In this large-scale retrospective study involving 3,511 adult cancer patients, we observed a negative linear association between CALLY levels and the risk of all-cause mortality, CVD mortality, and cancer mortality, with lower CALLY levels associated with increased risk. These findings remained robust after extensive sensitivity and stratification analyses.
Previous research has identified the CALLY index as a potential prognostic marker in various cancers, including colorectal[9, 25], hepatocellular[7], gastric[26], other gastrointestinal tumors[27], and lung cancer[8]. High CALLY levels have been independently linked to longer overall survival times and disease-free survival, while a low preoperative CALLY index has been recognized as a risk factor for postoperative complications, including surgical site infections. Our study corroborates these previous findings and contributes additional insights with its larger sample size. To our knowledge, this is the first research to explore the relationship between the CALLY index and both all-cause and cause-specific mortality across all cancer types, utilizing the NHANES database.
The prognosis of cancer patients is frequently linked to their immune function, nutritional status, and level of inflammation. Factors such as malnutrition, chronic uncontrolled inflammation, and autoimmune dysfunction can accelerate tumor progression and lead to cachexia in cancer patients, ultimately exerting a profound negative impact on survival and quality of life. Consequently, various indicators that reflect the immune, nutritional, and inflammatory states of patients are garnering increased attention as potential biomarkers for predicting cancer prognosis. The CALLY index, which leverages serum albumin levels, lymphocyte counts, and CRP levels as markers of nutritional status, immune function, and inflammatory response respectively, represents an enhanced scoring system for immune, inflammatory, and nutritional assessment. It is cost-effective, readily accessible, and straightforward to compute, thus offering substantial utility in clinical settings.[7] Although this study corroborates the prognostic relevance of the CALLY index in cancer, the specific mechanisms of the association between a high CALLY index and reduced mortality remain unclear.
The influence of inflammation tumors has been widely explored, but to date, the exact mechanisms by which inflammation develops into cancer are unknown. Nevertheless, inflammation does affect every stage of a tumor from onset to metastasis, and cancer cells may rely on the production of pro-inflammatory mediators to proliferate, evade the body's immunity, and promote tumor angiogenesis and metastasis. The contribution of cytokines such as tumor necrosis factor-alpha, interleukin 6, and interleukin 1 in inducing cancer cachexia is well established. Their elevated levels activate multiple pathways that promote skeletal muscle atrophy in malignant stroma[28]. The tumor microenvironment includes innate immune cells, adaptive immune cells, cancer cells and their surrounding stroma[29]. During tumor development, the inflammatory microenvironment promotes the proliferation of mutant cells[30–32]. In addition, inflammatory cells can act as a source of reactive oxygen species and reactive nitrogen intermediates, inducing DNA damage and genomic instability, thereby increasing the mutation rate[33, 34]. During cancer development, accompanied by sustained cell death and inflammatory cell infiltration, the production of a large number of cytokines, chemokines, and growth factors facilitates cell proliferation[35]. CRP serves as a typical acute-phase protein with plasma concentrations that increase rapidly and significantly in response to inflammation, infection, tissue injury, and cancer[36]. CRP transcription is regulated by various cytokines and transcription factor complexes, with IL-6 being the primary inducer of the CRP gene[37]. Serum CRP levels, which serve as the denominator of the CALLY index, reflect the systemic inflammatory response.
With the advancement of modern tumor immunology, the interaction between the immune system and tumors throughout their development has become increasingly recognized[38]. It is acknowledged that drugs alone cannot entirely eliminate all tumor cells within the body, underscoring the importance of the body's own immune cells in combating residual tumor cells. Consequently, monitoring immune function is crucial for cancer prevention, tracking cancer progression, and predicting prognosis. The immune status of patients with tumors is a vital parameter for assessing prognosis and adjusting treatment strategies. Lymphocytes, as the primary immune cells of the body, play a pivotal part in immune surveillance[39]. They inhibit the proliferation, invasion, and migration of tumor cells through their cytotoxic activity and the induction of tumor cell apoptosis, thereby potentially controlling tumor growth[40].
Serum albumin is widely used to assess nutritional status and visceral protein synthesis. Notably, in patients with extensive diseases, serum albumin synthesis can be impeded by malnutrition and systemic inflammation. Prior research has indicated that diminished levels of albumin and lymphocytes can negatively impact prognosis across various tumor types. In a study involving 582 pancreatic cancer patients post-resection, Xu et al[41]. reported that low serum levels of lymphocytes and albumin may predict poorer overall survival and recurrence-free survival. The Lymphocyte-Albumin (LA) index, calculated by multiplying lymphocyte count by albumin concentration, has been shown to be a prognostic marker. For example, Yamamoto et al[42]. observed that patients with stage II/III rectal cancer and low LA values had significantly reduced OS. Consistent with previous studies, Alagappan M et al. showed that low albumin levels and NLR > 5 (NLR defined as neutrophil-lymphocyte ratio) prior to radiotherapy were associated with reduced survival in patients with locally advanced pancreatic cancer treated with Stereotactic body radiotherapy[43]. Moreover, low serum albumin levels have been recognized as an independent risk factor for survival in pancreatic cancer patients[44]. Prognostic Nutritional Index (PNI) values, derived from albumin levels, have been shown to enhance survival predictions in pancreatic cancer patients, with lower PNI levels linked to poor prognosis[45, 46].
This study has several strengths and limitations. This is a large retrospective study of the CALLY index and all-cause, cause-specific mortality in oncology patients using the Nhanes database, and to our knowledge, this study included a larger sample size than its predecessors. We adjusted for demographics and other covariates that may affect the relationship between the CALLY index and mortality to increase the confidence and generalizability of the results. Multiple sensitivity and subgroup analyses further confirmed the robustness of our results. However, this study has some limitations. First, due to database limitations, detailed cancer staging as well as treatment information was not available in our study, and thus it was not possible to explore whether there were differences in the correlation between CALLY and prognosis in patients with tumors of different severity. Second, this was a retrospective study and some selection bias may exist.