Citations

Objective To describe an expanded phenotypic spectrum and longitudinal outcome in 256 LGI1‐IgG–seropositive and/or CASPR2‐IgG–seropositive patients. Methods Patients were identified through service neural autoantibody evaluation. Ninety‐five had longitudinal follow‐up (7–456 months; median = 35). Results Among 3,910 patients tested, 196 were LGI1‐IgG positive, 51 were CASPR2‐IgG positive, and 9 were dual positive. Cerebrospinal fluid testing was less sensitive than serum testing, detecting only 24 of 38 (63%) LGI1‐IgG–positive and 5 of 6 (83%) CASPR2‐IgG–positive patients. LGI1‐IgG–positive specimens had higher voltage‐gated potassium channel–IgG immunoprecipitation values (0.33nmol/l, range = 0.02–5.14) than CASPR2‐IgG–positive specimens (0.10nmol/l, range = 0.00–0.45, p < 0.001). Of patients presenting with pain or peripheral nervous system (PNS) manifestations, 39% were LGI1‐IgG seropositive (7% had solely neuropathy or pain). Multivariate analysis identified age as the only significant predictor of central nervous system (CNS) versus PNS involvement (>50 years; odds ratio = 15, p < 0.001). Paroxysmal dizziness spells (PDS), a unique LGI1‐IgG accompaniment (14% of patients), frequently delayed the diagnosis. T2‐mesiotemporal hyperintensity was more common in LGI1‐IgG–positive (41%) than in CASPR2‐IgG–positive patients ( p = 0.033). T1‐bright basal ganglia were confined to LGI1‐IgG–positive patients with faciobrachial–dystonic seizures (9 of 39, 31%). Cancer was found in 44% of LGI1‐IgG/CASPR2‐IgG dual seropositive patients (one‐third thymoma). Response to initial immunotherapy was favorable in 97%; mean modified Rankin score was 3 (range = 1–5) at onset and 1.74 (range = 0–6) at last follow‐up, with 9% having severe refractory disability, 20% being asymptomatic, 28% receiving immunotherapy, and 58% receiving antiepileptic medication. Interpretation Older age is a strong predictor of CNS involvement in patients seropositive for CASPR2‐IgG or LGI1‐IgG. Pain, peripheral manifestations, and stereotypic paroxysmal dizziness spells are common with LGI1‐IgG. Response to initial immunotherapy is often favorable, but some patients remain severely disabled, requiring long‐term immunotherapy and/or antiepileptic medications. Ann Neurol 2017;82:79–92

AbstractAn 8‐year‐old girl born to a family with more than three generations of dominant dystrophic epidermolysis bullosa (DDEB) presented with life‐threatening confluent skin erosions, mitten hand deformity, and failure to thrive. Reassessment of her family history and genetic testing showed compound heterozygous COL7A mutations, one inherited from her DDEB‐affected mother and one from her unaffected, healthy father. This family illustrates the risk of unexpected, severe, autosomal recessive epidermolysis bullosa (EB) in a family with milder, multigenerational autosomal dominant EB. Clinicians should recognize the clinical spectrum of dystrophic EB and recommend genetic consultation when the phenotype conflicts with family history.

Objective: To summarize the epidemiology and outcomes of children with multiple organ dysfunction syndrome as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development multiple organ dysfunction syndrome workshop (March 26–27, 2015). Data Sources: Literature review, research data, and expert opinion. Study Selection: Not applicable. Data Extraction: Moderated by an experienced expert from the field, issues relevant to the epidemiology and outcomes of children with multiple organ dysfunction syndrome were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities. Data Synthesis: Summary of presentations and discussion supported and supplemented by the relevant literature. Conclusions: A full understanding the epidemiology and outcome of multiple organ dysfunction syndrome in children is limited by inconsistent definitions and populations studied. Nonetheless, pediatric multiple organ dysfunction syndrome is common among PICU patients, occurring in up to 57% depending on the population studied; sepsis remains its leading cause. Pediatric multiple organ dysfunction syndrome leads to considerable short-term morbidity and mortality. Long-term outcomes of multiple organ dysfunction syndrome in children have not been well studied; however, studies of adults and children with other critical illnesses suggest that the risk of long-term adverse sequelae is high. Characterization of the long-term outcomes of pediatric multiple organ dysfunction syndrome is crucial to identify opportunities for improved treatment and recovery strategies that will improve the quality of life of critically ill children and their families. The workshop identified important knowledge gaps and research priorities intended to promote the development of standard definitions and the identification of modifiable factors related to its occurrence and outcome.

Abstract Background. We previously reported an alternative ESR1 somatic gain-of-function chromosomal translocation event in a patient presenting with aggressive, endocrine therapy resistant estrogen receptor (ER) positive disease, producing an in-frame fusion gene consisting of N-terminal ESR1 and the C-terminus of the Hippo pathway coactivator YAP1 (ESR1-YAP1). We recently identified another ESR1 fusion through RNA sequencing (RNA-seq) in advanced stage ER+ disease from a chest wall recurrence in a male patient that was refractory to multiple lines of treatment. Two examples of fusions discovered in primary breast cancer samples include ESR1 fused in-frame to C-terminal sequences from NOP2 (ESR1-NOP2), identified in a resistant cohort from a RNA-seq screen focused on 81 primary breast cancers from aromatase inhibitor clinical trials, and a second ESR1 fusion, fused in-frame to the entire coding sequence of POLH (ESR1-POLH), that was identified from RNA-seq analysis of 728 Cancer Genome Atlas breast samples. This current study extends our previous characterization of ESR1-YAP1 by comparing functional and pharmacological properties of these three additional ESR1 gene fusion events of both early stage and advanced breast cancers. Methods. In vitro and in vivo experiments were conducted to test ESR1 fusions to induce therapeutic resistance, and metastasis. The transcriptional and binding properties of each fusion was also examined. Pharmacological inhibition with Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, was utilized to assess drug sensitivity in ESR1 fusion containing breast cancer cells and in a patient derived xenograft (PDX) model expressing ESR1-YAP1 (WHIM18). Results. The YAP1 and PCDH11x fusions conferred estrogen-independent and fulvestrant-resistant growth. Immunohistochemistry revealed significantly higher numbers of ER+ cells in lungs of mice xenografted with T47D cells expressing the YAP1 and PCDH11x fusions compared to YFP control, NOP2 and POLH fusions. Results from ChIP-seq and microarray studies suggest that these two fusions promote proliferation and metastasis through genomic action by binding estrogen response elements (ERE) and subsequent gene activation. We thereby define these fusions as “canonical” fusions compared to “non-canonical” NOP2 and POLH fusions, which demonstrated dramatically decreased genomic binding ability. The non-canonical fusions induced genes associated with basal-like breast cancer and promoted HER2, EGFR, and MAPK gene expression signatures in contrast to genes associated with cell cycle/proliferation induced by canonical fusions. The proliferative ability of canonical fusion-containing ER+ cells was inhibited by Palbociclib in a dose-dependent manner. In vivo WHIM18 tumors in mice fed with Palbociclib-containing chow demonstrated significantly reduced tumor volume, growth rate, and weight compared to tumors in mice on control chow. Conclusions. In-frame ERE activating canonical fusions occur in end-stage drug resistant advanced breast cancer and can be added to ESR1 point mutations as a class of recurrent somatic mutation that may cause acquired resistance. Growth induced by these fusions can be antagonized by Palbociclib and is potentially clinically helpful. Citation Format: Lei JT, Shao J, Zhang J, Iglesia M, Cao J, Chan DW, He X, Kosaka Y, Schmidt C, Matsunuma R, Haricharan S, Crowder R, Hoog J, Phommaly C, Goncalves R, Ramalho S, Lai W-C, Hampton O, Rogers A, Tobias E, Parikh P, Davies S, Ma C, Suman V, Hunt K, Watson M, Hoadley KA, Thompson A, Chen X, Perou CM, Creighton CJ, Maher C, Ellis MJ. Recurrent functionally diverse in-frame ESR1 gene fusions drive endocrine resistance in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD2-03.

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

BackgroundMagnetic resonance imaging (MRI) in patients with non‐MRI‐conditional cardiac implantable electronic devices (CIEDs) has been shown to be safe when performed under closely monitored protocols. However, the safety of MRI in patients with devices with a nearly depleted battery has not been reported.MethodsProspective data were collected between January 2008 and May 2015 in patients with non‐MRI‐conditional CIEDs undergoing clinically indicated MRI under institutional protocol. Patients who were pacemaker dependent were excluded. Patients whose devices were at elective replacement indicator (ERI) at the time of MRI or close to ERI (ERI or replacement for battery depletion within 3 months of scan) were identified through database review and analyzed for clinical events.ResultsMRI scans (n = 569) were performed in 442 patients. Of these, we identified 13 scans performed with a nearly depleted battery in nine patients. All scans with implantable cardioverter defibrillators (ICDs, n = 9) were uneventful. However, two scans with pacemakers close to ERI resulted in a power‐on‐reset (PoR) event. One scan with a pacemaker close to ERI that was programmed to DOO mode reached ERI during MRI and automatically changed to VVI mode. Additionally, one scan with a pacemaker at ERI did not allow programming. All pacemakers with events were implanted before 2005.ConclusionPatients with pacemakers and ICDs with a nearly depleted battery can safely undergo MRI when patients are not pacemaker dependent. Attention should be paid because old devices can result in PoR or ERI during MRI, which may lead to oversensing and inhibition of pacing.