Citations

Background: Familial transthyretin amyloidosis is a disease caused by misfolded transthyretin aggregates that can impair multiple organ systems. Liver transplantation is the first-line treatment for familial transthyretin amyloidosis. Research Question: Our objective is to study outcomes and survival among patients with familial transthyretin amyloidosis after transplantation. Design: All patients undergoing orthotopic liver transplant for familial transthyretin amyloidosis at Mayo Clinic between 1997 and 2012 were reviewed. Baseline clinical characteristics, organs transplanted, and posttransplant clinical course were assessed. Results: Of the 40 patients, 7 patients had the V30M mutation and 33 had other mutations. Nineteen patients received liver only, 19 liver and heart, and 2 combined liver, heart, and kidney transplants. The 5-year overall survival was 85% for those receiving multiple organ transplant and 52% for those receiving liver transplant only ( P = .057). There was no difference in overall survival based on mutation (V30M vs other mutations), but survival was confounded by varied disease involvement and organs transplanted. Those who had early death (≤24 months from liver transplant) had a higher incidence of baseline peripheral neuropathy, autonomic neuropathy, lower modified BMI, and higher alkaline phosphatase. Discussion: Outcomes of orthotopic liver transplant in familial transthyretin amyloidosis are variable due to heterogeneity in mutations and patient status at the time of transplant. Familial transthyretin amyloidosis can progress, despite liver transplantation. Patients receiving combined liver, heart/kidney transplant demonstrated improved survival compared to liver transplant alone.

Abstract Estrogen receptor positive (ER+) breast cancer is treated with endocrine therapy but intrinsic resistance occurs in ~1/3 of patients and acquired resistance in ~1/5 of the remainder. While many resistance mechanisms have been explored, therapeutic strategies to overcome resistance in the clinical setting have seen mixed outcomes, and appear most effective in the acquired resistance setting. Understanding mechanisms of resistance and finding therapeutic strategies to target them, therefore, remain important challenges facing breast cancer researchers. In this study we systematically examine the role of DNA damage repair defects in inducing endocrine therapy resistance, a relatively understudied question of recent interest. We use in silico analysis of clinical datasets, in vitro experiments evaluating endocrine therapy resistance in response to DDR dysregulation in multiple breast cancer celllines, and in vivo validation using cellline xenograft and patient-derived xenograft models. We also use gene expression microarrays and RPPA data from cell lines, patient-derived xenografts and primary ER+ breast tumors to uncover therapeutic options that are validated in vitro and in vivo and corroborated by clinical trial data. The results of this study uncover an intriguing link between mismatch repair (MMR) deficiency, specifically of the MutL complex (MLH1/3, PMS1/2), and poor prognosis in ER+ disease. We find a direct role for MutL loss in endocrine therapy resistance in vitro and in vivo by knocking down multiple MutL genes using CRISPR and stable shRNA approaches validated using standard rescue experiments. We identify the underlying mechanism: MutL deficiency in ER+ breast cancer abrogates Chk2-mediated feedback inhibition of CDK4/6 that appears necessary for endocrine therapy responsiveness. Consequently, pharmacological targeting of CDK4/6 in vitro and in vivo significantly inhibits growth of endocrine therapy resistant MutL-deficient ER+ breast cancer cells. These results are corroborated by data from a neoadjuvant clinical trial demonstrating that cell cycle regulation of MutL-mutant tumors tends to be estrogen-independent but sensitive to CDK4/6 inhibitors. The results of this study provide important biological and clinically relevant insights. 1) MMR deficiency is unexpectedly causal to intrinsic endocrine therapy resistance 2) This causal effect appears to be mediated by abrogation of cell cycle checkpoint activation in response to endocrine therapy 3) MMR deficiency in a subset of ER+ tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy resistant tumors. While there are currently no biomarkers to guide the use of CDK4/6 inhibitors for ER+ breast cancer, markers of MMR dysregulation could identify patients in whom CDK4/6 inhibition should be used to prevent disease recurrence. Citation Format: Svasti Haricharan, Jacob Schmelz, Cheryl Schmidt, Purba Singh, Kimberly R. Holloway, Meenakshi Anurag, Shunqiang Li, Shyam M. Kavuri, Shixia Huang, Dean P. Edwards, Vera Suman, Kelly Hunt, John A. Olson, Jeremy Hoog, Cynthia X. Ma, Matthew N. Bainbridge, Matthew J. Ellis. Mismatch repair defects and endocrine therapy resistance in estrogen receptor positive breast cancer [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 489. doi:10.1158/1538-7445.AM2017-489

Key Points Over the last decade, allogeneic HCT has been increasingly administered in the United States to adults aged 70 and older with hematologic malignancies. Allogeneic transplant outcomes were reasonable; high comorbidity and ablative conditioning regimens were associated with inferior outcomes.

Abstract Aims Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone-marrow-derived, lineage-directed, autologous cardiopoietic mesenchymal stem cells (C3BS-CQR-1) on LV remodelling in patients with advanced HF enrolled in the CHART-1 study. Methods and results Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF <35%) were randomized to receive C3BS-CQR-1 or a sham procedure. In a post hoc analysis we examined the effect of C3BS-CQR-1 on LV reverse remodelling within 1 year of the procedure and the influence of C3BS-CQR-1 dosing in the 271 patients treated as randomized. Delivery of C3BS-CQR-1 was associated with a progressive decrease in both LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) within 52 weeks after treatment. At 1 year, the LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than controls (P=0.006 and P=0.017, respectively). The effect on LVEDV was maintained after multivariable adjustment for baseline age, systolic blood pressure, LVEDV, LVEF and history of myocardial infarction. The largest reverse remodelling was evident in the patients receiving a moderate number of injections (<20). Conclusion In CHART-1, intramyocardial administration of cardiopoietic stem cells led to reverse remodelling as evidenced by significant progressive decreases in LVEDV and LVESV through the 52 weeks of follow-up. Further studies are needed to explore the dose response with regard to cell number and injected volume, and reverse remodelling.

BackgroundAcute myocardial infarctions (AMI) continue to be common in the United States. Mechanical complications of AMI can lead to cardiogenic shock (CS) and death. The aim of this study was to review the cases of papillary muscle ruptures in the setting of myocardial infarctions at a tertiary care center, with a focus on the clinical presentation and echocardiographic diagnosis.MethodsThis was a retrospective study from January 1, 2000 through December 31, 2014. In all, 22 patients with AMI and papillary muscle rupture (AMI‐PMR) who had surgical intervention were identified.ResultsThe average age was 70 (±11) with 16 (73%) males. Six patients presented with ST‐elevation myocardial infarctions (STEMI) and all underwent emergent revascularization with primary percutaneous coronary intervention (PCI) prior to the diagnosis of AMI‐PMR. The other 16 patients presented with a non‐STEMI. In total, 17 (77%) of the 22 patients were diagnosed with an AMI‐PMR within 7 days from their onset of symptoms. In all, 12 patients (55%) had anterolateral papillary muscle ruptures (ALPMR), and the other 10 had posteromedial papillary muscle ruptures (PMPMR). Ruptures were complete in 10 patients (45%). Patients presented with pulmonary edema early (<7 days) more commonly than late (>14 days). Transthoracic echocardiography was able to demonstrate severe mitral regurgitation in 86% and a definitive or suggestive diagnosis in 93%. All 22 patients survived to operative management, and the overall in‐hospital mortality rate was 9%.ConclusionIn conclusion, ischemic papillary muscle ruptures continue to occur, but with prompt diagnosis by echocardiography and rapid surgical management, the mortality rate continues to decline.

SummaryObjectiveEvaluate the seizure‐reduction response and safety of mesial temporal lobe (MTL) brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of mesial temporal lobe origin.MethodsSubjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events.ResultsThere were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy‐six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow‐up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty‐nine percent of subjects experienced at least one seizure‐free period of 6 months or longer, and 15% experienced at least one seizure‐free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device‐related adverse event was soft tissue implant‐site infection (overall rate, including events categorized as device‐related, uncertain, or not device‐related: 0.03 per implant year, which is not greater than with other neurostimulation devices).SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

SummaryObjectiveEvaluate the seizure‐reduction response and safety of brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of neocortical origin.MethodsPatients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset.ResultsThere were 126 patients with seizures of neocortical onset. The average follow‐up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty‐six percent of patients experienced at least one seizure‐free period of 6 months or longer and 14% experienced at least one seizure‐free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices.SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Background: Surgical indications for Scheuermann kyphosis are variable. We sought to evaluate the characteristics of patients undergoing operative versus nonoperative treatment of Scheuermann kyphosis to better understand current practices and the factors which contribute to the decision for surgical management. Methods: Multicenter prospective cohort study. We evaluated consecutive patients presenting with Scheuermann kyphosis. Patients underwent either surgical or nonoperative management according to surgeon and patient discretion. Preoperative patient-reported outcome measures (Scoliosis Research Society and Spinal Appearance Questionnaire scores), demographics, and radiographic characteristics were assessed. Results: Overall, 150 patients with Scheuermann kyphosis were enrolled, with 77 choosing nonoperative treatment and 73 treated operatively. Compared with the nonoperative cohort, patients treated operatively were older (16.3±2.0 vs. 15.1±2.2, P=0.0004), and had higher body mass index (26.3±7.2 vs. 22.7±6.5, P=0.003), had greater T2-T12 kyphosis (71±14 degrees vs. 61±12 degrees, P<0.001), increased pelvic incidence (46 vs. 41 degrees, P=0.03) and pelvic tilt (10 vs. 3 degrees, P=0.03). There was no detected difference in maximal sagittal Cobb angle in the operative versus nonoperative patients (73±11 vs. 70±12 degrees, P=0.11). Functionally, the operative patients had worse Scoliosis Research Society pain scores (3.7±0.9 vs. 4.1±0.7, P=0.0027) and appearance scores (2.9±0.7 vs. 3.4±0.8, P <0.0001). Conclusions: Patients undergoing surgical management of Scheuermann disease were more likely to have large body mass index and worse pain scores. Other factors beyond radiographic measurement likely contribute to the decision for surgical management of Scheuermann kyphosis. Level of Evidence: Level II.