Impact of cachexia on outcomes in aggressive lymphomas

Karmali, Reem; Alrifai, Taha; Fughhi, Ibtihaj; Ng, Raymond W. M.; Chukkapalli, Vineela; Shah, Palmi; Basu, Sanjib; Nathan, Sunita; Szymanski-Grant, Kelly; Gordon, Leo I.; Venugopal, Parameswaran; Penedo, Frank J.; Borgia, Jeffrey A.

doi:10.1007/s00277-017-2958-1

Cited by 38 publications

(44 citation statements)

References 28 publications

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“…Altogether, we identified 21 studies published between 1980 and 2017 and reporting on 31 047 cancer patients as shown in Table . These studies provided acceptably reliable data for all of the 14 cancer entities selected for analysis.…”

Section: Methods and Resultsmentioning

confidence: 99%

Orphan disease status of cancer cachexia in the USA and in the European Union: a systematic review

Anker

Holcomb

Muscaritoli

et al. 2019

J cachexia sarcopenia muscle

136

118

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Background Cachexia has significant impact on the patients' quality of life and prognosis. It is frequently observed in patients with cancer, especially in advanced stages, but prevalence data for the overall population are lacking. Good quality estimates of cancer cachexia in general and for each of the major cancer types would be highly relevant for potential treatment development efforts in this field. Both the USA and European Union (EU) have implemented special clinical development rules for such rare disorders what are called ‘orphan diseases’. The cut‐off level for a disease to be considered an orphan disease in the USA is 200 000 people (0.06% of the population) and EU is 5 per 10 000 people (0.05% of the population). Methods For this systematic review, we searched at PubMed (from inception to 31 January 2018) to identify clinical studies that assessed the prevalence of cachexia in cancer patients at risk. Studies reporting the prevalence of either cancer cachexia or wasting disease in the top‐10 cancer types and 4 other selected cancer types known to be particularly commonly complicated by cachexia were included in this analysis (i.e. prostate cancer, breast cancer, colorectal cancer, melanoma, endometrial cancer, thyroid cancer, urinary bladder cancer, non‐hodgkin lymphoma, lung cancer, kidney and renal pelvis cancer, head and neck cancer, gastric cancer, liver cancer, and pancreatic cancer). We calculated the current burden of cancer cachexia, disease by disease, in the USA and in the EU and compared them to the current guidelines for the definition of orphan disease status. Results We estimate that in 2014 in the USA, a total of 527 100 patients (16.5 subjects per 10 000 people of the total population), and in 2013 in the EU, a total of 800 300 patients (15.8 subjects per 10 000 people of the total population) suffered from cancer cachexia (of any kind). In the 14 separately analysed cancer types, the prevalence of cancer cachexia in the USA ranged between 11 300 (0.4/10 000, gastric cancer) and 92 000 patients (2.9/10 000, lung cancer) and in the EU between 14 300 (0.3/10 000, melanoma of the skin) and 150 100 (3.0/10 000, colorectal cancer). Conclusions The absolute number of patients affected by cancer cachexia in each cancer group is lower than the defined thresholds for orphan diseases in the USA and EU. Cancer cachexia in each subgroup separately should be considered an orphan disease.

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Section: Methods and Resultsmentioning

confidence: 99%

Orphan disease status of cancer cachexia in the USA and in the European Union: a systematic review

Anker

Holcomb

Muscaritoli

et al. 2019

J cachexia sarcopenia muscle

136

118

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“…Cancer cachexia is a multifactorial condition of involuntary weight loss that leads to progressive functional impairment in patients and has been associated with treatment failure and poor survival (Camus et al , ; Karmali et al , ). Recent research has identified a number of inflammatory pathways and cytokines and metabolic dysregulation that contribute to the development of cachexia (Kumar et al , ; Kemik et al , ; Martin et al , ).…”

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confidence: 99%

Evaluation of the impact of cachexia on clinical outcomes in aggressive lymphoma

et al. 2019

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Summary Cancer cachexia is a state of involuntary weight loss and altered body composition triggered by an underlying malignancy. We sought to correlate measures of cachexia with clinical outcomes in aggressive lymphomas and to identify biological pathways involved in the cachexia phenotype for possible druggable targets. Radiographic measures of cachexia were collected in a retrospective cohort of 109 patients with aggressive B‐cell lymphoma and followed for clinical outcome. We found males with sarcopenia had reduced progression‐free survival (5·4 vs. 72·3 months, P < 0·0005) and overall survival (OS; 30·2 months vs. not reached, NR, P = 0·02); males with adipopenia also had decreased OS (21·6 months vs. NR, P = 0·04). A trend for increased OS was observed in female sarcopenics only (32·8 months vs. NR, P = 0·08). Additionally, we analysed a prospective cohort of 14 patients for differences in circulating molecular targets involved in various biological pathways. There was a significant correlation with cachexia for reduced serum levels of mediators within the glucose utilization [insulin ‐like growth factor (IGF)‐binding protein 6, P = 0·04; IGF‐1, P = 0·02], inflammation (lymphotoxin‐like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells; LIGHT, P = 0·005), and energy intake/expenditure (leptin, P = 0·004). We conclude that cachexia in patients with aggressive lymphomas has sex‐specific prognostic utility and correlates with measurable changes in metabolism and immune function.

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“…Alternatively, we hypothesised that lymphoma cells can mobilise FAs from adipose tissues, leading to an elevation in plasma FA levels concomitantly with body fat loss. This metabolic syndrome, called cancer cachexia-associated adipopenia, is observed in DLBCL patients, and is associated with poorer prognostic outcomes than that of non-adipopenic patients (Camus et al, 2014;Huang et al, 2013;Karmali et al, 2017). Hence, our results combined with others indicate that lymphoma causes a systemic increase in FA levels via increased FA synthesis and/or mobilisation from adipose tissues.…”

Section: Discussionsupporting

confidence: 69%

“…Lymphoma cells and the splenic lymphoma environment upregulated FA synthesis, forming an environment that actively synthesize lipid. As discussed, lymphoma growth was also associated with development of cachexia-associated fat loss, which has been observed to increase or to be associated with systemic FA levels Karmali et al, 2017). We speculate that the lipid excess-NK suppression axis may also extend to other forms of tumours, as increased lipid metabolism and development of cancer-cachexia are commonly observed in cancers (Baron et al, 2004;Liu et al, 2017;Porporato, 2016).…”

Section: The Nutrient and Metabolite Levels In B Cell Lymphoma Enviromentioning

confidence: 59%

“…Aggressive forms of tumours cause a severe weight loss associated with decreased muscle and fat mass. This metabolic syndrome is called cancer cachexia, and can be observed in aggressive lymphomas, eventuating in a systemic increase in FA levels (Camus et al, 2014;Huang et al, 2013;Karmali et al, 2017). We therefore hypothesised that Eμ-myc lymphoma caused cancer cachexiaassociated fat loss, thereby increasing systemic FA levels.…”

Section: Eµ-myc Lymphoma Causes Severe Fat Lossmentioning

confidence: 99%

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Metabolic regulation of NK cells in blood cancers: Lipid-rich environment in blood cancers is associated with metabolic and functional changes of NK cells

Kobayashi¹

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Immunological responses suppress tumour development and are a major target of immunotherapies. Natural killer (NK) cells are highly effective at killing malignant cells and modulate other immune effectors, and therefore are a primary target of tumour-targeted monoclonal antibody (MAb) therapies.In haematological malignancies, optimal function of NK cells is essential for suppressing tumour growth and the success of immunotherapeutic regimens, such as rituximab, an anti-CD20 MAb therapy for B cell malignancies. Advanced stages or aggressive lymphomas are associated with functional defects of NK cells, which leads to suboptimal responses of immunotherapeutic effects. However, the mechanisms by which lymphomas dampen NK cell function are largely unexplored, and understanding this process is critical for better designs and development of therapeutic strategies for lymphoma.Recent advances in immunological research uncovered the importance of cellular metabolism in determining functional fates of immune cells. Accumulating evidence also suggests that malignant cell metabolism does not only potentiate accelerated growth of tumours, but also has a significant impact on surrounding metabolic environments. Therefore, we hypothesized that blood cancers, which disseminate into lymphoid organs, cause a metabolic catastrophe in the critical immune niches Kobayashi T and Mattarollo SR. (2017). Natural killer cell metabolism. Mol immunol. 2017 Nov 24. Publications included in this thesis Contributions by others to the thesisNcr CreT/+ and Ncr CreT/+ Pparg fl/fl mice were provided by Belz G (WEHI). Immune cell sorting and PCR confirmation of Tg mouse genotype were conducted by Jacquelot N (WEHI) from Belz Lab. Eµ-myc and AML survival curves and tumour burdens were obtained by Lam PY Spleens derived from AT3 tumour-bearing mice were provided by Mazzieri R NK cell mitochondrial images were taken by Kobayashi T and Tay J LC-MS for quantifying plasma FA levels were conducted by Kobayashi T, Jiang H (Hill Lab, UQDI), and Hill M (UQDI/QIMR) RNA sequencing from the sample preparation to the sequencing was conducted by Gloury R and Kallies A (PDI). RNAseq data was analysed by Kobayashi T, Murigneux V, Tuong ZK.Glucose, lactate, cholesterol, TG quantification were conducted by UQ Veterinary Laboratory

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Impact of cachexia on outcomes in aggressive lymphomas

Cited by 38 publications

References 28 publications

Orphan disease status of cancer cachexia in the USA and in the European Union: a systematic review

Orphan disease status of cancer cachexia in the USA and in the European Union: a systematic review

Evaluation of the impact of cachexia on clinical outcomes in aggressive lymphoma

Metabolic regulation of NK cells in blood cancers: Lipid-rich environment in blood cancers is associated with metabolic and functional changes of NK cells

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