Angelika Bezan

The Preoperative AST/ALT (De Ritis) Ratio Represents a Poor Prognostic Factor in a Cohort of Patients with Nonmetastatic Renal Cell Carcinoma

PURPOSE Aminotransaminases, which are strongly involved in cellular metabolism and cancer cell turnover, represent easily measureable, potential blood based biomarkers. We evaluated the prognostic value of the preoperatively assessed AST/ALT (De Ritis) ratio on clinically meaningful end points in a large European cohort of patients with nonmetastatic renal cell carcinoma. MATERIALS AND METHODS We retrospectively evaluated clinicopathological data on 698 patients with nonmetastatic renal cell carcinoma operated on between 2005 and 2013 at a single tertiary academic center. The potential prognostic value of the AST/ALT ratio was analyzed using the Kaplan-Meier method, and univariate and multivariate Cox proportional regression models. The impact of the ratio on the predictive accuracy of the Leibovich prognosis score was determined by the Harrell c-index. RESULTS An increased (1.26 or greater) preoperative AST/ALT ratio was statistically significantly associated with several well established prognostic factors, including pathological T stage, as well as with histological tumor necrosis (p <0.05). On multivariate analysis an increased preoperative AST/ALT ratio was an independent prognostic factor for metastasis-free survival (HR 1.61, 95% CI 1.25-2.07, p <0.001) and overall survival (HR 1.76, 95% CI 1.34-2.32, p <0.001). The Harrell c-index was 0.77 using the Leibovich prognosis score and 0.81 when AST/ALT was added. CONCLUSIONS In our study cohort with nonmetastatic renal cell carcinoma the preoperatively assessed AST/ALT ratio represented an independent prognostic factor. This ratio might further improve the predictive accuracy of well established prognosis scores.

Can Multistate Modeling of Local Recurrence, Distant Metastasis, and Death Improve the Prediction of Outcome in Patients With Soft Tissue Sarcomas?

BackgroundExploration of the complex relationship between prognostic indicators such as tumor grade and size and clinical outcomes such as local recurrence and distant metastasis in patients with cancer is crucial to guide treatment decisions. However, in patients with soft tissue sarcoma, there are many gaps in our understanding of this relationship. Multistate analysis may help us in gaining a comprehensive understanding of risk factor-outcome relationships in soft tissue sarcoma, because this methodology can integrate multiple risk factors and clinical endpoints into a single statistical model. To our knowledge, no study of this kind has been performed before in patients with soft tissue sarcoma.Questions/purposesWe implemented a multistate model of localized soft tissue sarcoma to statistically evaluate the relationship among baseline risk factors, recurrence, and death in patients with localized soft tissue sarcoma undergoing curative surgery.MethodsBetween 1998 and 2015, our center treated 539 patients for localized soft tissue sarcoma with surgery as curative intent. Of those, 96 patients (18%) were not included in this single-center retrospective study owing to missing baseline histopathology data (n = 3), not yet observed followup (n = 80), or because a neoadjuvant treatment approach in the presence of synchronous distant metastasis was used (n = 13), leaving 443 patients (82%) for the current analysis, of which 40 were lost to followup during the first year after surgery. All patients had tumors of the stages I to III according to the American Joint Committee on Cancer Stages. The median age of the patients was 62 years (range, 16–96 years), and 217 patients (49%) were female. Three hundred-forty-six patients (78%) had tumors of high grade (Grades 2 and 3), and 310 (70%) tumors were greater than 5 cm in maximum diameter. Patients who had died during the first year of followup were included in this analysis. Median followup for the 443 study patients was 6 years, with 84%, 52%, and 23% of patients being followed for more than 1, 5, and 10 years, respectively. The 15-year cumulative incidences of local recurrence, distant metastasis, and death from any cause, using a competing risk analysis, were 16% (95% CI, 11%–22%), 21% (95% CI, 17%–26%), and 55% (95% CI, 44%–67%), respectively. Wide resection with a margin of 1 mm was the preferred treatment for all patients, except for those with Grade 1 liposarcoma where a marginal resection was considered adequate. Multistate models were implemented with the mstate library in R.ResultsIn multistate analysis, patients who experienced a local recurrence were more likely to have distant metastasis develop (hazard ratio [HR] = 8.4; 95% CI, 4.3–16.5; p < 0.001), and to die (HR = 3.4; 95% CI, 2.1–5.6; p < 0.001). The occurrence of distant metastasis was associated with a strong increase in the risk of death (HR = 12.6; 95% CI, 8.7–18.3; p < 0.001). Distant metastasis occurring after a long tumor-free interval was not associated with a more-favorable prognosis with respect to mortality than distant metastasis occurring early after surgery (estimated relative decrease in the adverse effect of distant metastasis on mortality for 1-year delay in the occurrence of distant metastasis = 0.9; 95% CI, 0.7-1.1; p = 0.28). High-grade histology (Grades 2 and 3) was associated with a higher risk of overall recurrence (defined as a composite of local recurrence and distant metastasis, HR = 3.8; 95% CI, 1.8–7.8; p = 0.0003) and a higher risk of death after recurrence developed (HR = 4.4; 95% CI, 1.1–18.2; p = 0.04). Finally, the multistate model predicted distinct outcome patterns depending on baseline covariates and how long a patient has remained free from recurrence after surgery.ConclusionsIn patients with localized soft tissue sarcoma undergoing resection, the occurrence of local recurrence and distant metastasis contributes to a dramatically impaired long-term survival outcome. Local recurrences are a substantial risk factor for distant metastasis. Multistate modeling is a very powerful approach for analysis of sarcoma cohorts, and may be used in the future to obtain highly personalized, dynamic predictions of outcomes in patients with localized soft tissue sarcoma.Level of EvidenceLevel III, therapeutic study

Blood-Based Biomarkers Are Associated with Disease Recurrence and Survival in Gastrointestinal Stroma Tumor Patients after Surgical Resection.

Background Inflammatory blood count biomarkers may improve recurrence risk stratification and inform long-term prognosis of cancer patients. Here, we quantify the prognostic impact of blood-based biomarkers on recurrence risk and long-term survival in a large cohort of gastrointestinal stroma tumor (GIST) patients after curative surgery. Methods One-hundred-forty-nine consecutive GIST patients were followed-up for a median period of 4.8 years. Local recurrence, distant metastasis, and death occurred in 9, 21, and 31 patients, respectively. Time-to-event and competing risk analysis were applied to study the association between haemoglobin (Hb) level, white blood cell count (WBC), neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte/monocyte ratio (LMR), and platelet/lymphocyte ratio (PLR) with risk of local or distant recurrence (RR), recurrence free survival (RFS), and overall survival (OS). Results A low Hb (p = 0.029), and elevations in the parameters WBC (p = 0.004), NLR (p = 0.015) and dNLR (p = 0.037) were associated with a poor OS in GIST patients in multivariate analysis. Moreover, a low Hb (p = 0.049) and an elevated WBC (p = 0.001), NLR (p = 0.007), dNLR (p = 0.043) and PLR (p = 0.024) were independently associated with decreased RFS after adjusting for Miettinen score. However, only an increase of dNLR/NLR showed a significant association to higher RR (p = 0.048). Inclusion of NLR or PLR to Miettinen risk score did not reasonably improve the clinical risk prediction of 2-year RFS. Conclusion Low Hb, elevated WBC, elevated dNLR, and elevated PLR are independent prognostic factors for a worse clinical outcome in GIST patients after curative resection.

Preoperative serum-gamma-glutamyltransferase (GGT) does not represent an independent prognostic factor in a European cohort of patients with non-metastatic renal cell carcinoma

Aims Increasing evidence suggests that the serum-gamma-glutamyltransferase (GGT) might correlate with tumour development and growth rates in various human cancer types. Thus, we decided to investigate the potential prognostic impact of the preoperatively assessed serum-GGT in a European cohort of patients with non-metastatic renal cell carcinoma (RCC). Methods Clinicopathological data from 700 consecutive patients with non-metastatic RCC, operated between 2000 and 2010 at a single tertiary academic centre, were evaluated retrospectively. Preoperative serum-GGT was assessed 1 day before surgery. Patients were categorised using a serum-GGT cut-off value of 40 U/L according to a calculation by receiver operating curve analysis. Patients’ cancer-specific survival (CSS), metastasis-free survival (MFS), as well as overall survival (OS) were assessed using the Kaplan-Meier method and Cox proportional models. Results In univariate analysis, an elevated preoperative serum-GGT level (<40 U/L vs ≥40 U/L) was statistically significantly associated with a shorter MFS (HR=1.517, 95% CI 1.047 to 2.197, p=0.027). In multivariate analyses, pathological T-Stage (pT-1 vs pT-2–4, HR=2.065, 95% CI 1.665 to 2.560), tumour grade (G-1+G-2 vs G-3+G-4, HR=1.671, 95% CI 1.261 to 2.213), as well as the presence of histological tumour necrosis (No vs Yes, HR=2.031, 95% CI 1.355 to 3.046) were independent predictors of MFS in patients with RCC, whereas the preoperative serum-GGT failed to reach independent predictor status (<40 U/L vs ≥40 U/L, HR=1.156, 95% CI 0.791 to 1.690). No prognostic role for GGT in OS or CSS could be identified. Conclusions In the cohort studied, patients with an elevated (≥40 U/L) preoperative serum-GGT had a subsequently shorter MFS only in univariate analysis. In contrast to previous studies, our data failed to demonstrate preoperatively assessed serum-GGT as an independent prognostic factor in patients with non-metastatic RCC.

Inflammatory biomarkers in metastatic colorectal cancer: prognostic and predictive role beyond the first line setting

Introduction Inflammatory biomarkers are useful prognostic tools in cancer patients. However, the prognostic and predictive value of inflammatory biomarkers beyond the 1st-line setting in metastatic colorectal cancer (mCRC) is unclear. Results In multivariate analysis 1 standard deviation increase in neutrophil-lymphocyte-ratio (NLR) was associated with an 8.5% absolute lower objective-response-rate (ORR) in 1st-line (p<0.0001), 3% lower ORR in 2nd-line (p< 0.0001), and 3% lower ORR in 3rd-line (p=0.24), respectively. Regarding progression free survival (PFS), an increase in the NLR was significantly associated with rising hazard-ratios (HR) over all treatment lines (HR=1.30, p= 0.021 1st-line); (HR=1.37, p<0.0001 2nd-line); (HR=1.44, p=0.042 3rd-line). The platelet-lymphocyte-ratio (PLR) was associated with 6-month PFS over all three treatment lines. Higher C-reactive-protein (CRP) predicted for worse PFS in the first two chemotherapy lines and in best supportive care (BSC). (HR=1.49 (p<0.0001 1st-line); HR=1.25 (p=0.007 2nd-line); HR=1.09 (95%CI 0.81–1.48, p=0.552 3rd-line and HR=1.43 (p= 0.002 in BSC)). Methods Two-hundred-fifty-eight patients with mCRC undergoing palliative chemo(immuno-)therapy were retrospectively included. Primary endpoints were 6-month PFS and ORR during 1st-line, 2nd-line, and 3rd-line treatment, and 6-month overall survival during BSC. Conclusion This study shows that inflammatory biomarkers are useful predictors of disease outcome and treatment response over several treatment lines in mCRC patients.

Frequency and clinical impact of preoperative circulating tumor cells in resectable non-metastatic lung adenocarcinomas

OBJECTIVES Despite successful surgery, 30-50% of patients with resectable non-small cell lung cancer develop tumor recurrence within 5 years of surgery. MATERIALS AND METHODS In this prospective study, we performed CTC enumerations in 40 patients with non-metastatic lung adenocarcinoma (NMLA) using a size-based microfilter. Additionally, cfDNA isolated from plasma was analyzed in 35 out of 40 patients. RESULTS CTCs were identified in 15 out of 40 patients (37.5%) with a range of 1-44 cells, whereas mutated cfDNA was only detected in 3 out of 35 patients (8.6%). Disease-free survival (DFS) was significantly associated with CTC positivity (log-rank p=0.025), grading (log-rank p=0.019), tumor stage (log-rank p=0.025) and lymph node status (log-rank p=0.029). Multivariate analysis, including tumor stage and grading, showed that CTC positivity (p=0.006), grading (0.039) and tumor stage (p=0.022) were independently associated with DFS. CONCLUSION Our study found that microfilter-based CTC enumeration in NMLA patients is an independent predictor of worse DFS. The used NGS-based cfDNA characterization had limited sensitivity to be clinically informative in our study cohort. CTC assessment before surgery can thus identify NMLA patients at high risk of disease recurrence.