Circulating complement component 4d (C4d) correlates with tumor volume, chemotherapeutic response and survival in patients with malignant pleural mesothelioma

Our plain-English summary of Circulating complement component 4d (C4d) correlates with tumor volume, chemotherapeutic response and survival in patients with malignant pleural mesothelioma, by T. Klikovits, P. Stockhammer, V. Laszlo, et al (Scientific Reports, 2017).

The study

• Authors: T. Klikovits, P. Stockhammer, V. Laszlo, Y. Dong, M.A. Hoda, B. Ghanim, I. Opitz, T. Frauenfelder, T.D.L. Nguyen-Kim, W. Weder, W. Berger, M. Grusch, C. Aigner, W. Klepetko, B. Dome, F. Renyi-Vamos, R. Oehler, B. Hegedus
• Journal: Scientific Reports
• Published: 2017;7(1):16456
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Only limited information is available on the role of complement activation in malignant pleural mesothelioma (MPM). Thus, we investigated the circulating and tissue levels of the complement component 4d (C4d) in MPM. Plasma samples from 55 MPM patients, 21 healthy volunteers (HV) and 14 patients with non-malignant pleural diseases (NMPD) were measured by ELISA for C4d levels. Tissue specimens from 32 patients were analyzed by C4d immunohistochemistry. Tumor volumetry was measured in 20 patients. We found no C4d labeling on tumor cells, but on ectopic lymphoid structures within the tumor stroma. Plasma C4d levels did not significantly differ between MPM, HV or NMPD. Late-stage MPM patients had higher plasma C4d levels compared to early-stage (p = 0.079). High circulating C4d was associated with a higher tumor volume (p = 0.047). Plasma C4d levels following induction chemotherapy were significantly higher in patients with stable/progressive disease compared to those with partial/major response (p = 0.005). Strikingly, patients with low C4d levels at diagnosis had a significantly better overall survival, confirmed in a multivariate cox regression model (hazard ratio 0.263, p = 0.01). Our findings suggest that circulating plasma C4d is a promising new prognostic biomarker in patients with MPM and, moreover, helps to select patients for surgery following induction chemotherapy.

In plain English

This Vienna study measured C4d, a protein fragment produced when the immune system's complement pathway is activated, in people with malignant pleural mesothelioma. Plasma came from 55 patients (May 2011 to December 2014), 21 healthy volunteers and 14 patients with non-malignant pleural diseases. Tumor tissue from 32 patients was stained for C4d. The article did not report participants' asbestos exposure. No C4d was found on tumor cells; it was seen in lymphoid structures within the tumor. Plasma C4d did not differ significantly between the three groups. Using a cut-off of 1.5 µg/mL, patients with high C4d had larger tumor volumes on CT scans (p = 0.047). After chemotherapy, patients whose disease was stable or progressing had higher C4d than those who responded (2.02 versus 0.52 µg/mL, p = 0.005). At diagnosis, the 9 patients with high C4d had worse survival than the 21 with low C4d (hazard ratio 7.33, confidence interval 1.71 to 31.44). This link remained after adjustment for tumor subtype, stage and treatment. The authors concluded that plasma C4d is a promising prognostic biomarker. They noted their work could not show how complement becomes activated.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory biomarker study: blood plasma C4d measured by ELISA in mesothelioma patients and two comparison groups, tissue staining, CT tumor volume measurement, and survival analysis
• Who was studied: 55 consecutive patients with histologically verified malignant pleural mesothelioma at the Medical University of Vienna, May 2011 to December 2014 (30 sampled at diagnosis, 25 after induction chemotherapy before surgery); 21 age-matched healthy volunteers; 14 patients with non-malignant pleural diseases. Tissue from 32 patients; tumor volume data for 20.
• Exposure: No asbestos exposure data were reported for participants. The factor studied was circulating plasma C4d (a complement cleavage product), split into high and low groups at 1.5 µg/mL. Plasma C3a and tissue C1q were also examined.
• Main results:
  • In tumor tissue from 32 patients, no C4d labeling was found on mesothelioma cells.
  • Strong C4d staining was seen in the germinal centers of ectopic lymphoid structures within the tumor.
  • Plasma C4d did not differ significantly between mesothelioma patients (mean 1.24 µg/mL), healthy volunteers (1.17 µg/mL, p = 0.833) and patients with non-malignant pleural diseases (1.30 µg/mL, p = 0.851).
  • Late-stage patients (IMIG III or IV) tended to have higher plasma C4d than early-stage patients (I or II): 1.43 versus 0.92 µg/mL. The difference was not statistically significant (p = 0.079).
  • In the tumor-volume subgroup (one of 20 patients excluded), patients with high C4d had larger CT-measured tumor volumes than those with low C4d: 366.7 versus 190.3 cubic centimeters (p = 0.047).
  • When C4d was correlated directly with tumor volume, there was a non-significant tendency for C4d to rise with volume (Pearson r 0.34, p = 0.099).
  • Higher plasma C4d was associated with higher plasma fibrinogen (Pearson r 0.48, p = 0.002) and C-reactive protein (Pearson r 0.44, p = 0.004). It was not associated with white blood cell count.
  • After platinum-based induction chemotherapy, patients with stable or progressive disease had higher plasma C4d than patients with partial or major response: 2.02 versus 0.52 µg/mL (p = 0.005).
  • Among 30 patients sampled at diagnosis, those with high C4d (n = 9) had significantly worse survival than those with low C4d (n = 21): hazard ratio 7.33, confidence interval 1.71 to 31.44, p = 0.007.
  • In a multivariate model adjusted for histological subtype, IMIG stage and treatment type, low versus high C4d at diagnosis was associated with overall survival: hazard ratio 0.263, 95% CI 0.096 to 0.725, p = 0.01.
  • Plasma C3a, another complement fragment, was higher in mesothelioma patients than in healthy volunteers: 132.30 versus 86.45 ng/mL (p = 0.013).
• The authors' conclusion: The authors concluded that their findings suggest circulating plasma C4d is a promising new prognostic biomarker in malignant pleural mesothelioma. They also suggested it helps select patients for surgery after induction chemotherapy.
• Limitations the authors state:
  • The authors stated that their correlative studies cannot reveal the upstream events or specific mechanisms of complement activation in mesothelioma. They said further preclinical studies are needed.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunohistochemistry, Chemotherapy, Overall Survival, Hazard Ratio, Biomarker.

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• Implementing CT tumor volume and CT pleural thickness into future staging systems for malignant pleural mesothelioma — O. Lauk, M. Patella, et al. (2021)
• Circulating FGF18 is decreased in pleural mesothelioma but not correlated with disease prognosis — B. Mosleh, K. Schelch, et al. (2023)
• The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma — V. Laszlo, Z. Valko, et al. (2019)
• Activation of Nrf2 pathways correlates with resistance of NSCLC cell lines to CBP501 in vitro — N. Mine, S. Yamamoto, et al. (2014)

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