Citations

Lymphedema is a condition in which protein-rich fluid accumulates in the tissue causing impaired limb function from swelling and stiffness. Understanding the mechanical properties of soft tissue in lymphedematous limbs is important in clinical diagnosis. We recently developed an ultrasound surface wave elastography (USWE) technique for measuring the shear wave speed of tissue. The aim of this study is to evaluate lymphedematous limb use USWE. A total of 11 patients with lymphedema were included. Both normal and affected extremities were measured. A 0.1-s harmonic vibration was generated by the indenter of the handheld shaker on the limb. Ultrasound probe was used for detecting the tissue motion. Shear wave speed of the tissue was measured using 2-D processing window technique. A region of interest was selected to measure superficial and deep fat tissues. The obtained results showed that the magnitudes of the wave speeds of both the superficial and deep fat tissue at lymphedema sites were statistically higher than those of the control sites, respectively. This suggests that USWE may be useful in assessing correlation between tissue stiffness and lymphedema and would enable physicians to monitor disease severity.

AbstractNuclear actin plays a critical role in mediating mesenchymal stem cell (MSC) fate commitment. In marrow-derived MSCs, the principal diaphanous-related formin Diaph3 (mDia2) is present in the nucleus and regulates intranuclear actin polymerization, whereas Diaph1 (mDia1) is localized to the cytoplasm and controls cytoplasmic actin polymerization. We here show that mDia2 can be used as a tool to query actin-lamin nucleoskeletal structure. Silencing mDia2 affected the nucleoskeletal lamin scaffold, altering nuclear morphology without affecting cytoplasmic actin cytoskeleton, and promoted MSC differentiation. Attempting to target intranuclear actin polymerization by silencing mDia2 led to a profound loss in lamin B1 nuclear envelope structure and integrity, increased nuclear height, and reduced nuclear stiffness without compensatory changes in other actin nucleation factors. Loss of mDia2 with the associated loss in lamin B1 promoted Runx2 transcription and robust osteogenic differentiation and suppressed adipogenic differentiation. Hence, mDia2 is a potent tool to query intranuclear actin-lamin nucleoskeletal structure, and its presence serves to retain multipotent stromal cells in an undifferentiated state.

Abstract Background: Carfilzomib (CFZ) is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of selectivity for the proteasome and has been shown in a phase 1 study to result in greater than 80% proteasome inhibition on a QDx2 consecutive day schedule. We piloted this agent in MM patients with relapsed and refractory disease, who had failed bortezomib (BTZ) and at least one immunomodulatory (IMiD) agent, e.g., thalidomide (THAL) and/or lenalidomide (LEN). Methods: PX-171-003 is an open-label, multicenter study enrolling pts with MM who have relapsed from at least 2 prior therapies and who are refractory; defined as progressing on or within 60 days of last therapy or<25% response to the last therapy. Pts received CFZ 20 mg/m2 IV Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in Cycle 1. Responses were evaluated by the International Uniform Response Criteria for Multiple Myeloma. Clinical benefit response (CBR) was defined as complete response (CR) + partial/very good partial response (PR/VGPR) + minimal response (MR, as defined by EBMT criteria). Responses were adjudicated by an independent review committee. Results: 46 pts were enrolled, including 78% with progression on or within 60days of last therapy and 22% with no response to last therapy. 39 pts initiated treatment, completed at least one cycle of CFZ, had measurable M-protein, and were evaluable (eval) for response. The mean number of prior therapies (excluding transplant) was 6.4(range 1 to 18). 100% of pts received prior BTZ, 91% prior THAL, 89% prior LEN, and 83% prior stem cell transplantation (SCT). To date, pts received a median of 3 cycles(range 1–9) of CFZ; 22 started at least 4 cycles. The CBR was 26% (10/39 eval pts), including 5 pts achieving PR, 5 pts achieving MR, and 16 additional patients achieving stable disease (SD). Time to response was rapid, frequently occurring in the 1st cycle. CFZ was generally well tolerated; the most common adverse events (AEs) were fatigue(65%), nausea (37%), upper respiratory infection (37%), and diarrhea (33%). Worsening of hematologic parameters: anemia (65%); thrombocytopenia (46%) and neutropenia(20%) were predominantly Grades 1 and 2. Increased creatinine, both drug and non-drug related, was seen in 15/46 pts (33%), but treatment was discontinued in only 3 patients due to a renal adverse event. Acute renal failure was documented in 4 pts (9%), 2 (4%) of whom also had possible tumor lysis. 78% of pts had Grade 1 or 2 peripheral neuropathy (PN) at baseline. Exacerbation of PN was rare, and there were no study discontinuations or dose reductions due to PN. Conclusions: In the context of this heavily pre-treated MM population, single agent CFZ was able to induce CBR in 26% of MM patients, the majority of whom had failed BTZ, LEN, THAL, and SCT. CFZ was generally well-tolerated, and toxicities were manageable. Importantly, exacerbation of pre-existing PN was rare and did not result in dose reduction or discontinuation of therapy. These observations support further evaluation of CFZ as a promising new agent in MM. Enrollment is proceeding at an escalated dose (based on tolerability) in this trial. Additional studies of CFZ in patients who are less heavily pretreated and in combination with other chemotherapy agents are ongoing.

Abstract Abstract 39 Three randomized trials have previously reported a progression-free survival (PFS) advantage for patients receiving thalidomide (T) maintenance post ASCT in MM. Two trials reported an overall survival (OS) advantage but the largest trial reported shows no OS advantage and in very high risk MM the use of T was deleterious. Recent trial reports demonstrate a PFS but not yet an OS advantage for patients receiving maintenance lenalidomide. We report results of NCIC CTG MY.10 which compared treatment with T (200 mg daily) and prednisone (50 mg alternate days) (T/P) until progression versus observation alone when used as maintenance therapy following ASCT. Importantly, OS was the 1ry endpoint of this study, 2ry endpoints were PFS, quality of life (QoL), toxicity, and the incidence of venous thromboembolism events (VTE). Eligibility: Patients with MM who had ASCT within 1 year of beginning initial treatment for their disease. Patients were randomized 60–100 days post ASCT and had no other medical condition precluding long term use of T/P. Results: 332 patients were enrolled. Median age was 58 years and the arms were balanced. Patients were stratified by age (<60 or >60), and CR status post transplant. Median follow up is 4 years. Only 14% of patients were in CR post transplant. 111 patients died (50 versus 61 in T/P vs. observation). The median OS was 5 years for observation, and has not yet been reached for T/P, however T/P maintenance therapy did not significantly prolong OS: p = 0.18, HR of maintenance vs. observation 0.77 (95% CI 0.53–1.13). The 4 year survival rate was 68% for T/P and 60% for observation. Age and response to transplant had no significant association with OS (p=0.21), while higher disease stage was associated with shorter OS (p=0.03). The median PFS was 28 months for T/P versus 17 months for observation: p<0.0001, HR of T/P vs. observation 0.56 (95% CI 0.43 – 0.73). The 4 year PFS rate was 32% for T/P treated patients versus 14% for patients on observation. At relapse, treatment by arm (T/P vs observation) included lenalidomide (39 vs 34%), T (13 vs 22%) or bortezomib (50 versus 46%). Non hematologic toxicities were seen in more patients with treatment (Grade 3: 92% T/P vs 49% observation, grade 4: 16% vs 7%). Common toxicities of all grades that were significantly higher in T/P treated patients included hyperglycemia, edema, hypertension, fatigue, Cushingoid appearance, constipation, mouth dryness, dyspepsia, anxiety, memory loss, sensory neuropathy, tremor, blurred vision, depressed consciousness, cataracts, dyspnea and bruising. 7% of patients on maintenance T/P developed a VTE in the absence of prophylaxis versus 0% on observation. NCIC CTG standardized response analysis was use to compare QoL data between the 2 treatment arms. Overall, patients on T/P had worse QoL specifically in physical (p=0.07), role (p=0.08), cognitive (p = 0.01) and global (p=0.06) domains, and worse symptoms with dyspnea (p = 0.0007), constipation (p<0.0001), thirst (p=0.003), swelling in leg (p=0.03), numbness (p=0.02), dry mouth (p<0.0001), and balance problems (p<0.0001). However, patients on T/P reported improvement in appetite (p 0.02), and sleep (p=0.04). Conclusions: T/P maintenance did not improve overall survival, the primary objective of this trial, although a trend in favor of T/P was seen. In contrast, PFS was significantly improved in the T/P arm while toxicity was demonstrably increased and quality of life diminished. Disclosures: Stewart: Millennium: Consultancy; Celgene: Honoraria. Trudel:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Research Funding, Speakers Bureau. White:Celgene: Honoraria, Research Funding. Meyer:Celgene: Honoraria.

Abstract Introduction: In multiple myeloma, randomized trials of maintenance therapy using thalidomide or lenalidomide following autologous transplant (ASCT) demonstrated prolonged progression-free survival (PFS), but overall survival benefit was inconsistent. The MY.10 trial (n=332) demonstrated improved PFS with thalidomide-prednisone maintenance therapy, but quality of life was inferior and overall survival was not improved. As a randomized trial with a no-treatment control arm and biospecimen collection, MY.10 provides a unique opportunity to identify predictors of benefit from therapy that could be used to personalize treatment. Immunomodulatory drug action is mediated in part through binding to cereblon (CRBN) and downregulation of IRF4. Candidate single nucleotide polymorphisms (SNPs) were selected from the CRBN/IRF4 pathway and other genes previously associated with myeloma prognosis, drug response and toxicity from literature review. The aim of this study was to investigate associations between candidate SNPs and benefit from immunomodulatory compound-based maintenance therapy, as well as prognostic impact. Methods: Genomic DNA was extracted from samples preserved in Trizol¨. SNPs were genotyped using TaqMan¨ genotyping assays on the ViiA7 qPCR platform. Analysis was performed on 187 patients with available samples and clinical data (86 in treatment arm; 101 in observation arm). Cox regression models were performed using SAS clinical 2.0 for prognostic impact of a single SNP on PFS, assessed with and without adjusted covariates (age, stage, performance status and response to ASCT). In treatment benefit analysis, PFS was modeled with genotype, treatment assignment and their interaction term. Results: SNPs with significant prognostic impact for PFS in all 187 patients were found in CRBN (rs1672753) (HR 0.59, 95%CI 0.4-0.86; p=0.006) and the following SNPs which had been found to be prognostic in prior studies were validated: CYP1A1 (rs1048943) (HR 1.98, 95%CI 1.19-3.27; p=0.008), CYP1B1 (rs1056836) (HR 0.72, 95%CI 0.52-0.99; p=0.043), and trend toward significance for SNP in CYP1A2 (rs2069514) (HR 2.02, 95%CI 0.98-4.15; p=0.057). Of these, only the CYP1A1 SNP was found to be possibly predictive of greater benefit from maintenance therapy. A SNP in ABCA1 (rs363717), previously associated with thalidomide-induced neuropathy,‎ was prognostic in this study (HR 1.44, 95%CI 1.03-2.02; p=0.033) but not predictive of treatment benefit. Table 1 lists SNPs associated with a differential level of benefit from maintenance therapy, including SNPs in FAM179a and ICAM1 that were possibly associated with harm from maintenance therapy. Table 1. SNPs and treatment interaction with significant impact on PFS. HR represent hazard ratio of treatment versus observation for a given genotype group. Asterisk Indicates trend toward significance. Wildtype Heterozygote & mutant p-value interaction Gene dbSNP ID SNP HR 95% CI HR 95% CI FAM179A rs1053667 T>C 0.46 0.33, 0.66 2.28 0.78, 6.65 0.003 ICAM1 rs1799969 G>A 0.51 0.36, 0.73 1.75 0.83, 3.70 0.007 CASP3 rs1049216 A>G 0.82 0.54, 1.25 0.41 0.25, 0.69 0.029 IRF4 rs12203592 C>T 0.69 0.47, 1.02 0.38 0.21, 0.69 0.062* CYP1A1 rs1048943 A>G 0.62 0.44, 0.87 0.11 0.02, 0.52 0.079* Conclusion: Previously identified SNPs in drug metabolism and drug efflux genes were validated to be prognostic in this cohort. The prognostic but not predictive significance of a SNP in CRBN suggests a possible role for CRBN in multiple myeloma disease biology independent of immunomodulatory therapy. SNPs predictive of differing degrees of benefit from immunomodulatory maintenance were found in genes involved in immunomodulatory activation, drug action and cell adhesion mediated drug resistance; SNPs in FAM179A and ICAM1 were possibly associated with harm from thalidomide maintenance and could potentially be used to identify patients unsuitable for immunomodulatory maintenance therapy. These results may be applicable to lenalidomide and pomalidomide, since immunomodulatory compounds exhibit similar chemical structures and mechanisms of action. Validation of these SNPs in prospective clinical trials involving other immunomodulatory can test this hypothesis. Further studies are needed to confirm our findings. Disclosures Off Label Use: thalidomide and prednisone maintenance for multiple myeloma. Bahlis:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Johnson & Johnson: Research Funding. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Celgene Canada: Honoraria, Research Funding. Chen:Celgene: Consultancy, Honoraria, Research Funding. Seftel:Celgene: Honoraria, Research Funding. Howsen-Jan:Celgene: Honoraria, Research Funding. Reece:Amgen: Honoraria; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Onyx: Consultancy; Millennium Takeda: Research Funding; Lundbeck: Honoraria; Otsuka: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Shepherd:Celgene: Honoraria, Research Funding. Chen:Celgene: Honoraria, Research Funding. Djurfeldt:Celgene: Research Funding. Reiman:Soricimed Biopharma Inc: Consultancy, Other: Scientific Advisory Board for Soricimed.

Background Periodic wellness assessments can provide an estimate of a person’s relative risks for major diseases, but wellness visits are underused. Our suggestion is to use a comprehensive device during a single visit. Objective The goal of this pilot study was to evaluate the feasibility of a novel one-stop wellness device (Preventiometer; iPEx5 GmbH, Greifswald, Germany) for performing multiple tests and providing a comprehensive wellness assessment in a short period. Methods A Preventiometer was used to provide wellness assessments for 10 healthy volunteers who then answered a 25-question survey to rate their satisfaction with the testing and their overall impression. Results All volunteers agreed or strongly agreed with the following: The assessment reports were easy to understand, the Preventiometer met their satisfaction, the participants were comfortable during the assessment, and all measurements and testing were well coordinated. Participants liked the instant test result feature. Most (90%) agreed that the machine was useful for a quick health assessment for busy people, and 70% felt that it was time efficient. Conclusion In this feasibility pilot study, the Preventiometer performed multiple tasks and provided a comprehensive wellness assessment in a short period. Participants reported remarkably high satisfaction with the tests. A larger study is needed to prove that this is a pragmatic approach to help individuals improve their health.

Abstract Background: Mild cognitive impairment (MCI) is an intermediate stage between the cognitive changes of normal aging and early dementia. Tai Chi (TC) may be particularly beneficial to patients with MCI due to its whole-body coordination characteristics. This systematic review protocol aims to outline the methods that will be used to assess the comparative effectiveness and safety of TC for MCI through a systematic review and meta-analysis. Methods: A systematic review will identify and evaluate randomized controlled trials (RCTs) that examined the effects and safety of TC compared to a placebo, conventional treatment, and no treatment on cognitive function in individuals with MCI. Studies from databases of MEDLINE, PubMed, Embase, Global Health, Cochrane Library, and Scopus from January 1990 to March 2019 reported in English will be searched. Two independent reviewers will screen the studies for inclusion with the eligibility criteria and extract data. Risk of bias of individual studies will be assessed in line with Cochrane risk of bias tool. The overall quality of cumulative evidence will be assessed using selected Grading of Recommendations, Assessment, Development, and Evaluations criteria. Statistics will be used for heterogeneity assessment, sensitivity analysis, data synthesis, generating funnel plots, and subgroup analysis. Meta-analysis will be performed, if sufficiently homogeneous studies are found. A narrative synthesis will be conducted, grouping studies by exposure and outcome definitions, and describing any differences by subgroups. Results: This study will provide practical and targeted evidence in investigating the impact of TC exercise for individuals with MCI. Conclusion: The findings of our study will provide updated evidence to determine whether TC is an effective intervention to patients with MCI. Trial registration number: International Prospective Register for Systematic Reviews (PROSPERO) number CRD42019125104.

AbstractBackgroundVascularized lymph node transfer (VLNT) is an emerging surgical treatment for lymphedema. However, literature‐comparing outcomes of upper limb lymphedema (ULL) and lower limb lymphedema (LLL) is limited. Hence, the aim of this study is to compare the long‐term clinical outcomes on ULL versus LLL in patients treated with VLNT.MethodsA retrospective study retrieving data from patients with International Society of Lymphology (ISL) stages II–III who underwent different VLNTs from July 2010 to July 2016 in our institution was performed. Demographics preoperatively, and clinical data (limb circumference, infectious episodes, lymphoscintigraphic studies) preoperatively and postoperatively were recorded. Clinical outcomes by extremity were also analyzed.ResultsA total of 83 patients with lymphedema (ULL: n = 30, LLL: n = 53) were included. Mean follow‐up time was 32.8 months (range 24–49 months). Mean circumference reduction was higher in patients with ULL compared to with LLL (28.6 ± 8.6 vs. 22.3 ± 10.1, p < .001), and for patients with secondary lymphedema (24.8 ± 9.6, p < .001) than for patients with primary lymphedema (18.9 ± 14, p > .05). Infectious episodes per year preoperative and postoperative showed that LLL patients had higher reduction on infection rate compared with ULL patients (2.4 ± 1.1 vs. 1.9 ± 1.2, p < .001).ConclusionVLNT is a promising surgical treatment option for patients with lymphedema. This study suggests that VLNT may have a more beneficial outcome in patients with ULL and with secondary lymphedema.

Abstract Background Platinum chemotherapy (carboplatin or cisplatin) + etoposide is the current 1L standard of care treatment (tx) for ES-SCLC. Despite high response rates on this regimen, patient (pt) outcomes remain poor. IMpower133 is a Ph1/3, double-blind, randomized, placebo (PBO)-controlled trial that is evaluating the efficacy and safety of adding PD-L1-inhibitor atezo or PBO to 1L tx for ES-SCLC (NCT02763579). Methods IMpower133 enrolled pts without prior tx for ES-SCLC; PD-L1 testing was not required. Pts were randomized 1:1 to four 21-day cycles of carboplatin (AUC 5 mg/mL/min IV, Day 1) + etoposide (100 mg/m2 IV, Days 1-3) with either atezo (1200 mg IV, Day 1) or PBO, then maintenance atezo or PBO until PD, unacceptable toxicity or loss of clinical benefit. Maintenance prophylactic cranial irradiation (PCI) was allowed per protocol, while definitive thoracic radiation (TR) was not. Coprimary endpoints were OS and investigator-assessed PFS. A key exploratory endpoint was outcomes by blood tumor mutation burden (bTMB) analyzed at prespecified cutoffs (≥ 16 vs &lt; 16 and ≥ 10 vs &lt; 10 mutations/Mb). Results Adding atezo to carboplatin + etoposide demonstrated significant improvement in efficacy (OS and PFS) in 1L ES-SCLC (Table). Survival benefits were consistent across key subgroups and prespecified bTMB cutoffs. 44 pts (22 in each arm [per ITT]) received PCI, and 7 (3 in atezo arm, 4 in PBO arm) received TR. Gr 3-4 tx-related adverse events (AEs) occurred in 57% of atezo pts vs 56% of PBO pts; serious tx-related AEs occurred in 23% vs 19%. Occurrence of CNS-related AEs in pts who had PCI are shown in the Table. Conclusion Adding atezo to carboplatin + etoposide resulted in a significant improvement in survival in this 1L ES-SCLC all-comers population. There were no new safety signals, including in pts who received PCI or TR. Atezo + carboplatin + etoposide may represent a new standard regimen for untreated ES-SCLC. Atezo + carboplatin + etoposiden = 201PBO + carboplatin + etoposiden = 202Co-primary endpointsMedian OS, mo12.310.3HR 0.70 (95% CI: 0.54, 0.91); P = 0.0069Median PFS, mo5.24.3HR 0.77 (95% CI: 0.62, 0.96) P = 0.017Secondary efficacy endpointsInvestigator-assessed confirmed ORR, %60.264.4Median DoR, mo4.23.9CNS-related AEs in pts who had PCI, n (%)a,bn = 23n = 21Headache8 (34.8)4 (19.0)Asthenia5 (21.7)2 (9.5)Dizziness2 (8.7)0Insomnia2 (8.7)1 (4.8)Fall2 (8.7)1 (4.8)aSafety population; safety analyses conducted according to tx received (1 pt randomized to the control arm received a dose of atezo).bIncludes AEs occurring in ≥ 2 patients. Citation Format: Aaron S. Mansfield, Stephen V. Liu, Aleksandra Szczęsna, Libor Havel, Maciej Kzrakowski, Maximilian J. Hochmair, Florian Huemer, György Losonczy, Melissa L. Johnson, Makoto Nishio, Martin Reck, Tony S. Mok, Sivuonthanh Lam, David S. Shames, Juan Liu, Fairooz Kabbinavar, Alan Sandler, Leora Horn. IMpower133: Primary efficacy and safety + CNS-related adverse events in a Ph1/3 study of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT199.