Citations

Abstract BACKGROUND Oligodendrogliomas are classified as either WHO grade II or III depending on histologic features. Grade often influences treatment decisions. However, there is variability in patient outcome within tumors of similar grade. We hypothesized that copy number burden (CNB) and specific copy number variants (CNV) might be associated with oligodendroglioma grade and prognosis. METHODS Copy number array analyses were performed on 285 molecular oligodendrogliomas (IDH-mutant, 1p/19q-whole arm-codeleted) from the Mayo Clinic internal and consult neuropathology practice and 167 TCGA molecular oligodendrogliomas. CNB was defined as the total number of copy number alterations. The association of CNB and CNV with grade and overall survival (when available) was assessed. All Mayo and TCGA data were evaluated using the ChAS software suite (Thermo- Fisher) and blindly reviewed by a clinical cytogeneticist (RBJ). RESULTS The mean CNB was 5.0 and 10.4 in the Mayo WHO grade II and III oligodendrogliomas, respectively (p = 5.4 x 10–17). Among the TCGA WHO grade II and III oligodendrogliomas the mean CNB was 4.4 and 5.3, respectively (p = 0.034). Common CNVs (occurring in at least 5% of cases) were -4/4q-, +8/8q+, -9/9p-/cnLOH 9p, +11/11q+, -14/14q-, -15 and -18/18q-. Of these, -9/9p-/cnLOH 9p was significantly associated with higher grade in both the Mayo and TCGA cohorts (p = 8.3 x 10-10 and 0.018, respectively). In the TCGA cohort the presence of >10 CNVs or +11/11q+ was associated with a poorer survival (p = 0.016 and 0.006, respectively). CONCLUSIONS CNB is significantly associated with WHO grade in IDH-mutant, 1p/19q co-deleted oligodendrogliomas. The presence of a significantly elevated CNB in some WHO grade II tumors may be suspicious for the presence of unappreciated grade III histologic features. Longer follow-up will be necessary to determine if CNB or single CNVs are associated with survival.

AbstractImportanceNeuromyelitis optica/neuromyelitis optica spectrum disorder patients' response to therapeutic plasma exchange (TPE) is currently incompletely characterized.ObjectiveOur study aims to understand the clinical status improvement of neuromyelitis optica/neuromyelitis optica spectrum disorder patients treated with TPE.Design, Setting, and ParticipantsThis is a multicenter retrospective study conducted between 1 January 2003 and 31 July 2017 at 13 US hospitals performing apheresis procedures. Subjects studied were diagnosed with neuromyelitis optica/neuromyelitis optica spectrum disorder who received TPE during presentation with acute disease.Main Outcomes and MeasuresThe primary outcome was clinical status improvement in patients treated with TPE. Secondary measures were procedural and patient characteristics associated with response to treatment.ResultsWe evaluated 114 patients from 13 institutions. There was a female predilection. The largest ethnic group affected was non‐Hispanic Caucasian. The average age of diagnosis was 43.1 years. The average time to diagnosis was 3.1 years. On average, five procedures were performed during each treatment series. The most commonly performed plasma volume exchange was 1.0 to 1.25 using 5% albumin as replacement fluid. Most patients (52%) did not require an additional course of TPE and noted “mild” to “moderate” clinical status improvement. Maximal symptom improvement appeared by the fourth or fifth TPE treatment.Conclusion and RelevanceTPE improved the clinical status of patients. Adults responded more favorably than children. Procedural characteristics, including number of TPEs, plasma volume exchanged, and replacement fluid used, were similar between institutions. TPE was well‐tolerated and had a low severe adverse event profile.

Abstract Heritable mitochondrial DNA (mtDNA) mutations are common, yet only a few recurring pathogenic mtDNA variants account for the majority of known familial cases in humans. Purifying selection in the female germline is thought to be responsible for the elimination of most harmful mtDNA mutations during oogenesis. Here we show that deleterious mtDNA mutations are abundant in ovulated mature mouse oocytes and preimplantation embryos recovered from PolG mutator females but not in their live offspring. This implies that purifying selection acts not in the maternal germline per se, but during post-implantation development. We further show that oocyte mtDNA mutations can be captured and stably maintained in embryonic stem cells and then reintroduced into chimeras, thereby allowing examination of the effects of specific mutations on fetal and postnatal development.

Abstract Background: Follicular lymphoma is a B-cell malignancy in which tumor-immune system interactions have the potential to profoundly influence malignant cell growth. Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a negative regulator of T cell activation that can serve to dampen anti-tumor immune responses. Administration of blocking anti-CTLA-4 monoclonal antibodies has been shown to improve host resistance to immunogenic tumors and amplify the anti-tumor effects of cancer vaccines in a variety of mouse tumor models. Recently, the anti-CTLA-4 antibody ipilimumab (MDX-010) has been shown to have significant clinical activity against melanoma, prostate, and ovarian cancers, with clinical responses associated with autoimmune events. Methods: We have therefore initiated a phase I/II trial of ipilimumab, a blocking fully human monoclonal antibody to CTLA-4, in patients with relapsed or refractory follicular lymphoma (grade 1 or 2). Enrollment is stratified into 2 cohorts, with half of patients required to be previously treated with a lymphoma vaccine (idiotype or other). It is hypothesized that previously vaccinated subjects are more likely to have anti-lymphoma T cells amenable to activation by an anti-CTLA-4 antibody. Study objectives include characterization of drug safety, immunologic activity and potential clinical efficacy. Treatment consists of MDX-010 at 3 mg/kg, then monthly at 1 mg/kg x 3, with plans to escalate to 3 mg/kg monthly x 4 if tolerated. Results: To date, 12 patients have been treated and accrual to the first dose level has been completed. All patients were previously treated and the median number of prior treatment regimens was 2 (range 1–4). Eight patients had previously received rituximab and 6 patients had received prior anti-idiotype vaccines. Nine patients have completed therapy with ipilimumab and 3 patients are still receiving treatment. Ipilimumab was generally well tolerated and the most common adverse events attributed to ipilimumab in the first 9 patients include diarrhea (grade 3–3 patients, grade 1–1 patient), abdominal pain (grade 2–4, grade 1–2), anorexia (grade 2-1, grade 1 – 2), fatigue (grade 2 -2, grade 1–3, and neutropenia (grade 3-1, grade 1– 2). Among 9 patients evaluable for clinical response, 1 previously vaccinated patient had partial regression of multiple abdominal nodes, ongoing at 10+ months. T cell proliferative responses to the recall antigens tetanus toxoid and keyhole limpet hemocycanin (in idiotype-vaccinated cases) were measured pre- and post-ipilimumab. In 3 of 5 cases tested, including the patient with a clinical response, T cell proliferation to KLH and/or tetanus was significantly increased (>2-fold) one month after initiation of ipilimumab, implying expansion and/or activation of the memory T cell pool. Conclusions: Blockade of CTLA-4 signaling using ipilimumab is well tolerated at the dose used thus far in this ongoing study and has anti-tumor activity in patients with follicular B-cell lymphoma. Further evaluation of the efficacy of ipilimumab at this and higher doses is therefore warranted.

Abstract Background Gastric electrical stimulation (GES) for treating gastroparesis symptoms is controversial. Methods We studied 319 idiopathic or diabetic gastroparesis symptom patients from the Gastroparesis Clinical Research Consortium (GpCRC) observational studies: 238 without GES and 81 with GES. We assessed the effects of GES using change in GCSI total score and nausea/vomiting subscales between baseline and 48 weeks. We used propensity score methods to control for imbalances in patient characteristics between comparison groups. Key Results GES patients were clinically worse (40% severe vs. 18% for non‐GES; P < .001); worse PAGI‐QOL (2.2. vs. 2.6; P = .003); and worse GCSI total scores (3.5 vs. 2.8; P < .001). We observed improvements in 48‐week GCSI total scores for GES vs. non‐GES: improvement by ≥ 1‐point (RR = 1.63; 95% CI = (1.14, 2.33); P = .01) and change from enrollment (difference = −0.5 (−0.8, −0.3); P < .001). When adjusting for patient characteristics, symptom scores were smaller and not statistically significant: improvement by ≥ 1‐point (RR = 1.29 (0.88, 1.90); P = .20) and change from the enrollment (difference = −0.3 (−0.6, 0.0); P = .07). Of the individual items, the nausea improved by ≥ 1 point (RR = 1.31 (1.03, 1.67); P = .04). Patients with GCSI score ≥ 3.0 tended to improve more than those with score < 3.0. (Adjusted P = 0.02). Conclusions and Inferences This multicenter study of gastroparesis patients found significant improvements in gastroparesis symptoms among GES patients. Accounting for imbalances in patient characteristics, only nausea remained significant. Patients with greater symptoms at baseline improved more after GES. A much larger sample of patients is needed to fully evaluate symptomatic responses and to identify patients likely to respond to GES.

Abstract Response to stem cell therapy in heart failure is heterogeneous, warranting a better understanding of outcome predictors. This study assessed left ventricular volume, a surrogate of disease severity, on cell therapy benefit. Small to large infarctions were induced in murine hearts to model moderate, advanced, and end-stage ischemic cardiomyopathy. At 1 month postinfarction, cardiomyopathic cohorts with comparable left ventricular enlargement and dysfunction were randomized 1:1 to those that either received sham treatment or epicardial delivery of cardiopoietic stem cells (CP). Progressive dilation and pump failure consistently developed in sham. In comparison, CP treatment produced significant benefit at 1 month post-therapy, albeit with an efficacy impacted by cardiomyopathic stage. Advanced ischemic cardiomyopathy was the most responsive to CP-mediated salvage, exhibiting both structural and functional restitution, with proteome deconvolution substantiating that cell therapy reversed infarction-induced remodeling of functional pathways. Moderate cardiomyopathy was less responsive to CP therapy, improving contractility but without reversing preexistent heart enlargement. In end-stage disease, CP therapy showed the least benefit. This proof-of-concept study thus demonstrates an optimal window, or “Goldilocks principle,” of left ventricular enlargement for maximized stem cell-based cardiac repair. Disease severity grading, prior to cell therapy, should be considered to inform regenerative medicine interventions. Significance statement This article documents that cardiac chamber enlargement postinfarction is a predictor of cardiopoietic stem cell therapy response. Left ventricular size pretherapy could thus serve to guide the selection of ischemic heart failure candidates most suitable to receive a regenerative intervention.

Abstract Background The treatment of oligometastatic (≤5 metastases) spinal disease has trended toward ablative therapies, yet to the authors’ knowledge little is known regarding the prognosis of patients presenting with oligometastatic spinal disease and the value of this approach. The objective of the current study was to compare the survival and clinical outcomes of patients with cancer with oligometastatic spinal disease with those of patients with polymetastatic (>5 metastases) disease. Methods The current study was an international, multicenter, prospective study. Patients who were admitted to a participating spine center with a diagnosis of spinal metastases and who underwent surgical intervention and/or radiotherapy between August 2013 and May 2017 were included. Data collected included demographics, overall survival, local control, and treatment information including surgical, radiotherapy, and systemic therapy details. Health‐related quality of life (HRQOL) measures included the EuroQOL 5 dimensions 3‐level questionnaire (EQ‐5D‐3L), the 36‐Item Short Form Health Survey (SF‐36v2), and the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ). Results Of the 393 patients included in the current study, 215 presented with oligometastatic disease and 178 presented with polymetastatic disease. A significant survival advantage of 90.1% versus 77.3% at 3 months and 77.0% versus 65.1% at 6 months from the time of treatment was found for patients presenting with oligometastatic disease compared with those with polymetastatic disease. It is important to note that both groups experienced significant improvements in multiple HRQOL measures at 6 months after treatment, with no differences in these outcome measures noted between the 2 groups. Conclusions The treatment of oligometastatic disease appears to offer a significant survival advantage compared with polymetastatic disease, regardless of treatment choice. HRQOL measures were found to improve in both groups, demonstrating a palliative benefit for all treated patients.

Abstract Background: The GALAD score is a serum biomarker–based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison with liver ultrasound for detection of HCC. Methods: A single-center cohort of 111 HCC patients and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) phase II HCC Study were analyzed. Results: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI), 0.93–97], which was higher than the AUC of ultrasound (0.82, P &lt;0.01). At a cutoff of −0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early-stage HCC detection remained high at 0.92 (95% CI, 0.88–0.96; cutoff −1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85–0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single-center cohort, achieving an AUC of 0.98 (95% CI, 0.96–0.99; cutoff −0.18, sensitivity 95%, specificity 91%). Conclusions: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score. Impact: The GALAD score was validated in the United States.