Citations

Abstract Introduction: The NCIC CTG previously reported the results of a dose-finding trial testing the combination of Melphalan (M) and Lenalidomide (L) in previously untreated patients with multiple myeloma who were ineligible for stem cell transplantation because of older age and/or comorbidity (White, Blood2007; 110: 63a). Using a 28-day schedule, M (dose indicated as mg/m2/day given on days 1–4) and L (dose indicated in mg/day given on days 1–21) was associated with excess toxicity with the regimens M9L10, M4L15 and M6L10. We concluded that phase II testing of M5L10 was warranted and now report the results of this testing. Methods: Previously untreated symptomatic and consenting patients with tissue-confirmed plasmacytosis and a measurable M-protein were eligible provided that they had acceptable hematologic and biochemical laboratory parameters and no precluding comorbidities. Planned treatment consisted of M 5 mg/m2 days 1–4 and L 10 mg days 1–21, given every 28 days for 12 cycles. As our intent was to determine dose levels that could be given independently of G-CSF, primary prophylaxis with G-CSF was not included but use of G-CSF for established neutropenia was permitted. A hematologic dose limiting toxicity (H-DLT) was defined as the need for 2 dose attenuations of L or 1 dose attenuation of M occurring within the first 3 treatment cycles. Responses to treatment were classified using 1998 EBMT criteria and assessed after 2 and 6 cycles of therapy. Results: The intended sample size was 41 patients; 35 patients (1 ineligible) were enrolled before the study was closed due to observing a frequency of DLTs that surpassed predefined boundaries. Of the 34 eligible patients, median age was 73.4 yrs and ISS was stage I = 13, stage II = 11 and stage III = 10. Prior to study closure, 27 patients were evaluable for DLT; 7 (26%) did not experience a DLT. Among the remaining 20 (74%) patients, non-hematologic (N=2) and hematologic (N=18) DLTs requiring dose attenuations were seen within the first 3 treatment cycles; the H-DLTs included severe or prolonged neutropenia (N=11), thrombocytopenia (N=2) or both (N=5). One fatal serious adverse event was observed, this was due to a stroke. The other non-hematologic DLT was a cranial nerve III palsy which subsequently resolved. Responses after 2 cycles were evaluable in 21 patients and included partial response (PR) = 11, minimal response = 6, no change = 2 and progressive disease (PD) = 2. For those patients without PD after 2 cycles, responses after 6 cycles were evaluable in 8 and included PR = 6, stable response = 1 and PD = 1. Conclusion: Although M + L is an active combination for previously untreated myeloma patients, the regimen is associated with considerable myelosuppression. Without the routine use of GCSF, the doses used in the MY.11 study were not tolerable. Inability to use planned doses may have compromised the efficacy of the combination.

Abstract Introduction. The NCIC CTG is conducting phase II testing to establish the tolerability and estimate the efficacy of combining lenalidomide (L) + melphalan (M) over multiple cycles for previously untreated patients with multiple myeloma who are ineligible for stem cell transplantation. We report the data from the preliminary safety phase of this trial. Methods. The MY.11 trial was initially designed as a randomized phase II test of M 9 mg/m2 given on days 1–4 (M9) plus either L 10 mg (L10) or 20 mg given on days 1–21 of a 28 day cycle. Primary prophylaxis with G-CSF was not included, but use of G-CSF for established neutropenia was permitted; our intent was to determine dose levels that could be given independently of G-CSF. A dose attenuation schedule was developed for neutropenia and/or thrombocytopenia that was severe and occurred during the administration of L or was persistent and caused a delay in the next treatment cycle. A hematologic dose limiting toxicity (H-DLT) was defined as the need for 2 dose attenuations of L or 1 dose attenuation of M. Prior to the randomized phase of the trial, a safety run-in phase testing M9+L10 in 6 patients was planned; closure of this arm was to occur if, during the first 3 treatment cycles, there were ≥ 3 H-DLTs or any non-hematologic serious adverse event (SAE) judged to be treatment related. Four of the planned 6 patients were entered; during their first 3 treatment cycles, each experienced a H-DLT and one died from sepsis. The study was therefore amended with the intent to conduct a randomized phase II test of M 4 mg/m2 days 1–4 plus L 15 mg days 1–21 (M4L15) and M 6 mg/m2 days 1–4 plus L 10 mg days 1–21 (M6L10). Prior to the randomized phase of testing, each regimen was tested in non-randomized safety run-ins that included 6 patients per arm. The same parameters as above for study arm closure were applied. If the M6L10 arm was closed, the trial would proceed to test M 5 mg/m2 days 1–4 and L 10 mg days 1–21 (M5L10). Results. Six patients were enrolled to M4L15: during their first 3 treatment cycles, 4 patients experienced H-DLTs related to severe or persistent grade 3–4 neutropenia and one other patient experienced an SAE related to hallucinations and multiple constitutional complaints. This arm was therefore closed to accrual. Six patients were enrolled to M6L10: during their first 3 treatment cycles, 3 patients experienced H-DLTs related to severe or persistent grade 3–4 neutropenia. One of these patients was hospitalized with pulmonary edema and another with febrile neutropenia. This arm was therefore closed and the MY.11 trial amended to proceed as a single-arm phase II testing M5L10. Conclusion. Although M + L holds promise as an effective combination for previously untreated myeloma patients, the regimen is associated with considerable myelosuppression. The efficacy of the combination when given at tolerable doses remains to be established.

Objectives: To understand from the perspective of patients who did, and did not attend ICU recovery programs, what were the most important components of successful programs and how should they be organized. Design: International, qualitative study. Setting: Fourteen hospitals in the United States, United Kingdom, and Australia. Patients: We conducted 66 semi-structured interviews with a diverse group of patients, 52 of whom had used an ICU recovery program and 14 whom had not. Interventions: None. Measurements and Main Results: Using content analysis, prevalent themes were documented to understand what improved their outcomes. Contrasting quotes from patients who had not received certain aspects of care were used to identify perceived differential effectiveness. Successful ICU recovery programs had five key components: 1) Continuity of care; 2) Improving symptom status; 3) Normalization and expectation management; 4) Internal and external validation of progress; and 5) Reducing feelings of guilt and helplessness. The delivery of care which achieved these goals was facilitated by early involvement (even before hospital discharge), direct involvement of ICU staff, and a focus on integration across traditional disease, symptom, and social welfare needs. Conclusions: In this multicenter study, conducted across three continents, patients identified specific and reproducible modes of benefit derived from ICU recovery programs, which could be the target of future intervention refinement.

OBJECTIVE Multiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal-dominant tumor disorder characterized by the development of pituitary tumors and other endocrine neoplasms. Diagnosis is made clinically based on the development of 2 or more canonical lesions (parathyroid gland, anterior pituitary, and enteropancreatic tumors) or in family members of a patient with a clinical diagnosis of MEN1 and the occurrence of one of the MEN1-associated tumors. The goal of this study was to characterize pituitary tumors arising in the setting of MEN1 at a single institution. The probability of tumor progression and the likelihood of surgical intervention in patients with asymptomatic nonfunctional pituitary adenomas were also analyzed. METHODS A retrospective review of a prospectively maintained institutional database was performed for patients with MEN1 diagnosed from 1970 to 2017. Data included patient demographics, tumor characteristics, treatment strategies, and outcomes. RESULTS A review of the database identified 268 patients diagnosed with MEN1, of whom 158 (59%) were female. Among the 268 patients, 139 (51.8%) had pituitary adenomas. There was a higher prevalence in women than in men (65% vs 35%, p < 0.005). Functional adenomas (57%) were more common. Prolactin-secreting adenomas were the most common functional tumors. Macroadenomas were seen in 27% of patients and were more likely to be symptomatic and locally aggressive (p < 0.001). Forty-nine patients (35%) underwent transsphenoidal resection at some point during their disease course. In 52 patients who were initially observed with MEN1 asymptomatic nonfunctional adenomas, only 5 (10%) progressed to need surgery. In MEN1 patients, an initial parathyroid lesion is most likely followed in order by pituitary, pancreatic, adrenal, and, finally, rare carcinoid tumors. CONCLUSIONS Asymptomatic nonfunctional pituitary adenomas in patients with MEN1 may be followed safely with MRI. In this series, parathyroid tumors developed at the lowest median age of all cardinal tumors, and development of additional cardinal MEN1 lesions followed a predictable pattern. This pattern of disease progression could have significant implications for disease surveillance in clinical practice and may help to target clinical resources to the lesions most likely to develop next. This may aid with early detection and treatment and warrants further study.

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P < 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P < 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS

Abstract Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600–mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.

Abstract Aims Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS. Methods and results Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort. Conclusions Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome. Trial registration ClinicalTrials.gov number: NCT01947621.

8522 Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2 complexes. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with advanced DLBCL, MM and select solid tumors were enrolled in parallel expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 35 subjects were enrolled including DLBCL (21) and MM (14). Results in solid tumor cohorts are reported separately. The most common (> 20%) related adverse events (all grades) were fatigue, hyperglycemia, rash, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (2), pneumonitis (1), renal insufficiency (2), pancreatitis (1) and thrombocytopenia (1). CC-223 dose reduction was required in 9 subjects (27%), usually during cycle 1 or 2, and 4 additional subjects with DLBCL dropped out during cycle 1 due to toxicity. Systemic exposure was similar between the two tumor cohorts and was associated with inhibition of TORC1 (p4EBP1) and TORC2 (pAKT) biomarkers in blood cells. Reduction in glucose uptake (32 – 98% decrease) on PET imaging at day 15 was observed in 7/7 DLBCL subjects with results currently available. Three of 17 evaluable subjects with DLBCL had partial responses (PR) after 2 cycles; two with rapid and near complete regression (> 90%) of target lesions by CT and PET with PR confirmed and treatment ongoing at 6 and 8 cycles. Both had failed multiple prior treatment regimens (5 and 3, respectively), including autologous stem cell transplant (ASCT). No responses were observed in 10/14 evaluable subjects with MM although 2 subjects have prolonged stable disease (SD) with treatment ongoing at 12 and 14 cycles. Conclusions: Encouraging signals of biomarker and clinical activity were observed in DLBCL, including two near complete responses, which are ongoing. Due to dose reductions and interruptions, a starting dose of 30 mg QD is recommended for future studies. Clinical trial information: NCT01177397.

10554 Background: Age at diagnosis is a prognostic factor in patients with RMS. We sought to determine whether AYA with metastatic alveolar (ARMS) or embryonal (ERMS) RMS had a different failure-free survival (FFS) compared to younger patients, and to identify treatment related factors that may be associated with outcome. Methods: COG ARST0431 patients were reviewed. The incidence of toxicities (AE, grade3/4 using CTCAEv3) by age was determined in 4 reporting periods (RP: wks 1-6; RP2:7-19; RP3: 20-34; RP4: 35-54). The AEs in younger patients (<=13 years) were compared with those in AYA. Fisher’s exact test was used to compare differences between the groups. Results: Of 109 patients, 60 (55%) were AYA. In RP1, they were more likely to have nausea/vomiting (4.1 vs. 16.9%, p=0.06), pain (6.1 vs. 20.3%, p=0.05), and metabolic disturbances (4.1 vs. 20.3%, p=0.02) compared to younger patients. In RP4, older patients trended to have less infection (15.8 vs. 30.1, p=0.07). All other toxicities were similar between the two age cohorts in the other RPs. AYA were less likely to complete therapy (52 vs. 73%, p=0.03) and more likely (in RP 4) to have unplanned dose modifications (outside of protocol guidelines) (23 vs. 2.7%). Of patients that completed therapy, there was no age-related difference in the time to completion. As shown in the table, younger patients had better 3-yr FFS, driven by a lower FFS for AYA with ARMS. Conclusions: This evaluation suggests that AYA with RMS were less likely to complete therapy and experienced a higher prevalence of pain and nausea compared to younger patients; the role of reporting bias and reasons for treatment discontinuation need further study. Children were more likely than AYA to have infection. Inferior FFS was only seen in AYA with ARMS suggesting a clear need for novel therapies for these patients. This study may be underpowered to demonstrate significant differences in other toxicities or in FFS among ERMS patients. [Table: see text]

Background Changes in white matter microstructural integrity are detectable before appearance of white matter lesions on magnetic resonance imaging as a manifestation of cerebral small‐vessel disease. The information relating poor white matter microstructural integrity to aortic stiffness, a hallmark of aging, is limited. We aimed to examine the association between aortic stiffness and white matter microstructural integrity among older adults. Methods and Results We conducted a cross‐sectional study to examine the association between aortic stiffness and white matter microstructural integrity among 1484 men and women (mean age, 76 years) at the 2011 to 2013 examination of the ARIC‐NCS (Atherosclerosis Risk in Communities Neurocognitive Study). Aortic stiffness was measured as carotid‐femoral pulse wave velocity. Cerebral white matter microstructural integrity was measured as fractional anisotropy and mean diffusivity using diffusion tensor imaging. Multivariable linear regression was used to examine the associations of carotid‐femoral pulse wave velocity with fractional anisotropy and mean diffusivity of the overall cerebrum and at regions of interest. Each 1‐m/s higher carotid‐femoral pulse wave velocity was associated with lower overall fractional anisotropy (β=−0.03; 95% CI , −0.05 to −0.02) and higher overall mean diffusivity (β=0.03; 95% CI , 0.02–0.04). High carotid‐femoral pulse wave velocity (upper 25th percentile) was associated with lower fractional anisotropy (β=−0.40; 95% CI , −0.61 to −0.20) and higher overall mean diffusivity (β=0.27; 95% CI , 0.10–0.43). Similar associations were observed at individual regions of interest. Conclusions High aortic stiffness is associated with low cerebral white matter microstructural integrity among older adults. Aortic stiffness may serve as a target for the prevention of poor cerebral white matter microstructural integrity.