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13 pages, 2476 KiB

Open AccessArticle

Longitudinal Muscle Biopsies Reveal Inter- and Intra-Subject Variability in Cancer Cachexia: Paving the Way for Biopsy-Guided Tailored Treatment

by Panagiotis Filis, Nikolaos P. Tzavellas, Dimitrios Stagikas, Christianna Zachariou, Panagiotis Lekkas, Dimitrios Kosmas, Evangelia Dounousi, Ioannis Sarmas, Evangelia Ntzani, Davide Mauri, Anastasios Korompilias, Yannis V. Simos, Konstantinos I. Tsamis and Dimitrios Peschos

Cancers 2024, 16(5), 1075; https://doi.org/10.3390/cancers16051075 - 6 Mar 2024

Viewed by 687

Abstract

In the rapidly evolving landscape of cancer cachexia research, the development and refinement of diagnostic and predictive biomarkers constitute an ongoing challenge. This study aims to introduce longitudinal muscle biopsies as a potential framework for disease monitoring and treatment. The initial feasibility and [...] Read more.

In the rapidly evolving landscape of cancer cachexia research, the development and refinement of diagnostic and predictive biomarkers constitute an ongoing challenge. This study aims to introduce longitudinal muscle biopsies as a potential framework for disease monitoring and treatment. The initial feasibility and safety assessment was performed for healthy mice and rats that received two consecutive muscle biopsies. The assessment was performed by utilizing three different tools. Subsequently, the protocol was also applied in leiomyosarcoma tumor-bearing rats. Longitudinal muscle biopsies proved to be a safe and feasible technique, especially in rat models. The application of this protocol to tumor-bearing rats further affirmed its tolerability and feasibility, while microscopic evaluation of the biopsies demonstrated varying levels of muscle atrophy with or without leukocyte infiltration. In this tumor model, sequential muscle biopsies confirmed the variability of the cancer cachexia evolution among subjects and at different time-points. Despite the abundance of promising cancer cachexia data during the past decade, the full potential of muscle biopsies is not being leveraged. Sequential muscle biopsies throughout the disease course represent a feasible and safe tool that can be utilized to guide precision treatment and monitor the response in cancer cachexia research. Full article

(This article belongs to the Special Issue Advances in Cancer Cachexia)

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16 pages, 2949 KiB

Open AccessArticle

Pancreatic Tumor Organoid-Derived Factors from Cachectic Patients Disrupt Contractile Smooth Muscle Cells

by Rianne D. W. Vaes, Annemarie A. van Bijnen, Steven W. M. Olde Damink and Sander S. Rensen

Cancers 2024, 16(3), 542; https://doi.org/10.3390/cancers16030542 - 26 Jan 2024

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Abstract

Patients with pancreatic cancer often suffer from cachexia and experience gastrointestinal symptoms that may be related to intestinal smooth muscle cell (SMC) dysfunction. We hypothesized that pancreatic tumor organoids from cachectic patients release factors that perturb the SMC’s contractile characteristics. Human visceral SMCs [...] Read more.

Patients with pancreatic cancer often suffer from cachexia and experience gastrointestinal symptoms that may be related to intestinal smooth muscle cell (SMC) dysfunction. We hypothesized that pancreatic tumor organoids from cachectic patients release factors that perturb the SMC’s contractile characteristics. Human visceral SMCs were exposed to conditioned medium (CM) from the pancreatic tumor organoid cultures of cachectic (n = 2) and non-cachectic (n = 2) patients. Contractile proteins and markers of inflammation, muscle atrophy, and proliferation were evaluated by qPCR and Western blot. SMC proliferation and migration were monitored by live cell imaging. The Ki-67-positive cell fraction was determined in the intestinal smooth musculature of pancreatic cancer patients. CM from the pancreatic tumor organoids of cachectic patients did not affect IL-1β, IL-6, IL-8, MCP-1, or Atrogin-1 expression. However, CM reduced the α-SMA, γ-SMA, and SM22-α levels, which was accompanied by a reduced SMC doubling time and increased expression of S100A4, a Ca²+-binding protein associated with the synthetic SMC phenotype. In line with this, Ki-67-positive nuclei were increased in the intestinal smooth musculature of patients with a low versus high L3-SMI. In conclusion, patient-derived pancreatic tumor organoids release factors that compromise the contractile SMC phenotype and increase SMC proliferation. This may contribute to the frequently observed gastrointestinal motility problems in these patients. Full article

(This article belongs to the Special Issue Advances in Cancer Cachexia)

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13 pages, 17759 KiB

Open AccessArticle

The Clinical Significance of Myosteatosis in Survival Outcomes in Patients with Hepatocellular Carcinoma Treated with Sorafenib

by Min Kyu Kang, Jeong Eun Song, Se Young Jang, Byung Seok Kim, Woo Jin Chung, Changhyeong Lee, Soo Young Park, Won Young Tak, Young Oh Kweon, Jae Seok Hwang, Byoung Kuk Jang, Yu Rim Lee, Jung Gil Park and on behalf of Daegu-Gyeongbuk Liver Study Group (DGLSG)

Cancers 2024, 16(2), 454; https://doi.org/10.3390/cancers16020454 - 20 Jan 2024

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Abstract

The role of body composition parameters in sorafenib-treated hepatocellular carcinoma (HCC) patients is still not fully elucidated. Here, we aimed to evaluate the impact of computed tomography (CT)-based body composition parameters on the survival of such patients. In this multicenter study, we analyzed [...] Read more.

The role of body composition parameters in sorafenib-treated hepatocellular carcinoma (HCC) patients is still not fully elucidated. Here, we aimed to evaluate the impact of computed tomography (CT)-based body composition parameters on the survival of such patients. In this multicenter study, we analyzed the data of 245 sorafenib-treated HCC patients from January 2008 to December 2019. Sarcopenia, visceral obesity, and myosteatosis were defined by using cross-sectional CT images at the third lumbar vertebra level. The effects of these parameters on overall survival (OS) and progression-free survival (PFS) were evaluated. The median age was 67.0 years (interquartile range: 61.0–78.0 year), and 211 patients (86.1%) were male. The median OS and PFS were 7.9 months and 4.8 months, respectively. Vascular invasion (hazard ratio (HR), 1.727; 95% confidence interval (CI), 1.258–2.371; p = 0.001), extrahepatic metastasis (HR, 1.401; 95% CI, 1.028–1.908; p = 0.033), alpha-fetoprotein level > 200 ng/mL (HR, 1.559; 95% CI, 1.105–2.201; p = 0.012), and myosteatosis (HR, 1.814; 95% CI, 1.112–2.960; p = 0.017) were associated with OS. Patient mortality was significantly higher in the group with two or more risk factors than in the group with fewer risk factors. In conclusion, myosteatosis may be a novel prognostic CT-based radiological biomarker in sorafenib-treated HCC patients. Full article

(This article belongs to the Special Issue Advances in Cancer Cachexia)

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11 pages, 635 KiB

Open AccessArticle

Lenvatinib Exacerbates the Decrease in Skeletal Muscle Mass in Patients with Hepatocellular Carcinoma, Whereas Atezolizumab Plus Bevacizumab Does Not

by Kenji Imai, Koji Takai, Shinji Unome, Takao Miwa, Tatsunori Hanai, Atsushi Suetsugu and Masahito Shimizu

Cancers 2024, 16(2), 442; https://doi.org/10.3390/cancers16020442 - 19 Jan 2024

Viewed by 781

Abstract

This study aimed to evaluate chronological changes in skeletal muscle index (SMI), subcutaneous and visceral adipose tissue indices (SATI and VATI), AFP, PIVKA-II, and ALBI scores during atezolizumab plus bevacizumab (AB) or lenvatinib (LEN) treatment for hepatocellular carcinoma (HCC) and the effect of [...] Read more.

This study aimed to evaluate chronological changes in skeletal muscle index (SMI), subcutaneous and visceral adipose tissue indices (SATI and VATI), AFP, PIVKA-II, and ALBI scores during atezolizumab plus bevacizumab (AB) or lenvatinib (LEN) treatment for hepatocellular carcinoma (HCC) and the effect of these changes on survival. A total of 94 patients with HCC (37 were on AB and 57 on LEN) were enrolled. SMI, SATI, VATI, AFP, PIVKA-II, and ALBI scores were analyzed at the time of the treatment introduction (Intro), 3 months after the introduction (3M), at drug discontinuation (End), and the last observational time (Last). The differences between chronological changes were analyzed using the Wilcoxon paired test. The independent predictors for survival and the changes in SMI during AB or LEN (c-SMI%) were analyzed using the Cox proportional hazards model treating all these factors as time-varying covariates and the analysis of covariance, respectively. SMI in the AB group was maintained over time (42.9–44.0–40.6–44.2 cm²/m²), whereas that in the LEN group significantly decreased during the Intro–3M (p < 0.05) and 3M–End (p < 0.05) period (46.5–45.1–42.8–42.1 cm²/m²). SMI (p < 0.001) was an independent predictor for survival together with AFP (p = 0.004) and ALBI score (p < 0.001). Drug choice (AB or LEN; p = 0.038) and PIVKA-II (p < 0.001) were extracted as independent predictors for c-SMI%. AB treatment was significantly superior to LEN in terms of maintaining skeletal muscle, which is an independent predictor for survival. Full article

(This article belongs to the Special Issue Advances in Cancer Cachexia)

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14 pages, 1221 KiB

Open AccessArticle

Muscle and Adipose Wasting despite Disease Control: Unaddressed Side Effects of Palliative Chemotherapy for Pancreatic Cancer

by Pamela N. Klassen, Vickie Baracos, Sunita Ghosh, Lisa Martin, Michael B. Sawyer and Vera C. Mazurak

Cancers 2023, 15(17), 4368; https://doi.org/10.3390/cancers15174368 - 1 Sep 2023

Cited by 2 | Viewed by 1037

Abstract

Muscle and adipose wasting during chemotherapy for advanced pancreatic cancer (aPC) are associated with poor outcomes. We aimed to quantify the contributions of chemotherapy regimen and tumour progression to muscle and adipose wasting and evaluate the prognostic value of each tissue loss. Of [...] Read more.

Muscle and adipose wasting during chemotherapy for advanced pancreatic cancer (aPC) are associated with poor outcomes. We aimed to quantify the contributions of chemotherapy regimen and tumour progression to muscle and adipose wasting and evaluate the prognostic value of each tissue loss. Of all patients treated for aPC from 2013–2019 in Alberta, Canada (n = 504), computed-tomography (CT)-defined muscle and adipose tissue index changes (∆SMI, ∆ATI, cm²/m²) were measured for patients with CT images available both prior to and 12 ± 4 weeks after chemotherapy initiation (n = 210). Contributions of regimen and tumour response to tissue change were assessed with multivariable linear regression. Survival impacts were assessed with multivariable Cox’s proportional hazards models. Tissue changes varied widely (∆SMI: −17.8 to +7.3 cm²/m², ∆ATI: −106.1 to +37.7 cm²/m²) over 116 (27) days. Tumour progression contributed to both muscle and adipose loss (−3.2 cm²/m², p < 0.001; −12.4 cm²/m², p = 0.001). FOLFIRINOX was associated with greater muscle loss (−1.6 cm²/m², p = 0.013) and GEM/NAB with greater adipose loss (−11.2 cm²/m², p = 0.002). The greatest muscle and adipose losses were independently associated with reduced survival (muscle: HR 1.72, p = 0.007; adipose: HR 1.73, p = 0.012; tertile 1 versus tertile 3). Muscle and adipose losses are adverse effects of chemotherapy and may require regimen-specific management strategies. Full article

(This article belongs to the Special Issue Advances in Cancer Cachexia)

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10 pages, 1040 KiB

Open AccessArticle

Lenvatinib or Sorafenib Treatment Causing a Decrease in Skeletal Muscle Mass, an Independent Prognostic Factor in Hepatocellular Carcinoma: A Survival Analysis Using Time-Varying Covariates

by Kenji Imai, Koji Takai, Shinji Unome, Takao Miwa, Tatsunori Hanai, Atsushi Suetsugu and Masahito Shimizu

Cancers 2023, 15(17), 4223; https://doi.org/10.3390/cancers15174223 - 23 Aug 2023

Cited by 4 | Viewed by 950

Abstract

This study aimed to assess the effects of lenvatinib (LEN) or sorafenib (SOR) treatment for hepatocellular carcinoma (HCC) on body composition and changes in body composition on survival. This study enrolled 77 HCC patients. Skeletal muscle index (SMI), subcutaneous and visceral adipose tissue [...] Read more.

This study aimed to assess the effects of lenvatinib (LEN) or sorafenib (SOR) treatment for hepatocellular carcinoma (HCC) on body composition and changes in body composition on survival. This study enrolled 77 HCC patients. Skeletal muscle index (SMI), subcutaneous and visceral adipose tissue indices (SATI and VATI), AFP, PIVKA-II, and ALBI scores were analyzed at the time of LEN/SOR introduction, three months after the introduction, at treatment discontinuation, and the last observational time. The differences between chronological changes in these values were analyzed using a paired t-test. The Cox proportional hazards model was used to analyze prognostic factors using time-varying covariates. The chronological changes in each factor were 45.5–43.6–40.6–39.8 (cm²/m²) for SMI, 41.7–41.6–36.3–33.7 (cm²/m²) for SATI, 41.9–41.1–37.1–34.8 (cm²/m²) for VATI, 2.379–26.42–33.61–36.32 (×10³ ng/mL) for AFP, 9.404–13.39–61.34–25.70 (×10³ mAU/mL) for PIVKA-II, and −2.56–−2.38–−1.99–−1.90 for the ALBI score. The presence of pre-treatment (p = 0.042), AFP (p = 0.002), PIVKA-II (p < 0.001), ALBI score (p < 0.001), and SMI (p = 0.001) were independent prognostic factors. Skeletal muscle mass decreases significantly during LEN/SOR treatment and is an independent prognostic factor for HCC. Full article

(This article belongs to the Special Issue Advances in Cancer Cachexia)

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14 pages, 460 KiB

Open AccessArticle

Mirtazapine versus Megestrol in the Treatment of Anorexia–Cachexia Syndrome in Patients with Advanced Cancer: A Randomized, Double-Blind, Controlled Phase II Clinical Trial

by Olga Laura Sena Almeida, Eduardo Ferriolli, Roberta Cristina Cintra Taveira, Meire Gallo Rosenburg, Daniela Dalpubel Campanari, Natália Maira da Cruz Alves, Karina Pfrimer, Liane Rapatoni, Fernanda Maris Peria and Nereida K. C. Lima

Cancers 2023, 15(14), 3588; https://doi.org/10.3390/cancers15143588 - 12 Jul 2023

Cited by 2 | Viewed by 1644

Abstract

This study compared mirtazapine with megestrol in the management of cancer-related anorexia–cachexia syndrome in patients with advanced cancer. A randomized, double-blind, controlled clinical trial involving patients with advanced cancer and anorexia–cachexia syndrome was performed. Participants received mirtazapine 30 mg/day or megestrol 320 mg/day [...] Read more.

This study compared mirtazapine with megestrol in the management of cancer-related anorexia–cachexia syndrome in patients with advanced cancer. A randomized, double-blind, controlled clinical trial involving patients with advanced cancer and anorexia–cachexia syndrome was performed. Participants received mirtazapine 30 mg/day or megestrol 320 mg/day for eight weeks. The primary endpoint was the effect of mirtazapine on weight gain and the secondary endpoints were its effect on appetite, muscle strength, physical performance, body composition, adverse events, and medication adherence. Linear regression model with mixed effects was applied and a significance level of 5% was adopted. Fifty-two patients were randomized. Mean age was 65.8 ± 8.4 years. There was weight gain in 52% of the participants in the megestrol group and in 38% in the mirtazapine group after four weeks (p = 0.040). Appetite improved in 92% of the participants in the megestrol group and in 56% in the mirtazapine group after eight weeks (p = 0.007). In the sub-analysis by sex, women showed improvement in appetite (p < 0.001) and weight gain (p < 0.005) in the mirtazapine group, which was not observed in men. Mirtazapine appears to be inferior to megestrol in weight and appetite improvement. However, there may be a difference in the therapeutic response between sexes. Full article

(This article belongs to the Special Issue Advances in Cancer Cachexia)

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21 pages, 15648 KiB

Open AccessArticle

Ursolic Acid Alleviates Cancer Cachexia and Prevents Muscle Wasting via Activating SIRT1

by Weili Tao, Ze Ouyang, Zhiqi Liao, Lu Li, Yujie Zhang, Jiali Gao, Li Ma and Shiying Yu

Cancers 2023, 15(8), 2378; https://doi.org/10.3390/cancers15082378 - 20 Apr 2023

Cited by 5 | Viewed by 2456

Abstract

Skeletal muscle wasting is the most remarkable phenotypic feature of cancer cachexia that increases the risk of morbidity and mortality. However, there are currently no effective drugs against cancer cachexia. Ursolic acid (UA) is a lipophilic pentacyclic triterpene that has been reported to [...] Read more.

Skeletal muscle wasting is the most remarkable phenotypic feature of cancer cachexia that increases the risk of morbidity and mortality. However, there are currently no effective drugs against cancer cachexia. Ursolic acid (UA) is a lipophilic pentacyclic triterpene that has been reported to alleviate muscle atrophy and reduce muscle decomposition in some disease models. This study aimed to explore the role and mechanisms of UA treatment in cancer cachexia. We found that UA attenuated Lewis lung carcinoma (LLC)-conditioned medium-induced C2C12 myotube atrophy and muscle wasting of LLC tumor-bearing mice. Moreover, UA dose-dependently activated SIRT1 and downregulated MuRF1 and Atrogin-1. Molecular docking results revealed a good binding effect on UA and SIRT1 protein. UA rescued vital features wasting without impacting tumor growth, suppressed the elevated spleen weight, and downregulated serum concentrations of inflammatory cytokines in vivo. The above phenomena can be attenuated by Ex-527, an inhibitor of SIRT1. Furthermore, UA remained protective against cancer cachexia in the advanced stage of tumor growth. The results revealed that UA exerts an anti-cachexia effect via activating SIRT1, thereby downregulating the phosphorylation levels of NF-κB and STAT3. UA might be a potential drug against cancer cachexia. Full article

(This article belongs to the Special Issue Advances in Cancer Cachexia)

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