Marker For Overall Survival Research Articles

Early ctDNA response to chemotherapy. A potential surrogate marker for overall survival

AimThe aim of the study was to compare ctDNA response rate and objective response rate as surrogate markers for overall survival (OS) in patients with metastatic cancer treated with chemotherapy. MethodsThe study included 420 patients distributed in five cohorts with colorectal, ovarian, and non–small cell lung cancer. It represents a retrospective analysis of patients enrolled in prospective biomarker studies and clinical trials. All patients had ctDNA measured before start of treatment and at the first evaluation of objective response. ctDNA response rate was defined as the fraction of patients converting from a measurable level at baseline to an unmeasurable level at the first evaluation of objective response.Aberrant, tumour specific, methylated DNA was measured in plasma. The method involves DNA isolation, bisulphite conversion and droplet digital PCR.The primary outcome measure was the correlation between ctDNA response rate, overall response rate (ORR) and median survival. ResultsThere was moderate correlation between ctDNA response rate and objective response at first evaluation (R2 = 0.68). The same applied to ctDNA response rate and ORR (R2 = 0.57). ctDNA held prognostic information in all the investigated tumour types (p < 0.05). There was a high correlation between ctDNA response and median survival across the included tumour types and treatments (R2 = 0.99) clearly outperforming both response at first evaluation and ORR (R2 = 0.70 and 0.57, respectively). ConclusionThe results suggest that ctDNA response might serve as a surrogate marker for OS. If validated, it may have great implications on the approval of new drugs.

Overexpression of DSCR1 prevents proliferation and predicts favorable prognosis in colorectal cancer patients

ObjectivesDown syndrome critical region 1 (DSCR1) is associated with carcinogenesis and tumor growth in several types of malignancy. However, little is known about the role of DSCR1 in CRC progression. The present study aimed to elucidate the clinicopathological significance, prognostic, and function roles of DSCR1 in CRC.MethodsFirstly, we analyzed DSCR1 expression in 58 paired CRC samples and Oncomine database. Then, we analyzed DSCR1 expression in two independent CRC cohorts (test cohort: n = 70; validation cohort: n = 58) and tested its overall survival (OS) by Kaplan-Meier survival analyses. Finally, we overexpressed DSCR1 in two CRC cell lines DLD1 and LoVo and analyzed its effect on cell cycle and senescence.ResultsDSCR1 expression was significantly decreased in CRC samples and associated with clinicopathologic features of CRC patients, such as tumor size, lymph node metastasis, and TNM stage. CRC patients with low expression of DSCR1 had shorter overall survival (OS). Kaplan-Meier survival analyses showed that the expression of DSCR1 was significant factor for OS in both cohorts. Multiple Cox regression analysis showed that DSCR1 expression was an independent prognostic marker for OS in test cohort. Overexpression of DSCR1 isoform 4 (DSCR1-4) increased p21, p16, p-NFAT1, and p-NFAT2, while decreased CDK2, CDK4, and Cyclin D1 in CRC cells. In addition, overexpression of DSCR1-4 prevented proliferation and colony formation, and induced senescence in vitro. Moreover, overexpression of DSCR1-4 inhibited tumor growth and tumor angiogenesis in vivo.ConclusionsOur study found high expression of DSCR1 contributes to favorable prognosis of CRC patients and prevents cell cycle and proliferation of CRC cells, indicating a critical tumor suppressive role in CRC progression.

Predictive Factors for RAI-Refractory Disease and Short Overall Survival in PDTC.

Simple SummaryPoorly differentiated thyroid cancer is a rare subtype of thyroid cancer. The course of this disease can vary substantially. Treatment options consist of surgery and radioactive iodine therapy, if possible, and in tyrosine kinase inhibitors for patients where this is not possible. The aim of this study was to identify risk factors for the development of disease that does not respond to radioactive iodine therapy and for premature death, in order to better identify patients in need of more extensive tumor staging and treatment. We identified primary tumor size and infiltration of the tissue surrounding the thyroid gland as risk factors for the development of disease that does not respond to radioactive iodine therapy and tumor volume as a risk factor for early death.Background: The clinical phenotype of poorly differentiated thyroid cancer (PDTC) can vary substantially. We aim to evaluate risk factors for radioiodine refractory (RAI-R) disease and reduced overall survival (OS). Methods: We retrospectively screened our institutional database for PDTC patients. For the assessment of RAI-R disease, we included patients who underwent dual imaging with 18F-FDG-PET and 124I-PET/131I scintigraphy that met the internal standard of care. We tested primary size, extrathyroidal extension (ETE), and age >55 years as risk factors for RAI-R disease at initial diagnosis and during the disease course using uni- and multivariate analyses. We tested metabolic tumor volume (MTV), total lesion glycolysis (TLG) on 18F-FDG-PET, and the progression of stimulated thyroglobulin within 4–6 months of initial radioiodine therapy as prognostic markers for OS. Results: Size of primary >40 mm and ETE were significant predictors of RAI-R disease in the course of disease in univariate (81% vs. 27%, p = 0.001; 89% vs. 33%, p < 0.001) and multivariate analyses. Primary tumor size was an excellent predictor of RAI-R disease (AUC = 0.90). TLG/MTV > upper quartile and early thyroglobulin progression were significantly associated with shorter median OS (29.0 months vs. 56.9 months, p < 0.05; 57.8 months vs. not reached p < 0.005, respectively). Discussion: PDTC patients, especially those with additional risk factors, should be assessed for RAI-R disease at initial diagnosis and in the course of disease, allowing for early implementation of multimodal treatment. Primary tumor size >40 mm, ETE, and age >55 are significant risk factors for RAI-R disease. High MTV/TLG is a significant risk factor for premature death and can help identify patients requiring intervention.

82P Multicenter analysis of neoadjuvant (chemo-)immunotherapy (C-IO) in stage IIB-IVB non-small cell lung cancer (NSCLC) resulting in curative surgery in routine clinical care (KOMPASS neo OP)

Background: Recent phase I and phase II trials report the feasibility of neoadjuvant C-IO prior to surgery. Furthermore, the studies report high pathological response rates which might be a surrogate marker for overall survival (OS).

Plasma Levels of Histidine-Rich Glycoprotein are Associated with the Development of Primary Graft Dysfunction after Lung Transplantation

<h3>Purpose</h3> Histidine-rich glycoprotein (HRG) is a 75 kDa plasma glycoprotein produced in and secreted from the liver. Recently, supplementary HRG treatment has been shown to inhibit acute respiratory distress syndrome (ARDS) and prevent septic lethality. The pathogenesis of primary graft dysfunction (PGD) after lung transplantation (LT) could be similar to that of ARDS. However, the relationship between plasma levels of HRG and PGD after LT remains unknown. <h3>Methods</h3> Blood samples were collected from a total of 68 patients who underwent LT, including the patients with PGD grade 0-1 (the non-PGD group, n = 43), those with PGD grade 2 (the moderate PGD group, n = 18) and those with PGD grade 3 (the severe PGD group, n = 7) at 72 hours after LT. Plasma levels of HRG were quantified using ELISA and compared among the three groups. Appropriate cut-off values of HRG levels were set for overall survival (OS) after LT. <h3>Results</h3> The median follow-up period was 1208 (286-2982) days. Plasma levels of HRG at 72 hours after LT in the severe PGD group were significantly lower than those of the other groups (the non-PGD group vs. the severe PGD group, P = 0.042; the moderate PGD group vs. the severe PGD group, P = 0.040) (Fig. 1). An ROC analysis of the performance of plasma levels of HRG as a marker of overall survival yielded an AUC of 0.61 at a threshold level of 34.4 µg/mL. Patients with plasma levels of HRG ≥ 34.4 µg/mL showed significantly better OS and chronic lung allograft dysfunction (CLAD) free survival than those with plasma levels of HRG < 34.4 µg/mL (OS, P = 0.037; CLAD-free survival, P = 0.046) (Fig. 2). <h3>Conclusion</h3> Plasma level of HRG at 72 hours after LT was associated with the development of PGD, suggesting its usefulness as a predictor of the development of CLAD and survival after LT.

Elastosis in Breast Cancer as a Surrogate Marker for Estrogen Receptor Positivity.

ObjectivesWe sought to describe the occurrence of stromal elastosis in breast carcinoma among Omani female patients using semi-quantitative methods. We also sought to investigate the relationship between stromal elastosis and estrogen receptor (ER), progesterone receptor (PR), HER2/neu receptor tumor grade, and Ki-67 index. Furthermore, we evaluated the diagnostic accuracy of hematoxylin and eosin (H&E) stain method in quantifying elastosis compared to Elastin van Gieson (EVG) stain and if elastosis can be used as prognostic marker for overall survival.MethodsThe content of elastic tissue in primary infiltrating carcinomas of the breast was assessed using semi-quantitative methods (H&E and EVG stains) in 80 female Omani patients by two independent pathologists. Data of primary breast cancer patients who were not treated with neoadjuvant therapy from 2009 to 2019 at the Armed Forces Hospital of Oman were collected from medical records. Demographic and clinical data, including age, menstrual status, tumor type and grade, ER, PR, HER2/neu status, and Ki-67 index were obtained. Follow-up data, including clinical remission, evidence of metastasis, death, or lost follow-up were traced from medical records.ResultsAmong the 80 cases studied, 80.0% were diagnosed with invasive ductal carcinoma, not otherwise specified, while 12.6% were diagnosed with infiltrating lobular carcinoma. Interobserver agreement of grading elastosis on H&E and EVG was strong (Kappa coefficient = 0.858). Using EVG, absent elastosis, grade 1, grade 2, and grade 3 were observed in 12.5%, 37.5%, 30.0%, and 20.0%, respectively. A statistically significant relationship between high elastosis and ER positivity (p = 0.015) and negative HER2/neu receptor (p = 0.045) was observed. No statistically significant relationship between elastosis and other entities, including menopausal status, tumor type and grade, PR, Ki-67, and prognosis. The sensitivity and specificity of quantifying elastosis on H&E stained sections compared to EVG stain (the gold standard) were 68.75% and 96.88%, respectively.ConclusionsElastosis occurrence varies in different breast cancer populations. Elastosis can be considered a surrogate marker for estrogen positivity and HER2/neu negativity in breast cancer patients. In addition, H&E stain is considered an accurate method for quantifying elastosis compared to the EVG staining method.

Genome-Scale Analysis Identified NID2, SPARC, and MFAP2 as Prognosis Markers of Overall Survival in Gastric Cancer.

BackgroundGastric cancer is the most common gastrointestinal tumor, and the rates of recurrence and metastasis are high. Research results on molecular biomarkers used for prognosis of gastric cancer remain inconclusive. This study aimed to explore the gene expression module of gastric cancer and to determine potential prognostic biomarkers.Material/MethodsThree microarray datasets (GSE13911, GSE79973, and GSE29272) from Gene Expression Omnibus (GEO), including 206 pairs of gastric tumors and adjacent normal samples, were used for analysis of differentially expressed genes (DEGs). The 3 microarray datasets yielded 144 genes associated with the progression and prognosis of gastric cancer. After this, a risk score model was developed for result validation using an independent dataset from The Cancer Genome Atlas.ResultsThe validation of the independent dataset showed significantly increased NID2, SPARC, and MFAP2 expression in gastric tumor tissues, which were associated with poor outcomes in gastric cancer patients. Moreover, the high risk score obtained was associated with poor overall survival (HR: 1.787; 1.069–2.986; P=0.027). Subgroup analyses revealed that these significant prognostic values were detected in patients aged <65.0 years, tumors in the antrum/distal colon, grade 3 tumors, or TNM-M0 stages of cancer.ConclusionsThe findings of this study show that NID2, SPARC, and MFAP2 are upregulated in gastric tumor tissues and are significantly associated with poor overall survival. Therefore, the predictive values of the risk score model employed for the prognosis of gastric cancer could be improved by using these 3 upregulated DEGs.

SLC1A4: A Powerful Prognostic Marker and Promising Therapeutic Target for HCC.

SLC1A4, a Na-dependent neutral amino acid transporter, was considered to participate in the various pathobiological process, including tumorigenesis. However, the correlation between SLC1A4 and Hepatocellular Carcinoma (HCC) remains unclear. In our study, integrative bioinformatics and functional profiling were performed to reveal the prognosis and potential function of SLC1A4 in HCC. The results showed that the mRNA and protein levels of SLC1A4 were elevated in HCC, and it was a powerful independent prognostic marker for overall survival (OS). The co-expressed genes analysis and GSEA analysis showed that SLC1A4 was related to cell cycle, metabolism, cancer-related pathway. Furthermore, the functional analysis revealed that silenced SLC1A4 inhibited cell proliferation, migration, cell cycle, and promoted cell apoptosis in HCC. Next, immune analysis showed that SLC1A4 expression was positively associated with immune infiltration and immune-related chemokine expression in HCC. Silenced SLC1A4 evidently reduced these chemokines expression in HCC cells. Finally, drug sensitivity analysis revealed potential five sensitivity drugs for HCC patients with high-expressed SLC1A4. In conclusion, our results suggested that SLCIA4 could be a novel predictor prognosis and immunotherapeutic targets of HCC, and the sensitivity drugs may be effective therapeutic strategy for HCC patients with high-expressed SLC1A4.

Glycogen Synthase Kinase-3 Beta Expression Correlates With Worse Overall Survival in Non-Small Cell Lung Cancer-A Clinicopathological Series.

BackgroundGlycogen Synthase Kinase-3 beta (GSK-3β) regulates diverse cell functions including metabolic activity, signaling and structural proteins. GSK-3β phosphorylates target pro-oncogenes and regulates programmed cell death-ligand 1 (PD-L1). This study investigated the correlation between GSK-3β expression and clinically relevant molecular features of lung adenocarcinoma (PDL1 score, PTEN expression and driver mutations).MethodsWe evaluated 95 lung cancer specimens from biopsies and surgical resections. Immunohistochemistry was performed to analyze the expression of GSK-3β, PTEN, and PDL1. Epidemiological data, molecular characteristics and staging were evaluated from medical records. The histologic classification was performed by an experienced pulmonary pathologist.ResultsMost patients were female (52.6%) and the majority had a positive smoking history. The median age was 68.3 years, with individuals over 60 years accounting for 82.1%. The predominant histological subtype was adenocarcinoma (69.5%), followed by squamous cell carcinoma (20.0%). GSK-3β expression in tumors was cytoplasmic with a dotted pattern and perinuclear concentration, with associated membranous staining. Seven (7.3%) tumors had associated nuclear expression localization. Seventy-seven patients (81.1%) had advanced clinical-stage tumors. GSK-3β was positive in 75 tumors (78%) and GSK3-positive tumors tended to be diagnosed at advanced stages. Among stage III/IV tumors, 84% showed GSK3 positivity (p= 0.007). We identified a statistically significant association between GSK-3β and PTEN in the qualitative analysis (p 0.021); and when comparing PTEN to GSK-3β intensity 2+ (p 0.001) or 3+ expression (> 50%) – p 0.013. GSK-3β positive tumors with a high histological score had a worse overall survival.ConclusionWe identified the histological patterns of GSK-3β expression and evaluated its potential as marker for overall survival, establishing a simple histological score to measure the evaluated status in resected tissues. The use of GSK-3β expression as an immune response biomarker remains a challenge. Future studies will seek to explain the role of its interaction with PTEN.

Early alkaline phosphatase dynamics as biomarker of survival in metastatic castration-resistant prostate cancer patients treated with radium-223

PurposeRadium-223 is a life-prolonging therapy for castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases. However, validated biomarkers for response monitoring are lacking. The study aim was to investigate whether early alkaline phosphatase (ALP) dynamics after the first radium-223 injection can act as surrogate marker for overall survival (OS).MethodsThis retrospective multicenter study included consecutive CRPC patients treated with radium-223. Patients were divided into four subgroups based on baseline ALP level (normal/elevated) and early ALP response, defined as ≥10% ALP decrease after the first radium-223 injection. Primary endpoint was OS among the subgroups. Secondary endpoints included time to first skeletal-related event, time to ALP progression, and treatment completion rate.ResultsA total of 180 patients were included for analysis. Median OS was 13.5 months (95% confidence interval 11.5–15.5). Patients with elevated baseline ALP without ALP response after the first injection had significantly worse OS when compared to all other patients (median OS 7.9 months versus 15.7 months, hazard ratio 2.56, 95% confidence interval 1.73–3.80, P < 0.001). Multivariate analysis demonstrated that elevated baseline ALP without ALP response after the first injection, the number of prior systemic therapies, baseline LDH level, and baseline ECOG performance status were prognostic factors of OS. Patients with elevated baseline ALP without ALP response after the first injection had significantly shorter times to ALP progression and first skeletal-related event, and more frequently discontinued radium-223 therapy when compared to other patients.ConclusionEarly treatment–induced changes in ALP after one radium-223 injection were associated with OS in metastatic CRPC patients.

Radiotherapy for locally advanced head and neck cancer in elderly patients: results and prognostic factors a single cohort.

The objective of this study was to assess the treatment outcomes and prognostic factors of elderly patients with locally advanced head and neck cancer (LAHNC) undergoing radiotherapy (RT). A retrospective cohort from a single institution, from 2000 to 2015, including patients older than 65 years old with LAHNC (stage III-IVa) treated by RT combined or not with chemotherapy (CRT). Univariate and multivariate analysis (MVA) were performed to identify prognostic factors associated with overall survival (OS), cancer-specific survival (CS), and locoregional control (LRC). A p-value < 0.05 was considered significant. 220 patients with LAHNC and > 65 years of age were identified. The median follow-up was 3.8 years, the 3/5 years estimated OS, CS, and LRC rate was 40%/30%, 49%/34%, 76%/45%, respectively. In the univariate analysis, clinical stage (III vs. IVa/b, p = 0.01), tumor stage (T1/2 vs. T3/4, p = 0.035), Karnofsky performance status (KPS, 60-70, p = 0.03) and tumor site (other than vs. hypopharynx, p = 0.0001) were associated with lower OS. Patients with clinical stage (III vs. IVa/b, p = 0.01), tumor stage (T1/2 vs. T3/4, p = 0.015), N stage (N0/1 vs. N2/3, p = 0.04), (KPS 60-70, p = 0.04) and tumor site (other than vs. hypopharynx, p = 0.0001) had worst CS. For the LRC, clinical stage (III vs. IVa/b, p = 0.02), tumor stage (T1/2 vs. T3/4, p = 0.02), treatment type (CRT vs. RT, p = 0.02), RT technique (IMRT vs. 2DRT/3DRT, p = 0.0001), and tumor site (other than vs. hypopharynx, p = 0.02) were significant. In the MVA, KPS maintained significant for OS and CS. For LRC, clinical stage (Iva/b, p = 0.007), tumor stage (T3/4, p = 0.047) and radiotherapy technique other than IMRT (p = 0.0001) were significant. The OS, CS, and LRC were associated with several prognostic factors. The clinical performance was the main marker of OS and CS. Chemoradiation should be offered to selected elderly patients using IMRT to improve LRC.

The lncRNAs LINC00261 and LINC00665 are upregulated in long-term prostate cancer adaptation after radiotherapy

Long non-coding RNAs (lncRNAs) have been shown to impact important biological functions such as proliferation, survival, and genomic stability. To analyze radiation-induced lncRNA expression in human tumors, we irradiated prostate cancer cells with a single dose of 10 Gy or a multifractionated radiotherapeutic regimen of 10 fractions with a dose of 1 Gy (10 × 1 Gy) during 5 days. We found a stable upregulation of the lncRNA LINC00261 and LINC00665 at 2 months after radiotherapy that was more pronounced after single-dose irradiation. Analysis of the The Cancer Genome Atlas (TCGA) and The Atlas of Non-coding RNAs in Cancer (TANRIC) databases showed that high expression of these two lncRNAs may be a potential negative prognostic marker for overall survival of prostate cancer patients. Knockdown of LINC00261 and LINC00665 in long-term survivors decreased survival after re-irradiation and affected DNA double-strand break repair. Mechanistically, both lncRNAs showed an interdependent expression and regulated expression of the DNA repair proteins CtIP (RBBP8) and XPC as well as the microRNA miR-329. Identifying long-term tumor adaptation mechanisms can lead to the discovery of new molecular targets, in effect opening up new research directions and improving multimodal radiation oncologic treatment.

Donor and Recipient Individual Factors As Predictive Markers of Overall Survival After Allogeneic Hematopoietic Stem Cell Transplantation; Dream or Reality

Low overall survival (OS) still is a major concern of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is affected by many individual and environmental factors. In this study, we retrospectively evaluated the association of donor and recipient individual factors with the overall survival of 206 patients who underwent allo-HSCT. Donor and recipient prognostic factors consisted of donor and recipient age, donor-recipient gender status, recipient body mass index (BMI), underlying disease, recipient cytomegalovirus (CMV) serostatus, and time from diagnosis to transplant (DTT) were included in the overall survival analysis. In univariable analysis, recipient age, donor-recipient gender status, underlying disease, recipient CMV serostatus, and DTT were significantly associated with the OS. The hazard of death in patients with DTT less than 14 months was 38% lower than those with a DTT higher than 14 months (P=0.06). Multivariate analysis showed that patients with aplastic anemia (HR=3.58; P=0.11) and Hodgkin’s disease (HR=3.89; P=0.11) have a much lower survival than unclassified diseases. Moreover, patients with acute myeloid leukemia and acute lymphoblastic leukemia showed better outcomes compared to the unclassified group. The donor and patient characteristics such as age, CMV serostatus, underlying disease, and time from diagnosis to transplantation could influence the overall survival of patients after allo-HSCT.

Biomarker Discovery in Patients with Immunotherapy-Treated Melanoma with Imaging Mass Cytometry.

Imaging mass cytometry (IMC) is among the first tools with the capacity for multiplex analysis of more than 40 targets, which provides a novel approach to biomarker discovery. Here, we used IMC to characterize the tumor microenvironment of patients with metastatic melanoma who received immunotherapy in efforts to find indicative factors of treatment response. In spite of the new power of IMC, the image analysis aspects are still limited by the challenges of cell segmentation. Here, rather than segment, we performed image analysis using a newly designed version of the AQUA software to measure marker intensity in molecularly defined compartments: tumor cells, stroma, T cells, B cells, and macrophages. IMC data were compared with quantitative immunofluorescence (QIF) and digital spatial profiling. Validation of IMC results for immune markers was confirmed by regression with additional multiplexing methods and outcome assessment. Multivariable analyses by each compartment revealed significant associations of 12 markers for progression-free survival and seven markers for overall survival (OS). The most compelling indicative biomarker, beta2-microglobulin (B2M), was confirmed by correlation with OS by QIF in the discovery cohort and validated in an independent published cohort profiled by mRNA expression. Using digital image analysis based on pixel colocalization to assess IMC data allowed us to quantitively measure 25 markers simultaneously on formalin-fixed, paraffin-embedded tissue microarray samples. In addition to showing high concordance with other multiplexing technologies, we identified a series of potentially indicative biomarkers for immunotherapy in metastatic melanoma, including B2M.

PD-L1 Expression Is Associated with Deficient Mismatch Repair and Poor Prognosis in Middle Eastern Colorectal Cancers.

Several clinical trials are investigating the use of immune-targeted therapy with Programmed death ligand-1 (PD-L1) inhibitors for colorectal cancer (CRC), with promising results for patients with mismatch repair (MMR) deficiency or metastatic CRC. However, the prognostic significance of PD-L1 expression in CRC is controversial and such data are lacking in CRC from Middle Eastern ethnicity. We carried out this large retrospective study to investigate the prognostic and clinico-pathological impact of PD-L1 expression in Middle Eastern CRC using immunohistochemistry. A total of 1148 CRC were analyzed for PD-L1 expression. High PD-L1 expression was noted in 37.3% (428/1148) cases and was correlated with aggressive clinico-pathological features such as high malignancy grade (p < 0.0001), larger tumor size (p = 0.0007) and mucinous histology (p = 0.0005). Interestingly, PD-L1 expression was significantly higher in patients exhibiting MMR deficiency (p = 0.0169) and BRAF mutation (p = 0.0008). Furthermore, the expression of PD-L1 was found to be an independent marker for overall survival (HR = 1.45; 95% CI = 1.06–1.99; p = 0.0200). In conclusion, the results of this study indicate that PD-L1 expression could be a valid biomarker for poor prognosis in Middle Eastern CRC patients. This information can help in decision-making for anti-PD-L1 therapy in Middle Eastern CRC, especially for patients with MMR deficient tumors.

Surprising impact of stromal TIL’s on immunotherapy efficacy in a real-world lung cancer study

IntroductionImmune checkpoint inhibitors (ICI), such as anti-PD-1 agents, have become part of the standard of care treatment of advanced non-small cell lung cancer (NSCLC). Predictive biomarkers are needed to identify patients that benefit from anti-PD-1 treatments. Tumor infiltrating lymphocytes (TILs) and PD-L1 are major players in the ICI mechanism of action. In this study, we assess the impact of real-world clinicopathological variables, including TILs and PD-L1, on anti-PD-1 efficacy. MethodsWe performed a monocenter retrospective study in advanced NSCLC treated with nivolumab or pembrolizumab between January 2015 and February 2019. The impact of baseline clinical and pathological variables was assessed by univariate and multivariate models. TILs, defined as CD8+T-cells, and PD-L1 were scored in tumor and stroma, and correlated with progression free survival (PFS) and overall survival (OS). ResultsWe included 366 patients of whom 141 were assessed for tumor and stromal TILs. The median follow-up time was 487 days. In the whole cohort, PFS was associated with high tumor PD-L1, high albumin and good performance. OS was associated with low LDH, high albumin, good performance and ‘first-line treatment’. In the TILs subcohort, stromal TILs had the strongest impact on PFS and OS. Stromal TILs were a stronger marker for PFS and OS than tumoral TILs, tumoral PD-L1 or stromal PD-L1. Remaining factors for PFS and OS were albumin and albumin with LDH, respectively. ConclusionsThis real-world study on clinicopathological features shows that stromal CD8 + TILs were the strongest predictor for PFS and OS in patients with advanced NSCLC on anti-PD-1 therapy. Other predictors for PFS and OS included albumin and albumin together with LDH, respectively. This study highlights the pivotal role of the stromal compartment in the mechanisms of action of ICI, and the need for further studies aiming to overcome this stromal firewall.

Prognostic significance of CD8+ T-cells density in stage III colorectal cancer depends on SDF-1 expression

Since colorectal cancer (CRC) remains one of the most common malignancies, a tremendous amount of studies keep taking place in this field. Over the past 25 years, a notable part of the scientific community has focused on the association between the immune system and colorectal cancer. A variety of studies have shown that high densities of infiltrating CD8+ T-cells are associated with improved disease-free and overall survival in CRC. Stromal cell-derived factor-1 (SDF-1) is a protein that regulates leukocyte trafficking and is variably expressed in several healthy and malignant tissues. There is strong evidence that SDF-1 has a negative prognostic impact on a variety of solid tumors. However, the existing data do not provide sufficient evidence that the expression of SDF-1 has an influence on CRC. Knowing nowadays, that the microenvironment plays a crucial role in the development of cancer, we hypothesized that the expression of SDF-1 in CRC could influence the prognostic significance of CD8+ T-cells, as an indicator of the essential role of the immune microenvironment in cancer development. Therefore, we explored the combined prognostic significance of CD8+ T-cell density and SDF-1 expression in a large CRC collective. We analyzed a tissue microarray of 613 patient specimens of primary CRCs by immunohistochemistry (IHC) for the CD8 + T-cells density and the expression of SDF-1 by tumor cells and tumor-infiltrating immune cells. Besides, we analyzed the expression of SDF-1 at the RNA level in The Cancer Genome Atlas cohort. We found that the combined high CD8+ T-cell infiltration and expression of SDF-1 shows a favorable 5-year overall survival rate (66%; 95% CI 48–79%) compared to tumors showing a high expression of CD8+ T-cell only (55%; 95% CI 45–64%; p = 0.0004). After stratifying the patients in nodal negative and positive groups, we found that the prognostic significance of CD8+ T-cell density in nodal positive colorectal cancer depends on SDF-1 expression. Univariate and multivariate Hazard Cox regression survival analysis considering the combination of both markers revealed that the combined high expression of SDF-1 and CD8+ T-cell density was an independent, favorable, prognostic marker for overall survival (HR = 0.34, 95% CI 0.17–0.66; p = 0.002 and HR = 0.45, 95% CI 0.23–0.89; p = 0.021, respectively). In our cohort there was a very weak correlation between SDF-1 and CD8+ T-cells (rs = 0.13, p = 0.002) and in the trascriptomic expression of these two immune markers display a weak correlation (rs = 0.28, p < 0.001) which was significantly more pronounced in stage III cancers (rs = 0.40, p < 0.001). The combination of high CD8+ T-cell density and expression of SDF-1 represents an independent, favorable, prognostic condition in CRC, mostly in patients with stage III disease.

Post-transplant ferritin level predicts outcomes after allogeneic hematopoietic stem cell transplant, independent from pre-transplant ferritin level.

Allogeneic hematopoietic stem cell transplantation (HCT) is associated with significant morbidity and mortality. Elevated pre-transplant ferritin level (ferritinPre-HCT) is reported to be associated with increased mortality following HCT. The present study attempted to determine whether post-transplant ferritin level (ferritinPost-HCT) is associated with outcomes post-HCT, especially in the subgroups which developed acute or chronic graft-versus-host disease (GVHD). Out of 229 patients with serum ferritin level measured post-HCT, median ferritinPost-HCT was 2178ng/mL. Patients were stratified into low- or high-risk groups using recursive partitioning, based on ferritinPost-HCT (≤ 3169 vs > 3169ng/mL) and ferritinPre-HCT (≤ 669 vs > 669ng/mL). Compared to the low ferritinPost-HCT group, the high ferritinPost-HCT group had lower 3-year overall survival (OS) (40.0% vs 66.7%, p < 0.001) and higher non-relapse mortality (NRM) (48.6% vs 17.8%, p < 0.001), but no difference in relapse (10.5% vs 19.7%, p = 0.079). Multivariate analysis confirmed ferritinPost-HCT as an independent prognostic factor for OS (p = 0.001, HR = 2.323) and NRM (p < 0.001, HR = 3.905). However, ferritinPre-HCT did not stratify well for OS or NRM. FerritinPost-HCT was also found to be an independent prognostic marker for OS and NRM in the subgroups which developed GVHD. In our cohort, high ferritinPost-HCT levels were significantly associated with decreased OS and increased NRM independent of ferritinPre-HCT or GVHD. Additional studies including larger sample sizes and prospective investigation are warranted to clarify the prognostic significance and pathophysiology of pre- and post-transplant hyperferritinemia.

A validation study on the lung immune prognostic index for prognostic value in patients with locally advanced non–small cell lung cancer

BackgroundBaseline lung immune prognostic index (LIPI) was reported as a potential predictive biomarker of immune checkpoint inhibitor treatment and a prognostic biomarker for metastatic non-small cell lung cancer (NSCLC). However, it remains unclear whether LIPI is associated with outcomes in locally advanced NSCLC (LA-NSCLC). Materials/methodsPatients with LA-NSCLC receiving radiotherapy between 2000 to 2017 were retrospectively reviewed. Based on pretreatment dNLR and LDH level made up LIPI per previous publications, patients were divided into good group (0 score) and intermediate-poor group (1 or 2 scores). Propensity score matching (PSM) was conducted to balance confounding variables. ResultsA total of 1079 patients were eligible for analysis. Patients with intermediate-poor pretreatment LIPI had inferior overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) than those with good LIPI. Multivariate analysis suggested that LIPI was an independent prognostic marker for OS (hazard ratio [HR] = 1.19, 95% CI: 1.02–1.40), PFS (HR = 1.18, 95% CI: 1.02–1.36), and LRRFS (HR = 1.22, 95% CI: 1.05–1.41) in patients with inoperable LA-NSCLC. PSM analysis further verified that intermediate-poor LIPI was an independent prognostic factor for shorter survivals (OS, PFS and LRRFS). ConclusionsLIPI is a simple and promising prognostic marker for patients with unresectable LA-NSCLC. Further prospected studies are warranted to validated these findings.

Preoperative Serum Axl/Gas6 Allow Stratification of Oncological Outcome in Patients Undergoing Liver Resection for Hepatocellular Carcinoma

Introduction: Liver resection is routinely performed in patients suffering from primary liver malignancies. Still, this group of neoplastic entities is known to have an unfavourable prognosis. Thus, preoperative risk assessment is vital for clinical decision making. Recently, Axl and its ligand Gas6 were found to be associated to unfavourable tumor characteristics in hepatocellular carcinoma (HCC). Further, a negative correlation with overall survival (OS) and disease-free survival (DFS) were observed, which suggests its potential use as a prognostic marker in HCC patients. Method: Serum was collected in 27 patients prior to liver resection for HCC. Levels of Axl/Gas6 were measured via ELISA and evaluated as markers for OS and DFS. Results: Indeed, Axl and Gas6 were elevated in patients with an OS of less than one year and showed a high predictive potential for death within this period as assessed via receiver operating characteristics (p=0.033,AUC=0.809, respectively). Using the Youden index, optimal cut-offs were identified at 45.00 ng/mL for Axl and at 50.00 ng/mL for Gas6. Interestingly, patients above the cut-off for Axl showed significantly reduced OS in Kaplan-Meier analysis (p=0.045), and a tendency towards earlier tumor recurrence (p=0.067). Similarly, patients with increased Gas6 levels tended to display reduced OS (p=0.072), while there was no association to DFS. Conclusion: The present data underlines a potential benefit of incorporation of Axl/Gas6 in clinical routine. Especially combination with other biological markers could further increase validity. Accordingly, clinical decision making and treatment evaluation could be adapted in concordance with these markers.