Elevated systemic levels of the matrix metalloproteinase inhibitor TIMP-1 correlate with clinical markers of cachexia in patients with chronic pancreatitis and pancreatic cancer.

BACKGROUND: Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a candidate diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). Here, we determined the possible association of systemic TIMP-1 levels with cachexia and jaundice, two common PDAC-associated conditions. METHODS: Plasma TIMP-1 was measured by ELISA in patients diagnosed with PDAC (n = 36) and chronic pancreatitis (CP) (n = 25). Patients without pancreatic pathologies and known malignancies of other origin served as controls (n = 13). TIMP-1 levels in these patients were tested for asscociation with jaundice and chachexia, and furthermore correlated with cachexia-related clinical parameters such as weight loss and ferritin, parameters of lung function, hemoglobin and liver synthesis parameters. RESULTS: TIMP-1 plasma levels were mostly higher in CP and PDAC patients with concomitant jaundice or cachexia. Elevated plasma TIMP-1 levels were also associated with clinical cachexia markers, including absolute and relative values of weight loss and lung function, as well as ferritin, hemoglobin, and cholinesterase levels. TIMP-1 levels significantly correlated with cachexia only in patients without jaundice. Jaundice also impaired the use of TIMP-1 as a prognostic marker in cancer patients. Relating to cachexia status alone, a slightly improved association of TIMP-1 levels with survival of PDAC patients was observed. CONCLUSION: This retrospective study reports for the first time that plasma levels of TIMP-1 are associated with pancreatic lesion-induced cachexia in patients without jaundice. TIMP-1 is counterindicated as a survival marker in patients with jaundice.

A novel tissue inhibitor of metalloproteinases-1/liver/cachexia score predicts prognosis of gastrointestinal cancer patients.

BACKGROUND: Cachexia, a devastating syndrome in cancer patients, critically determines survival and life quality. It is characterized by impaired homeostasis of multiple organs including the liver, involves tissue wasting, and is conventionally diagnosed and classified by weight loss (WL). However, recent studies pointed at the problem that WL is not sufficient for precise classification of cancer patients according to disease severity (i.e. prognosis). Tissue inhibitor of metalloproteinases-1 (TIMP-1) is an easily accessible cachexia-associated biomarker in the blood, known to alter liver homeostasis. Here, we investigated the value of combining blood levels of TIMP-1 with parameters of liver functionality towards establishment of a cachexia-associated clinical score, which predicts survival of cancer patients, reflects the clinical manifestation of cachexia, and is easily accessible in the clinic. METHODS: The TIMP-1/liver cachexia (TLC) score, expressed as numerical value ranging from 0 to 1, was calculated by categorizing the blood levels of TIMP-1 and parameters of liver functionality (C-reactive protein, ferritin, gamma-glutamyl transferase, albumin, and total protein) for each patient as below/above a certain risk threshold. The TLC score was tested in a cohort of colorectal cancer (CRC) patients (n = 82, 35.4% women, 64.6% men, median age: 70 years) and validated in a cohort of pancreatic cancer (PC) patients (n = 84, 54.8% women, 45.2% men, median age: 69 years). RESULTS: In CRC patients, the TLC score positively correlated with presence of cachexia-related symptoms (WL, impaired liver function), predicted survival [P < 0.001, hazard ratio (HR): 96.91 (9.85-953.90)], and allowed classification of three prognostically distinct patient subpopulations [low (LO)-risk, intermediate (IM)-risk, and high (HI)-risk groups; LO vs. IM: P = 0.003, LO vs. HI: P < 0.001, IM vs. HI: P = 0.029]. The prognostic power of the cachexia-associated TLC score [P < 0.001, HR: 7.37 (2.80-19.49)] and its application to define risk groups (LO vs. IM: P = 0.032, LO vs. HI: P < 0.001, IM vs. HI: P = 0.014) was confirmed in a cohort of PC patients. The prognostic power of the TLC score was independent of presence of liver metastases in CRC or PC patients and was superior to clinically established staging classifications. CONCLUSIONS: The TLC score, a result of straightforward determination of blood parameters, is an objective cachexia-associated clinical tool for precise survival prediction of gastrointestinal cancer patients.