Pan-immune-inflammation value and body mass index to predict survival in diffuse large B-cell lymphoma

Background Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), constituting 31% of all NHL. Malignancy and inflammation are closely linked. Inflammatory processes have been identified to play an important role in the pathogenesis of lymphoma. Obesity is a well-known risk factor not only for the development of cardiovascular disease and diabetes but also for the development of several types of cancer, including lymphomas. Objective To find out the association of pan-immune-inflammation value (PIV) and body mass index (BMI) with survival in adults with diffuse large B-cell lymphoma. Patients and methods We conducted an observational retrospective study on 110 patients to unravel the association of PIV and BMI with survival outcome in a cohort of adults diagnosed as de novo DLBCL (NOS) and treated at the hematology units of International Medical Center, Helwan and Menoufia University Hospitals, in the period from 2014 to 2018. Results The mean age of the studied patients was 54.27 years, the mean BMI was 28.91, and the median and IQR for PIV were 195.84 (96.20–498.52). The cutoff value for detecting mortality in BMI was 29.74 kg/m 2 with poor sensitivity (44.4%) and poor specificity (67.2%). The cutoff value for detecting mortality in PIV was 250.49 with poor sensitivity (50.0%) and poor specificity (67.2%). The mean duration of overall survival was 21.596 months. There was nonsignificant difference regarding 2-year overall survival according to BMI grouping ( p -value = 0.195) and PIV grouping ( p -value = 0.275). Conclusion Neither PIV nor BMI were associated with 2-year overall survival in patients with DLBCL.


Introduction
NHL is the 10th most common cancer in the world in 2018 [1], while the most common NHL subtype is DLBCL, comprising approximately 30% of NHL [2].In Egypt, lymphoma is considered the fourth most common tumor in adults; it represents 76.6% NHL and 23.4% HL [3].DLBCL is the most common subtype of NHL in Egypt, representing about 49% of all NHL cases presenting to the National Cancer Institute (NCI) [4].
Pro-inflammatory cytokines (or chemokines) and inflammatory cells and in tumor microenvironment were proved to promote tumor growth, DNA damage, angiogenesis, and immune suppression and to be associated with poor survival outcomes of patients [5][6][7].Interleukin-10 (IL-10) is an immune regulatory cytokine [8].Elevated plasma IL-10 levels correlated with adverse DLBCL features and poor prognosis and considered as a useful marker for evaluation of disease activity [9].Programmed death ligand-1 (PD-L1) is responsible for T-cell activation, proliferation, and cytotoxic secretion to produce anti-tumor and immune responses [10].High PD-L1 expression in DLBCL is associated with aggressive clinicopathological features and a decreased response to R-CHOP [11].
Recently, a new biomarker that takes into account all routinely assessed blood cell populations reflecting systemic inflammation and immunity, i.e., neutrophils, monocytes, lymphocytes, and platelets, has been proposed as a stronger and more reliable predictor of clinical outcomes in patients with advanced colorectal cancer [12].
Neutrophil to lymphocyte (NLR) is a reliable marker for polymorphonuclear leukocyte (PMNL) [13] and considered as an effective and noninvasive biomarker for poor prognosis and aggressive DLBCL [14].Red cell distribution width (RDW) is a simple and immediately available inflammatory biomarker [15].And its high level predicted an unfavorable prognosis in patients with DLBCL [16].The mean platelet volume (MPV) describes the average platelet size reported in femtoliters, measures of the heterogeneity in platelet size [17].Its low baseline is an independent prognostic marker of poor outcome in patients with DLBCL [18].This biomarker, which was defined as pan-immuneinflammation value (PIV), is calculated by multiplying neutrophil count (10 3 /mmc) by platelet count (10 3 / mmc) and monocyte count (10 3 /mmc) and finally dividing the result of this product by lymphocyte count (10 3 /mmc) [19].
Obesity, a key modifiable factor and surrogate of many lifestyle factors, is increasing worldwide, and the prevalence is highest in the United States.High or low BMI is associated with increased all-cause mortality risk as well as cancer-specific mortality in some cancers such as breast cancer [20][21][22].

Patients and methods
On 110 patients, we conducted a retrospective study to elicit the association of PIV and BMI with survival outcome in a cohort of adults (≥ 18 years old) diagnosed as de novo DLBCL (NOS) according to the 2008 World Health Organization (WHO) classification of lymphoid neoplasm [23] and completed the standard R-CHOP protocol at the hematology units of International Medical Center, Helwan and Menoufia University Hospitals, from the beginning of 2014 until the end of 2018.

Statistical analysis
The data collected were tabulated and analyzed by SPSS ).Two types of statistics were done: Descriptive statistics, e.g., percentage (%), mean (x), and standard deviation (SD), and analytic statistics, e.g., univariate and multivariate regression analysis which measure the relationship between the categorical dependent variables and one or more independent variables.Overall survival (OS) was done to define the prognostic indices such a case.Receiver operator characteristic (ROC) curve was done to determine the cutoff value, sensitivity, and specificity of the studied variables.

Results
Our study showed that 63.6% of the studied patients were males; most of them (69.In the last two decades, the relationship between chronic inflammation and cancer has become very popular, and both the diagnostic and therapeutic value of inflammatory markers have been studied extensively.Inflammation has been shown to promote tumor initiation and progression, whereas escape from immune surveillance may favor cancer invasiveness [32].In the tumor microenvironment, neutrophils, monocytes-derived macrophages, and platelets have adverse prognostic significance by promoting tumoral angiogenesis and tumor growth, whereas tumor-infiltrating lymphocytes portend favorable outcomes [33,34].
Obesity and cancer have been linked in a cause and effect relationship as supported by several reports.Obesity-related cancers are becoming more common, making this disease spectrum a public health priority [35].
Medical oncologists are frequently confronted with overweight and obese patients, including their specific set of comorbidities [36] and differential pharmacokinetics [37].Drug distribution and elimination are reported to be influenced by obesity, an effect especially relevant for lipophilic drugs [38].Drug metabolism may be altered by obesity-induced liver steatosis and changed hepatic blood flow, as well as the partially increased enzymatic activity of the cytochrome P450   superfamily in obese individuals [39].Underdosing of chemotherapy is frequently seen in patients with a calculated body surface area of > 2 m 2 [40], and a higher body mass index (BMI) might, in part, counterbalance tumor cachexia in advanced disease.
According to our knowledge, our study is the first to unravel the association of PIV with survival in adults with DLBCL.
While Ligorio et al. found that high PIV was associated with worse OS in Human Epidermal Growth Factor Receptors Positive Advanced Breast Cancer (HER2+aBC) patients treated with first line trastuzumab-pertuzumabcontaining biochemotherapy [26].
Against our results, Fuca et al. found that PIV showed a strong association with progression-free survival (PFS) and OS in patients with advanced colorectal cancer, and the prognostic value of the PIV was stronger than that of other well-established immune-inflammatory biomarkers (e.g., NLR).OS & PFS were significantly longer in patients with low baseline PIV as compared to high PIV [19].
According to our study, the cutoff point for detecting mortality in BMI was 29.74 kg/m 2 with poor sensitivity (44.4%) and poor specificity (67.2%).There was insignificant difference regarding 2-year overall survival according to BMI grouping (p-value = 0.195).
Unlike Chihara et al. who found that obesity before the time of diagnosis but not at the time of diagnosis was associated with shorter lymphoma specific survival (LSS) in patients with follicular lymphoma (FL).But similar to our study, BMI was not associated with survival following DLBCL and chronic/small lymphocytic leukemia (CLL/SLL), except for individuals who were under weight or who experienced decrease in BMI prior to diagnosis, which likely represents lymphomarelated weight loss [28].
The lack of association that they observed between BMI prior or BMI at the time of diagnosis (BMI-dx) for survival outcomes in DLBCL and CLL/SLL was consistent with the US intergroup study that evaluated patients who were treated on three Eastern Cooperative Oncology Group (ECOG) phase III clinical trials and the Scandinavian Lymphoma Etiology study [41,42].
While Gay et al. showed that patients who have high body surface area (BSA), which significantly correlates with high BMI, tend to have higher treatment-related mortality, but the dose capping of anthracycline by BSA was not associated with survival outcomes in DLBCL [43].
Recently, a cancer registry analysis reported significantly prolonged OS for overweight (BMI 25 to < 30 kg/ m 2 ) and obese (BMI ≥ 30 kg/m 2 ) patients with diffuse large B-cell lymphoma (DLBCL) when compared with normal weight patients that was against our study [44,45].

Conclusion
Neither PIV nor BMI were associated with 2-year overall survival in patients with DLBCL.

Recommendation
Finally, we acknowledge the limitation of our study due to its retrospective design, short duration and limited number of patients recommending a prospective study design, long duration, and large number of patients.
(Statistical Package for Social Sciences) version 23.0 on IBM compatible computer (SPSS Inc.Released 2015.IBM SPSS statistics for Windows version 23, Armonk, NY, USA: IBM Corp.

Table 1
Baseline characteristics of the studied DLBCL patients (n = 110) ECOG Eastern Cooperative Oncology Group, LDH Lactate dehydrogenase, ULN Upper limit normal, SD Standard deviation, R-IPI Revised International Prognostic Index, BMI Body mass index, PIV pan-immune-inflammation value, IQR Interquartile range

Table 2
Two-year survival outcome among the studied patients

Table 3
ROC curve for BMI in kg/m 2 ROC Receiver operator curve, PPV Positive predictive value, NPV Negative predictive value, AUC Area under curve, CI Confidence interval

Table 4
ROC curve for PIV

Table 5
Two-year overall survival according to BMI

Table 6
Two-year overall survival according to PIV

Table 7
Uni-and multivariate Cox regression analyses for predictors of overall survival