6 research outputs found
Characterizing Muscle Phenotype and Prognosis in Patients with Multiple Myeloma
No full textBackground/Objective:
Low muscle mass (myopenia), poor muscle quality, myosteatosis, and muscle loss are associated with mortality in solid tumors. However, their impact in hematological malignancies remains unclear. We sought to determine how muscle phenotype relates to survival in patients with multiple myeloma.
Methods:
We performed a retrospective review of patients with multiple myeloma treated at Indiana University Hospital from 2012-2016. Total skeletal muscle area (SMA) (cm2) and radiodensity were measured on baseline (closest to diagnosis) and last CT scans at the third lumbar vertebrae area. SMA was normalized to height (SMA cm2/m2) to define skeletal muscle index (SKMI). Myopenia was defined as (SKMI) <52.4 cm2/m2 (men) and <38.5 cm2/m2 (women). Myosteatosis and obesity were defined per published BMI-specific cutoffs. Difference in survival between groups was estimated using log rank test.
Results:
Of 455 patients with multiple myeloma, 137 had more than one CT scan; 42 of these have been assessed to date. Half (21/42) were myopenic. Myopenia was equally prevalent across BMI categories and showed no association with survival. More than half of patients displayed myostetatosis; however, this was not associated with survival. Obesity and myopenic obesity were likewise not correlated with survival. Below-median baseline SKMI correlated with mortality, HR 2.721 (95% CI, 1.160-5.564: P=0.0129). As well, below-median final SMA correlated with mortality, HR 2.381 (95% CI, 1.094-5.181, P=0.0213). On average patients lost .7129% of SMA (95% CI; -6.072%-4.646%). Females had higher mortality, HR 2.355 (95% CI 0.9895-5.604, P=0.0215).
Conclusion and Potential Impact:
Although this study represents a fraction of treated patients to date, myopenia was prevalent among patients at diagnosis of multiple myeloma. Low muscle mass and sex appear to be important prognostic factors for survival. Additional measurements as well as univariate and multivariate analyses are necessary to verify these findings and identify additional factors that contribute to survival in multiple myeloma. 
Sex specificity of pancreatic cancer cachexia phenotypes, mechanisms, and treatment in mice and humans: role of Activin
No full textBACKGROUND: Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting was clinically tested for cancer cachexia therapy. However, sex‐specific manifestations and mechanisms are poorly understood, constraining development of effective treatments. METHODS: Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc were assessed in LSL‐Kras ( G12D/+ ), LSL‐Trp53 ( R172H/+ ), and Pdx‐1‐Cre (KPC) mice with autochthonic PDAC. Effects of PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC‐cell conditioned medium (CM) and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients with PDAC. RESULTS: Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior muscles were reduced (−21.7%, −18.9%, and −20.8%, respectively, all P < 0.001), with only gastrocnemius reduced in females (−16%, P < 0.01). Sex differences disappeared in late PDAC. Plasma Activin A was similarly elevated between sexes throughout, while oestrogen and testosterone levels suggested a virilizing effect of PDAC in females. Estradiol partially protected myotubes from KPC‐CM induced atrophy and promoted expression of the potential Activin inhibitor Fstl1. Early‐stage female mice showed greater muscle expression of Activin inhibitors Fst, Fstl1, and Fstl3; this sex difference disappeared by late‐stage PDAC. ACVR2B/Fc initiated in early PDAC preserved muscle and fat only in male KPC mice, with increases of 41.2%, 52.6%, 39.3%, and 348.8%, respectively, in gastrocnemius, quadriceps, tibialis, and fat pad weights vs. vehicle controls, without effect on tumour. No protection was observed in females. At protein and RNA levels, pro‐atrophy pathways were induced more strongly in early‐stage males, with sex differences less evident in late‐stage disease. As with mass, ACVR2B/Fc blunted atrophy‐associated pathways only in males. In patients with resectable PDAC, muscle expression of Activin inhibitors FSTL1, FSLT3, and WFIKKN2/GASP2 were higher in women than men. Overall, among 124 patients on first‐line gemcitabine/nab‐paclitaxel for PDAC, only men displayed muscle loss (P < 0.001); average muscle wasting in men was greater (−6.63 ± 10.70% vs. −1.62 ± 12.00% mean ± SD, P = 0.038) and more rapid (−0.0098 ± 0.0742%/day vs. −0.0466 ± 0.1066%/day, P = 0.017) than in women. CONCLUSIONS: Pancreatic ductal adenocarcinoma cachexia displays sex‐specific phenotypes in mice and humans, with Activin a preferential driver of muscle wasting in males. Sex is a major modulator of cachexia mechanisms. Consideration of sexual dimorphism is essential for discovery and development of effective treatments
Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia
No full textMost patients with pancreatic adenocarcinoma (PDAC) suffer cachexia; some do not. To model heterogeneity, we used patient-derived orthotopic xenografts. These phenocopied donor weight loss. Furthermore, muscle wasting correlated with mortality and murine IL-6, and human IL-6 associated with the greatest murine cachexia. In cell culture and mice, PDAC cells elicited adipocyte IL-6 expression and IL-6 plus IL-6 receptor (IL6R) in myocytes and blood. PDAC induced adipocyte lipolysis and muscle steatosis, dysmetabolism, and wasting. Depletion of IL-6 from malignant cells halved adipose wasting and abolished myosteatosis, dysmetabolism, and atrophy. In culture, adipocyte lipolysis required soluble (s)IL6R, while IL-6, sIL6R, or palmitate induced myotube atrophy. PDAC cells activated adipocytes to induce myotube wasting and activated myotubes to induce adipocyte lipolysis. Thus, PDAC cachexia results from tissue crosstalk via a feed-forward, IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6, all targetable mechanisms for treatment of cachexia
Randomized Phase II Study of Nab-Paclitaxel and Gemcitabine With or Without Tocilizumab as First-Line Treatment in Advanced Pancreatic Cancer:Survival and Cachexia
No full textPurposeThis randomized phase-II trial (ClinicalTrials.gov identifier: NCT02767557) compared efficacy of gemcitabine/nab-paclitaxel (Gem/Nab) with or without the anti–interleukin-6 (IL-6) receptor antibody tocilizumab (Toc) for advanced pancreatic cancer (PC).MethodsA safety cohort received Gem 1,000 mg/m2 and Nab 125 mg/m2 on days 1, 8, and 15, and Toc 8 mg/kg on day 1 for each 28-day cycle. Participants with modified Glasgow prognostic scores of 1 or 2 were randomly assigned 1:1 to receive Gem/Nab/Toc or Gem/Nab. The primary end point was the overall survival (OS) rate at 6 months (OS6). Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety. Exploratory end points were cachexia, quality of life, and biomarkers, including the cachexia-promoting protein, growth differentiation factor 15 (GDF15).ResultsOverall, 147 patients were treated, including six safety cohort participants. The median follow-up period was 8.1 months (IQR, 4.2-13.9). OS6 was 68.6% (95% CI, 56.3 to 78.1) for the Gem/Nab/Toc group and 62.0% (49.6-72.1) for the Gem/Nab group (P = .409). OS for Gem/Nab/Toc versus Gem/Nab improved at 18 months (27.1% v 7.0%, P = .001). No differences in median OS, PFS, or ORR were observed. Incidence of grade-3+ treatment-related adverse events (TrAEs) was 88.1% for Gem/Nab/Toc and 63.4% for Gem/Nab (P < .001). Gem/Nab/Toc decreased muscle loss versus Gem/Nab, with median change +0.1013% versus –3.430% (P = .0012) at 2 months and +0.7044 versus –3.353% (P = .036) at 4 months. Incidence of muscle loss was 43.48% on Gem/Nab/Toc versus 73.52% on Gem/Nab at 2 months (P = .0045) and 41.82% versus 68.75% (P = .0062) at 4 months. GDF15 was not changed by Gem/Nab or Gem/Nab/Toc.ConclusionAlthough the primary end point was not met and TrAEs were increased by Toc, increased survival at 18 months and reduced muscle wasting support an anticachexia effect of IL-6 blockade independent of GDF15. Further studies could leverage these findings for precision anticachexia therapy.PURPOSE This randomized phase-II trial (ClinicalTrials.gov identifier: NCT02767557) compared efficacy of gemcitabine/nab-paclitaxel (Gem/Nab) with or without the anti-interleukin-6 (IL-6) receptor antibody tocilizumab (Toc) for advanced pancreatic cancer (PC).METHODSA safety cohort received Gem 1,000 mg/m2 and Nab 125 mg/m2 on days 1, 8, and 15, and Toc 8 mg/kg on day 1 for each 28-day cycle. Participants with modified Glasgow prognostic scores of 1 or 2 were randomly assigned 1:1 to receive Gem/Nab/Toc or Gem/Nab. The primary end point was the overall survival (OS) rate at 6 months (OS6). Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety. Exploratory end points were cachexia, quality of life, and biomarkers, including the cachexia-promoting protein, growth differentiation factor 15 (GDF15).RESULTSOverall, 147 patients were treated, including six safety cohort participants. The median follow-up period was 8.1 months (IQR, 4.2-13.9). OS6 was 68.6% (95% CI, 56.3 to 78.1) for the Gem/Nab/Toc group and 62.0% (49.6-72.1) for the Gem/Nab group (P =.409). OS for Gem/Nab/Toc versus Gem/Nab improved at 18 months (27.1% v 7.0%, P =.001). No differences in median OS, PFS, or ORR were observed. Incidence of grade-3+ treatment-related adverse events (TrAEs) was 88.1% for Gem/Nab/Toc and 63.4% for Gem/Nab (P <.001). Gem/Nab/Toc decreased muscle loss versus Gem/Nab, with median change +0.1013% versus -3.430% (P =.0012) at 2 months and +0.7044 versus -3.353% (P =.036) at 4 months. Incidence of muscle loss was 43.48% on Gem/Nab/Toc versus 73.52% on Gem/Nab at 2 months (P =.0045) and 41.82% versus 68.75% (P =.0062) at 4 months. GDF15 was not changed by Gem/Nab or Gem/Nab/Toc.CONCLUSIONAlthough the primary end point was not met and TrAEs were increased by Toc, increased survival at 18 months and reduced muscle wasting support an anticachexia effect of IL-6 blockade independent of GDF15. Further studies could leverage these findings for precision anticachexia therapy.</p
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Korean art and the avant-garde dilemma
No full textThe thesis covers Korean avant-garde art history and the dilemma that faced Korean artists at the end of the Japanese Colonial Period (1910-1945). Current literature adequately details avant-garde as progressive fine arts; however, there is limited literature on Korean art in this period. This thesis suggests the term avant-garde dilemma to indicate Korean artists‘ difficulty in style selection to follow a traditional aesthetical trend or progressive socio-political attitude for the foundation of Korean post-modernism. A salient démarche is found when Korean political avant-garde artists meet this dilemma in the midst of the Korean Demonstration Era (1976-1989) that initiates the decline of aesthetical activism and Demonstrative Art. Several styles of avant-garde dilemma after the Korea War are critiqued in the avant-garde evolution; subsequently, there arise hybrid styles between socio-political avant-garde and aesthetical avant-garde styles in Contemporary Korean Art. The examples included are Nam-Jun Baik‘s Video Art (a combination of art and technology), Do-Ho Suh‘s combination of meticulous sculpture with installation to satire Korean neo-capitalist society, Doo-Shik Lee‘s combination of oriental color with western gesture, and Suk-Chang Hong‘s free calligraphy to combine still-life, landscape, calligraphy, and scribbling
