective data elements from the electronic health record may miss important sources of information available to nurses.MethodsWe recorded nurses’ perception of patient potential for deterioration in 2 medical and 2 surgical adult hospital units using a 5-point score at the start of the shift (the Worry Factor [WF]), and any time a change or an increase was noted by the nurse. Cases were evaluated by three reviewers. Intensive care unit (ICU) transfers were also tracked.Results31 159 patient-shifts were recorded for 3185 unique patients during 3551 hospitalizations, with 169 total outcome events. Out of 492 potential deterioration events identified, 380 (77%) were confirmed by reviewers as true deterioration events. Likelihood ratios for ICU transfer were 17.8 (15.2–20.9) in the 24 hours following a WF > 2, and 40.4 (27.1–60.1) following a WF > 3. Accuracy rates were significantly higher in nurses with over a year of experience (68% vs 79%, P = 0.04). The area under the receiver operator characteristic curve (AUROC) was 0.92 for the prediction of ICU transfer within 24 hours.DiscussionThis is a higher accuracy than most published early warning scores.ConclusionNurses’ pattern recognition and sense of worry can provide important information for the detection of acute physiological deterioration and should be included in the electronic medical record.

Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma.

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.

Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations.

Astroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined. We performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM. Strikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival (p = .021). Mitogen-activated protein kinase pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma. We suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with MN1 alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway. Astroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.

Characteristics and prognosis of IgG4-related periaortitis/periarteritis: A systematic literature review.

Immunoglobulin G4 (IgG4)-related disease is a systemic chronic fibroinflammatory disease that can affect almost every organ of the body. IgG4-related periaortitis/periarteritis is a newly recognized subset of IgG4-related disease, and its characteristics and prognosis remain unclear. We investigated the clinical characteristics and prognosis of IgG4-related periaortitis/periarteritis. We performed a systematic literature review of IgG4-related periaortitis/periarteritis. Additionally, we have summarized the characteristics and prognosis of IgG4-related coronary arteritis. We investigated 248 patients with IgG4-related periaortitis/periarteritis. All studies reported the condition in elderly patients, and male predominance was observed. The infra-renal abdominal aorta and iliac arteries were the most commonly affected sites. Most reports showed the serum C-reactive protein elevation in this disease entity, in contrast to non-vascular IgG4-related disease. Based on radiological findings observed in 27 patients with IgG4-related coronary arteritis, vasculitic lesions were classified into 3 types: stenotic (67% of patients), aneurysmal (42%), and diffuse wall thickening type (92%). Serum IgG4 level, but not C-reactive protein level, was associated with the number of affected organs in IgG4-related coronary arteritis. Corticosteroid treatment with or without cardiac surgery or percutaneous coronary intervention was effective in most patients with IgG4-related coronary arteritis; however, 33% of patients showed an unfavorable clinical course including disease progression, relapse, or death. Pre-treatment stenosis and/or aneurysms were associated with progression of stenosis or aneurysm after corticosteroid treatment. Most clinical characteristics were similar between the IgG4-related periaortitis/periarteritis and the non-vascular IgG4-related disease groups; however, serum C-reactive protein level elevation was observed only in the former. Although corticosteroid treatment was effective, this disease can be life-threatening secondary to myocardial infarction, aortic dissection, and aneurysmal rupture. Pre-treatment evaluation of stenosis or aneurysms is important for predicting progression of stenosis or aneurysm after corticosteroid treatment.

Clinical and socio-demographic features in childhood vs adolescent-onset anorexia nervosa in an Asian population.

Childhood-onset anorexia nervosa (AN) may be under-recognised and under-treated due to atypical presentations. The aims of this study are: (1) describe features of AN in patients ≤ 18years in an Asian population; and (2) compare childhood-onset and adolescent-onset AN. This study involved a retrospective chart review of patients ≤ 18years in a Asian population who were treated for anorexia nervosa at the Eating Disorders Service at Singapore General Hospital between Jan 2003 and Dec 2014 (n = 435). Childhood-onset AN was defined as onset < 13years, while adolescent-onset AN was defined as onset between 13 and 18years. Patients were predominantly female (95.4%) and Chinese (83%). The childhood-onset group (8.3%) had mean age of onset 11.5 ± 1.0years, compared to 15.2 ± 1.6years for the adolescent-onset group. The childhood and adolescent-onset groups were similar in socio-demographic variables, as well as gender distribution, AN subtype, number of psychiatric comorbidities, family history of psychiatric illness, body image issues and excessive exercise. The childhood-onset group had significantly longer duration of illness prior to presentation (4.75 vs 2.62years), greater frequency of comorbid obsessive-compulsive disorder (19.4% vs 5.3%) and were more likely to report teasing as a trigger for AN (58.3% vs 31.6%). The childhood-onset group had significantly longer duration of inpatient stay (5.97 vs 3.22weeks), as well as a greater number of total admissions (2.78 vs 1.37). Our results suggest that cultural factors may impact the development or identification of AN in an Asian context. Possible delay in diagnosis of childhood-onset AN may lead to a more unfavorable clinical course. Level V, descriptive study.

Lymph node ratio predictive of recurrence, distant metastasis, and survival in submandibular gland carcinoma patients

Submandibular gland (SMG) carcinoma has an unfavorable clinical course and a low survival rate. Specific tumor and nodal findings might help predict posttreatment recurrence and survival in SMG carcinoma patients. This study evaluated factors predictive of posttreatment recurrence and survival in SMG carcinoma patients. This study enrolled 99 consecutive patients with previously untreated SMG carcinoma. All patients underwent tumor and metastatic lymph node resection along with or without radiation/chemo-radiation. The predictive clinical and pathological factors for disease-free survival (DFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were determined using univariate and multivariate Cox proportional hazards regression analyses. The median tumor size was 2.7cm and 53 patients (53.5%) had high-grade tumors. The rates of initial nodal and distant metastasis at initial presentation or follow-up were 45.5% and 42.4%, respectively. The actuarial 5-year DFS, DMFS, DSS, and OS rates were 46.4%, 55.9%, 61.5%, and 59.7%, respectively. The independent factors associated with poor DFS, DMFS, DSS, and OS outcomes (all p < 0.05) were T3-T4 classification and lymph node ratio. A histological high-grade tumor was an independent prognostic factor predictive of poor DMFS, DSS, and OS outcomes (all p < 0.05). A high rate of distant site failure is associated with SMG carcinoma, resulting in a poor survival rate. Lymph node ratio might help predict recurrence, distant metastasis, and death due to SMG carcinoma.

A Clinical and Pathological Comparison of Different Immunomorphological Subvariants of Nodular Lymphocyte-Predominant Hodgkin’s Lymphoma at Initial Diagnosis

Background. Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) is a rare Hodgkin's lymphoma subtype with a variable growth pattern and immune tissue architecture of tumor. Clustering of patients into subgroups based on immunohistochemical (IHC) tumor subvariants is essential for prognosis assessment and development of new differentiated treatment approaches. Aim. To study clinical course of NLPHL in patients with different IHC-subvariants of the disease and identify a poor prognosis subgroup. Materials &amp; Methods. From 2010 to 2017 the Department of Anatomic Pathology at the National Medical Hematology Research Center undertook morphological and IHC-analysis of lymph node and bone marrow core biopsies of 60 NLPHL patients: 47 men and 13 women (male/female ratio of 3.6:1) aged 17-68 years (median 37 years). IHC-analysis with expanded panel of antibodies was performed in all cases of determining IHC-subvariants in accordance with WHO-2017 classification. Results. The clinical and immunomorphological comparative study of NLPHL with variant immune tissue architecture allowed to divide the patient population into three subgroups with differently manifested areas similar to T-cell/ histiocyte-rich large B-cell lymphoma (THRLBCL) in lymph node sections or other site biopsies. These subgroups are characterized by different clinical course of the disease. The subgroup with ≥ 50 % THRLBCL-like areas was marked by the prevalence of clinical stage IV and significantly larger amount of extranodal lesions. Conclusion. In NLPHL the most unfavorable clinical course is typical of the patients whose biopsies contain ≥ 50 % THRLBCL-like areas. Semi-quantification of THRLBCL-like areas allowed to define a spectrum of NLPHL IHC-subvariants correlating with the clinical course of the disease. The true transformation into diffuse large B-cell lymphoma is a rare event, it occurred in 2 (3 %) out of 60 patients.

Implications of TP53 alterations for Therapy Response in Multiple Myeloma

Deletion of the tumor suppressor gene TP53is significantly associated with an unfavorable clinical course of Multiple Myeloma (MM). In addition, point mutations that abrogate p53 function similarly shorten survival. Most recently ‘double hit’, bi-allelic TP53inactivated MM was identified as an ultimate high risk feature of MM, affecting 3.7% of newly diagnosed MM patients (NDMM, Walker et al., Leukemia 2018).For TP53genetic analysis we combined data from two targeted sequencing M3P cohorts with targeted sequencing and FISH data, one of NDMM (n=142, Kortüm et al. Blood Cancer J. 2016), and one of multirefractory patients (rMM, n=40; Kortüm et al. Blood 2016). We also included two independent cohorts with paired NDMM and rMM, one with mutational data (n=43; Corre J et al 2017) and one with paired FISH analysis (Merz M et al. Haematologica 2017). We confirmed an increase of mutations in TP53 (8% NDMM / 16.9% rrMM), as well as del17p (12.6% / 22%). Similarly, mono- (12.7% / 22.5%) and bi-allelic events (5.6% / 17.5%) both demonstrated a significant increase over time (Figure, top). Importantly we observed deletion after mutation and vice versa in our cohorts.Next we established an AMO-1 MM cell line model (TP53+/+) mimicking mono and bi-allelic TP53-inativation. After CRISPR/Cas9-mediated TP53destruction, we introduced a modified Sleeping Beauty (SB) vector with two separate expression cassettes (p53 wt / wt and mutant p53 (R282W or R175H). Functionality of the p53 system was confirmed using nutlin-3, as inhibitor of MDM2-p53 interaction, as described elsewhere.Results: Doxorubicin and Melphalan are commonly used compounds in the treatment of MM. The IC50 of Melphalan in AMO1 naïve cells was 5µM and 5.5 µM after the reintroduction of 2 copies of wt TP53 in the KO model, with cell viability at 10µM of 30% and 31% respectively, measured by AlamarBlue Assay. Strikingly, we observed significant resistance induction in our hemizygous systems (del/wt p53; cell viability at 10µM 60% and mut/wt (62%). This furthermore increased within our homozygous models (TP53 del/del (85%); TP53 mut/del 80%) (Figure, bottom). Similar results were observed under doxorubicin treatment. Remarkably, this effect was absent against proteasome inhibition.ConclusionsHere we present first evidence of TP53 inactivation impacting drug response to Melphalan and Doxorubicin, which might lead to the clonal selection of MM subclones harboring increased risk. The fact, that response to proteasome inhibition was not affected in our model might, at least in part, might explain their ability to confine high risk in MM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Donor Core Body Temperature on Graft Survival After Heart Transplantation.

A previous donor intervention trial found that induction of mild therapeutic hypothermia in the brain-dead donor reduced the dialysis requirement after kidney transplantation. Consequences on the performance of cardiac allografts after transplantation were not explored to date. Cohort study investigating 3-year heart allograft survival according to spontaneous core body temperature (CBT) assessed on the day of organ procurement. The study is nested in the database of the randomized trial of donor pretreatment with low-dose dopamine (ClinicalTrials.gov identifier: NCT000115115). Ninety-nine heart transplant recipients who had received a cardiac allograft from a multiorgan donor enrolled in the dopamine trial were grouped by tertiles of the donor's CBT assessed by a mere temperature reading 4 to 20 hours before procurement (lowest, 32.0-36.2°C; middle, 36.3-36.8°C; highest, 36.9-38.8°C). Baseline characteristics considering demographics of donors and recipients, concomitant donor treatments, donor hemodynamic, and respiratory parameters as well as underlying cardiac diseases in recipients, pretransplant hemodynamic assessments, including pretransplant inotropic/mechanical support, urgency, and waiting time were similar. A lower CBT was associated with inferior heart allograft survival (hazard ratio, 0.53; 95% confidence interval, 0.31-0.93, per tertile; P = 0.02, and hazard ratio, 0.68; 95% confidence interval, 0.50-0.93°C; P = 0.02) when CBT was included as continuous explanatory variable in the Cox regression analysis. A lower CBT in the brain-dead donor before procurement may associate with an unfavorable clinical course after heart transplantation. More research is required, before therapeutic hypothermia can routinely be used in multiorgan donors when a cardiac transplantation is intended.

Influence of unplanned excisions on the outcomes of patients with stage III extremity soft-tissue sarcoma.

Soft-tissue sarcomas (STSs) are a heterogeneous group of malignant tumors that can be difficult to treat. This is particularly true after incomplete or unplanned excisions and especially for patients with American Joint Committee on Cancer stage III tumors, who are at high risk for relapse. Numerous studies have shown that an inadequate sarcoma excision is associated with a worse prognosis. However, other reports have suggested an improved prognosis for patients with an initial unplanned excision and subsequent re-excision in comparison with patients who undergo planned primary surgery. The purpose of this study was to determine the impact of an unplanned excision on treatment and subsequent oncologic and functional outcomes for patients with stage III extremity STS. From the prospectively collected database at a tertiary-referral sarcoma center, all patients with stage III STS of the extremities treated between 1989 and 2010 were identified. Patient records were reviewed to identify patient demographics, tumor details, treatments, complications, and functional and oncologic outcomes. Five hundred patients with stage III STSs of the extremities were identified, and 94 of these patients (18.8%) were referred after inadequate excisions had been performed elsewhere. All 94 patients with unplanned excisions underwent re-excision in an attempt to achieve clear margins, and 83% of these patients had residual tumor in the re-excision specimen. In the re-excision group, the rates of plastic reconstruction (eg, skin grafts and rotational or free flaps) and amputation were significantly higher in comparison with the rates for patients who underwent a primary planned resection (P = .023 and P = .03, respectively). The rates of local recurrence, metastasis-free survival, and overall survival were not significantly different between the 2 groups, nor were the functional outcomes. Unplanned excision of stage III STS leads to an unfavorable clinical course and necessitates more extensive surgery. As a result of aggressive re-excision and multidisciplinary treatment, a negative effect on oncologic outcomes cannot be confirmed.

The Changing Appearance of Cardiac Amyloidosis

A fast and reliable diagnosis of cardiac amyloidosis requires a significant amount of clinical awareness. It is especially important to come to an early diagnosis in patients with cardiac AL amyloidosis in order to improve the otherwise unfavourable clinical course in these patients. There is a significant increase in the number of patients with cardiac amyloidosis of the ATTR wild-type variety. These patients are often elderly males presenting with predominantly right sided heart failure. We present a diagnostic pathway enabling a structured approach to these patients using multimodality cardiac imaging and endomyocardial biopsy. Early chemotherapy is the key to improving symptoms in patients with AL amyloidosis. In contrast, pharmacologic approaches for treating cardiac ATTR amyloidosis need further research and clinical trials.

Chronic hand eczema: A prospective analysis of the Swiss CARPE registry focusing on factors associated with clinical and quality of life improvement.

Hand eczema (HE) is common and may follow a chronic disease course. So far, prospective studies investigating the risk factors for disease progression as a prerequisite for targeted prevention are scarce. To evaluate the overall association of HE-associated factors with clinical and quality of life (QoL) improvement during a follow-up of 2 years. Data of the prospective patient cohort (N = 199) followed by the Swiss chronic HE (CHE) registry on long-term patient management (CARPE-CH) were analysed by means of both classic regression and semantic map analyses. Both severity of HE and QoL significantly improved over the period of 2 years (P < .001). However, 20% of patients had moderate to severe HE after 2 years of follow-up. As factors associated with an unfavourable CHE clinical course and QoL, environmental exposures, male sex, occupational skin disease, job loss or change at baseline, allergic contact dermatitis, a chronic disease course, palmar localization and widespread eczema were identified. Analysis of prospective data from CARPE-CH shows a complex pattern of associations among variables as shown by semantic map and classic statistical analyses. Factors related to occupational exposure had the highest impact on CHE.

Diagnostics and antibiotic therapy for spondylodiscitis.

Purpose. Spondylodiscitis as a rare disease has increased in recent years; there are only a few recommendations regarding the diagnostics and treatment. The objective of this retrospective study was to characterise these patients and identify factors for a favourable healing process - with an emphasis on antibiotic therapy.Methodology. Findings/treatment regimens for all patients with spondylodiscitis treated at a tertiary care hospital in 2012/2013 were recorded. The patients were classified into two groups, depending on the healing process.Results. Fifty-seven patients met the clinical/radiological criteria for spondylodiscitis. The main symptom was massive back pain, combined with a moderate CRP elevation (median 96 mg l-1), and occasionally fever (39 %). CT-guided aspiration - in addition to blood cultures - improved the detection rate for the causative pathogen from 49 to 82 %. Thirty patients had a favourable clinical course; 25 had an unfavourable clinical course (prolonged clinical course, recurrence, death). Pathogen-specific antibiotic therapy had a decisive effect on the clinical course: initial high-dose intravenous therapy for at least 14 days was associated significantly more often with a favourable clinical course (90 vs 30 % after 24 months, P<0.001). Fourteen days after the start of treatment, marked pain reduction and a CRP reduction of at least 50 % were good prognostic parameters and markers of effective antibiotic therapy.Conclusion. Pathogen detection and establishment of an optimal antibiotic regimen are cornerstones of successful conservative therapy for spondylodiscitis. Targeted initial intravenous therapy for at least 14 days with a bactericidal antibiotic leads to a better clinical course.

Characterization of clinically aggressive meningiomas by mutational signatures associated with DNA mismatch repair and aging.

e14044Background: Up to 20% of meningiomas behave aggressively with high recurrence rates and reduced survival. There is a lack of biomarkers predicting the risk of an unfavorable clinical course a...

Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations.

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding(t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.

Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines.

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton's tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment. To overcome ibrutinib resistance, new therapeutic approaches are needed. As checkpoint kinase 1 (Chk1) inhibitors have recently been shown to be effective as single agents in MCL, we assessed the combination of ibrutinib with Chk1 inhibitors. We examined the activity of ibrutinib combined with the Chk1 inhibitor PF-00477736 in eight MCL cell lines and analyzed underlying cellular and molecular effects. The combination was synergistic in all tested cell lines through different mechanisms. The treatment induced apoptosis in ibrutinib-sensitive cell lines, while in ibrutinib-resistant cells the effect was mainly cytostatic and occurred at micromolar concentrations of ibrutinib. The pharmacological approach of simultaneously targeting cell cycle checkpoints (by Chk1 inhibitors) and pro-survival pathways (by ibrutinib) might offer a promising new therapeutic strategy for MCL patients.

Abstract TP118: The Topography and Predictors of Blood Brain Barrier Disruption After Carotid Artery Stenting

Background: One major issue related to carotid artery revascularization procedures is their potential for inducing disturbances in blood brain barrier (BBB) permeability, which is considered to play a critical role in the pathophysiology of hyperperfusion syndrome. In this study, our aim was to evaluate the predictors of impaired BBB permeability and its topographic distribution among patients undergoing carotid artery stenting. Methods: Clinical information (including demographic data, cardiovascular risk factors, degree of stenosis, indication and timing of the procedure), together with pre- and immediate post- (&lt;24 hours) procedural magnetic resonance imaging (MRI) data was prospectively collected in a consecutive series of patients. BBB integrity was specifically evaluated on post-contrast FLAIR sequences. Regions of contrast extravasation were semi-automatically outlined and co-registered to a standard template in order to determine the topography of BBB disruption. Results: Evidence for BBB disruption was observed in 11 out of 43 patients (26%) prior to stenting, a feature that was solely related to a recent history of ischemic stroke (&lt;30 days) in multivariate analysis (p=0.033). New-onset or increased BBB disruption following the procedure was seen in 22 patients (51%); increased permeability was primarily observed in the ipsilateral cortical watershed territories (Figure) and was inversely related to the duration elapsed between carotid revascularization and MRI (p=0.036). Hyperperfusion syndrome developed in 7% of our patients, all of whom also having evidence of increased BBB permeability on post-stenting MRI. Conclusion: Our findings highlight that BBB disruption in the peri-stenting setting is a frequently common observation, with specific spatial and temporal characteristics. Its predictive utility for predicting hyperperfusion syndrome and unfavorable clinical course, on the other hand, is fairly low.

Abstract 494: Frequent NRG1 genomic rearrangements in invasive mucinous adenocarcinoma from caucasian patients

Abstract Invasive Mucinous Adenocarcinoma (IMA) accounts for 2-5% of lung adenocarcinomas and it is associated with an unfavorable clinical course, mainly due to lack of effective treatments. Current knowledge of the molecular alterations involved in IMAs is limited. Recently, the NRG1 genomic rearrangement was identified as a subtype-specific molecular feature of Asiatic IMA cohorts since it acts as a strong inductor of the aberrant tyrosine kinase activity of ErbB2/ErbB3 heterodimers through PI3K–AKT and MAPK cellular cascades. In light of these premises we explored the occurrence and frequency of NRG1 fusions in a cohort of 90 Formalin Fixed Paraffin Embedded (FFPE) lung adenocarcinoma from Caucasian patients (35 non-IMAs and 55 IMAs) by performing FISH analysis to study the NRG1 genomic region (β-III isoform, chr 8p12). In total, 16 out of 55 (29%) IMAs showed NRG1 rearrangements, whereas in non-mucinous lung adenocarcinoma group it was found with a frequency of 3% (1/35). The functional effect of the genomic rearrangement was confirmed by RT-PCR and sequencing in three cases with available RNA, where NRG1-CD74 fusion transcripts were identified. An aberrant expression of pErbB3 was also observed in these three NRG1 rearranged cases by performing immunohistochemistry analysis, thus confirming the ErbB3 cascade activation. Our results strongly confirm NRG1 rearrangements as potentially treatable oncogenic driver alterations associated with a definite lung adenocarcinoma subtype in Caucasian population and support a clear molecular rationale to novel therapeutic opportunity for these aggressive tumors. Note: This abstract was not presented at the meeting. Citation Format: Domenico Trombetta, Giulio Rossi, Angelo Sparaneo, Federico P. Fabrizio, Maria C. Manzorra, Evaristo Maiello, Vito M. Fazio, Paolo Graziano, Lucia A. Muscarella. Frequent NRG1 genomic rearrangements in invasive mucinous adenocarcinoma from caucasian patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 494. doi:10.1158/1538-7445.AM2017-494