Stable Disease Group Research Articles

Favourable outcome of planned pregnancies in systemic sclerosis patients during stable disease

Objective: Studies evaluating pregnancy outcomes in systemic sclerosis (SSc) are limited. SSc is associated with maternal complications and adverse neonatal outcomes. This study investigated the impact of disease stage (stable vs active) on the maternal and neonatal outcomes of pregnancies of patients followed at an Israeli medical centre. Method: The charts of 354 SSc female patients followed during 2003–2020 were reviewed. Data on clinical and laboratory features, number of pregnancies close to SSc diagnosis, and maternal and neonatal outcomes were analysed. Patients were divided into a stable disease and an active/early disease group. Results: The active/early disease group included 26 patients [19 diffuse SSc (dSSc)], with 38 pregnancies. Median disease duration was 1 year, except for four patients who were first diagnosed during pregnancy. SSc was exacerbated in all patients during pregnancy or shortly after delivery [skin, lung, and heart involvement in dSSc; severe vasculopathy in limited SSc patients]. Six patients had hypertensive disorders of pregnancy; four pregnancies ended with foetal death. Thirty-three children were born, 60% with intrauterine growth retardation (IUGR)/low birthweight (LBW). The stable disease group included 19 patients, including seven with previously active disease, now stabilized (five dSSc), and 32 pregnancies. All pregnancies were planned and monitored closely. Disease remained stable in all patients. Four patients had hypertensive disorders of pregnancy; 12/29 newborns had LBW (41%). Conclusion: Active maternal disease during pregnancy poses an increased risk of SSc aggravation. The maternal and neonatal outcomes in planned pregnancy during stable disease are favourable. IUGR/LBW is common among neonates, even in stable disease.

Primary refractory follicular lymphoma: a poor outcome entity with high risk of transformation to aggressive B cell lymphoma

BackgroundPrimary refractory (PREF) follicular lymphoma (FL) has a completely different clinical course from that of FL that responds to front-line treatments. In addition to having poor responses to salvage therapies, it seems that patients with PREF are at increased risk of histological transformation (HT). The Aristotle consortium presented the opportunity of investigating the risk of HT in a very large series of cases. Thus, we investigated the risk of HT in patients with PREF FL compared with that of responding patients or in stable disease and ultimately their outcome. MethodsSix thousand three hundred thirty-nine patients from the Aristotle database were included in the analysis. These patients had a histologically confirmed grade 1, 2 or 3a FL diagnosed between 1997 and 2013. The primary end-points were the cumulative incidence (CI) of HT at the first progression or relapse and the survival after transformation. Findings.The 5-year CI of HT among patients with PREF was 34% (95% confidence interval (CI): 27–43), whilst it was 7.1% (95% CI: 6.0–8.5) in the group of patients with partial response (PR) or stable disease (SD) (PR + SD) and 3.5% (95% CI: 3.0–4.2) in the group of patients achieving complete response (CR). The 5-year survival after relapse (SAR) was 33% (95% CI: 28–39) for the PREF group, 57% (95% CI 54–61) in patients with PR, 51% (95% CI 43–58) in the SD group after first-line therapy and 63% (95% CI: 66–72) in patients with CR after initial treatment (p-value <0.001). The 5-year SAR for those patients with PREF who developed HT was 21% (95% CI: 12–31), clearly diminished when compared with those patients with PREF who did not experience HT (38% [95% CI: 31–44]) (p-value = 0.001). Interpretation.Patients with PREF FL have a dismal outcome and an associated very high rate of HT that further worsens their poor prognosis.

The study of novel inflammatory markers in takayasu arteritis and its correlation with disease activity

ObjectivesCurrently, erythrocyte sedimentation rate (ESR) and highly sensitive serum C-reactive protein (hsCRP) levels are used to monitor disease activity and guide therapy in Takayasu Arteritis (TA). However, non-specificity of these markers suggests the need for novel biomarkers. In this pilot study, we explore the role of novel biomarkers for evaluating disease activity in TA. MethodsA total of 40 patients with TA were divided into active and stable disease groups. Disease activity was assessed according to the National Institutes of Health criteria proposed by Kerr et al. Routine blood investigations were obtained and serum tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-18, ESR, hsCRP levels and NLR (neutrophil to lymphocyte ratio) were assayed at baseline and after 6 months. ResultsAmong the 40 patients enrolled, 18 were classified as active while 22 were stable at baseline and with a similar pattern at 6 months. Along with ESR and hsCRP, IL-6 and IL-18 levels were significantly higher in the active disease group than in the stable disease group (p < 0.005). The levels of other novel biomarkers (IL-1, TNF-α) and NLR were not significantly higher in active disease group. ConclusionSerum IL-6 and IL-18 levels correlates well with disease activity in TA which suggests their important role in disease pathogenesis and may be helpful in guiding and monitoring therapy in active TA patients.

Plasma Fibrinogen as a Biomarker of Stable and Exacerbated Chronic Obstructive Pulmonary Disease

Study Design: An experimental, comparative, cross-sectional study Place and Duration of Study: Department of Physiology, Federal Post Graduate Medical Institute (FPGMI), Sheikh Zayed Medical Complex Lahore, Pakistan from August 2013 to 2014 Background: Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease, but is a partially reversible chronic inflammatory condition characterized by airway obstruction. COPD remains under-diagnosed and under-treated because the only available diagnostic method at present is testing lung functions by spirometry which is not helpful to determine the severity and clinical outcomes of the disease. Circulating biomarkers are under consideration for various diseases worldwide. Plasma fibrinogen is emerging as one of the most promising biomarkers of COPD in smokers. Objective: The objective of this study is to investigate if plasma fibrinogen can serve as a diagnostic biomarker of COPD in smokers, and if its further higher levels are seen in the exacerbated state of the disease in comparison to the stable disease. Materials and Methods: 75 middle-aged to old-age smokers of either gender were selected. Lung functions of every participant were measured to determine Forced Expiratory Volume in the first second (FEV1), Forced Vital Capacity (FVC), and the ratio of FEV1/FVC by spirometry. On the basis of the results of the tests, subjects were divided into three groups; firstly, the control group of chronic smokers without COPD, secondly, smokers with COPD in a stable state, and thirdly, patients in an exacerbated state of COPD. Plasma fibrinogen was quantitatively estimated in every individual of all three groups by the Clauss method using the Hemostat Fibrinogen kit. Results: The average Plasma fibrinogen level was found to be 235.008 mg/dl in healthy smokers (control group), while an average of 440.12mg/dl was measured in patients with stable COPD. The difference in plasma fibrinogen levels was found to be significant, having a p-value of (0.000). In the third group with declined lung function predicting acute exacerbated COPD, fibrinogen was found to be &gt; 453.2 mg/dl, which was significantly higher than in the stable disease group (p-value &gt; 0.0017) Conclusion: Plasma fibrinogen level measurement is a reliable and accessible test in terms of a diagnostic marker of COPD, as compared to conventional lung function testing done in the past.

DIAGNOSTIC UTILITY OF LEUKOCYTE PARAMETERS IN THE PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

Background. Inflammation is one of the key players in acute myocardial infarction (AMI). One of the ways to evaluate it indirectly is to analyze leukocyte parameters of complete blood count (CBC), which is a routine and affordable method of diagnosis. Leukocyte counts can provide additional information about the course, as well as a potential prognosis for complications of AMI. We suggest that the dynamic changes of CBC during the treatment of the patients with AMI may be of value to assess the prognosis of the course of the disease, and therefore require further study. Objective. The aim of the study to evaluate the diagnostic and prognostic potential of leukocyte indexes of CBC, in particular the levels of leukocytes, lymphocytes, neutrophils and N/L, WBC/MPV, PLT/L ratios in the patients with AMI at the time of hospitalization and on the 7th day of hospital stay. Methods. The study involved 204 individuals: 152 patients with AMI (Group 1), 30 patients with stable coronary heart disease (Group 2) and 24 healthy volunteers (Group 3). Hemogram parameters and their ratios, in particular the levels of leukocytes, lymphocytes, neutrophils, ESR, as well as the ratios of N/L and PLT/L were studied. Results. Levels of leukocytes, neutrophils, lymphocytes, as well as N/L, WBC/MPV, MPV/L ratios were significantly higher in the patients with AMI compared to other groups. The best diagnostic value had such indicators as the total number of leukocytes (sensitivity 71.7%, specificity 69.7%, AUC 0.794), the absolute number of granulocytes (sensitivity 81.7%, specificity 77.4%, AUC 0.803), the N/L ratio (sensitivity 75.0%, specificity 71.7%, AUC 0.791) and the WBC/MPV ratio (sensitivity 76.7%, specificity 62.3%, AUC 0.760). The PLT/L ratio calculated on the 7th day of hospital stay correlated with the risk of in-hospital (r=0.369, p=0.002) and 6-month mortality (r=0.338, p=0.004) according to the GRACE score. Conclusions. Leukocytes, granulocytes, N/L and WBC/MPV ratios had a fairly high diagnostic value for the patients with AMI. Regarding the prognostic potential assessment, only the PLT/L ratio on the 7th day of hospitalization correlated with the risk of in-hospital and 6-month mortality. This proves the importance of assessing CBC parameters not only at the time of hospitalization, but also in the dynamics of AMI.

Comprehensive Medical System for Early Diagnosis of Rheumatoid Arthritis Based on Autoimmune Antibodies

With the development of understanding of the pathogenesis of rheumatoid arthritis, it has led to the development of new treatment targets and new treatment guidelines. In the past 10 years, the treatment effect of RA patients has improved significantly. Due to the special clinical symptoms of RA, it is very important to have a clear assessment of the overall activity of the patient’s disease and timely adjustment of treatment through joint monitoring of symptoms and laboratory indicators. Clinicians have always relied on clinical manifestations and imaging progress as the key basis for diagnosis. In addition, some markers that reflect disease activity are used to aid the diagnosis of RA, but in other autoimmune diseases, these markers are usually increased. The emergence of specific autoantibodies makes it easier for clinicians to distinguish RA from other autoimmune diseases and osteoarthritis. This study collected a large number of medical records through retrospective analysis, analyzed the epidemiological data, clinical characteristics, and laboratory indicators of RA patients, and analyzed the characteristics and laboratory indicators of patients in the stable disease group and active disease group. In order to further understand the clinical features, disease activity and related factors of RA in our country, and some new biomarkers for early rheumatoid arthritis, for example, the study found that the specificity of RF for the diagnosis of RA was 71.1%, the sensitivity was 73.3%, the combined detection of anti‐CCP antibody + RF increased the specificity to 97.8%, and anti‐CCP the combined diagnosis of antibody+RF + GPI antigen increases the specificity of diagnosis to 100%, which significantly reduces the sensitivity compared with all tests. These autoimmune antibodies can more effectively prevent the progression of the disease in the early diagnosis and treatment of rheumatoid arthritis, achieve long‐term remission, and obtain very effective therapeutic effects.

Clinical Outcomes of Mixed Response to Pembrolizumab in Advanced Urothelial Carcinoma After Platinum-based Chemotherapy.

Despite the presence of a mixed response (MR) in patients with urothelial carcinoma (UC) who receive immune checkpoint inhibitors, the clinical outcome of these patient has not been reported. We evaluated the clinical outcome of MR to pembrolizumab for advanced UC. Advanced UC patients who received pembrolizumab after platinum-based chemotherapy failure with measurable disease in multiple organs were retrospectively analyzed. Among 31 patients, MR [including progressive disease (PD)+complete response (CR) or partial response (PR)] was confirmed in 4 (12.9%). The median overall survival (OS) of the CR+PR (including CR+SD±PR), stable disease (SD), PD (including PD±SD) and MR groups was 16.0, 5.1, 5.4 and 4.3 months, respectively. There was no significant difference in the OS between the MR and CR+PR response groups (log-rank test, p=0.069). A mixed response to pembrolizumab in advanced UC was not uncommon. Despite the non-significant difference in the OS between the mixed and CR+PR response groups, the OS of the MR group tended to be similar to that of the SD and PD response groups.

Tracking Peripheral Memory T Cell Subsets in Advanced Non-Small Cell Lung Cancer Treated with Hypofractionated Radiotherapy and PD-1 Blockade in the ABSCOPAL-1 Clinical Trial

Background: Hypofractionated radiotherapy (HFRT) or chemotherapy combined with programmed death-1 (PD-1) blockade has achieved good clinical control in advanced non-small cell lung cancer (NSCLC). However, the effects of the distinct cell-killing mechanisms induced by radiotherapy and chemotherapy on immune memory remain unclear. We compared T memory subset differentiation in responders and non-responders treated with HFRT combined with PD-1 blockade to those in responders treated with chemo-immunotherapy. Methods: Thirty-eight patients with advanced NSCLC were enrolled in the trial. The frequencies of naive (Tn; CD45RA+CCR7+ ), central memory (Tcm; CD45RA–CCR7+), effector memory (Tem; CD45RA–CCR7–), and effector memory RA (TemRA; CD45RA+ CCR7–) T cell subsets and PD-1 expression were analyzed in CD4+ and CD8+ T cells using flow cytometry on single-cell suspensions from peripheral blood samples. Subsets were compared between healthy control and untreated NSCLC groups; among partial response, stable disease, and progressive disease groups treated using HFRT+PD-1 blockade; and between those treated with chemo-immunotherapy pre- and post-treatment. The correlations of memory T cell subsets and PD-1 expression with overall survival were examined using logistic regression. Findings: NSCLC patients showed expansion of the Tcm and Tem cell subsets among both CD4+ and CD8+ T cells compared with healthy controls. Patients with partial response to HFRT+PD-1 blockade showed reduction in Tn and expansion in TemRA cell subpopulations among CD8+ T cells and reduced PD-1+ CD4+ and PD-1+ CD8+ T cell counts, all of which were significantly correlated with overall survival. The responders to chemo-immunotherapy showed expansion of the TemRA CD4+ T cell subpopulation, decrease in Tcm CD4+ T and CD8+ T cell subpopulation. Conclusion: HFRT+PD-1 blockade and chemo-immunotherapy combination therapies induce differential memory T cell subset differentiation, offering predictive markers for treatment response. Trial Registration: ChiCTR-1900027768 Funding: This research was entirely funded by Functional study of Mir-183 in initiating cells of CD133+/CD326+ lung adenocarcinoma, 2013/01-2015/12, Project leader, Youth Fund project of National Natural Science Foundation of China； Immune mechanism of 3D guided Hypofractionation Radiotherapy in the treatment of lung adenocarcinoma， 2017/01-2019/12， Project leader， Luzhou People's Government - Southwest Medical University science and technology strategic cooperation fund；Luzhou Municipal Government and Southwest Medical University (2019LZXNYDC04);the joint project of People’s Government of Luxian County and Southwest Medical University (2019LXXNYKD-06);Joint Project of Sichuan University and Luzhou Industrial Research Institute (2020CDLZ-24). Declaration of Interest: None to declare. Ethical Approval: This prospective trial was approved by our ethics committee (No. KY2019276)

CTIM-19. MOLECULAR AND GENETIC DETERMINANTS OF RESPONSE TO PD-1 BLOCKADE IN RECURRENT GLIOBLASTOMA PATIENTS

Abstract Despite immune checkpoint inhibitors having success in several other tumor types, many glioblastoma (GBM) patients fail to respond or maintain a sustained response. Work published by our group (Cloughesy et al, 2019) demonstrated that relative to adjuvant programmed cell death-1 (PD-1) blockade, neoadjuvant treatment doubled the median overall survival (OS) for recurrent GBM patients and resulted in an enhanced interferon-γ signature. This suggests that anti-PD-1 given in the neoadjuvant setting may improve outcomes for recurrent GBM patients. The challenge remains in identifying the molecular and genetic signatures associated with response to immune checkpoint blockade. To address this, we analyzed the tumor sample and clinical response data from the patients treated in this clinical trial (n=31). We stratified patients as stable disease (SD) versus progressive disease (PD) based on their response assessment in neuro-oncology criteria (RANO) scores from cycle 2 of treatment post-surgery. Among the SD patients, 77.8% received neoadjuvant treatment while 22.2% received adjuvant therapy. In this group, a median OS was not reached. Among the PD patients, 40.9% received neoadjuvant treatment and 59.1% received adjuvant therapy, with a median OS of 257 days. Next, we analyzed factors that impact response to immunotherapy, which includes somatic mutational burden and interferon-γ pathway induction. We calculated somatic mutational variants, copy number variants (CNVs), and differential gene expression from the bulk tumor exome and RNA-sequencing data. The total mutation counts were similar between groups and no association was identified with increased mutational burden. In addition, total CNV stability was similar between groups. However, when looking at genes involved in the JAK/STAT signaling pathway, there were notably more copy number losses of JAK2 in the PD group when compared to the SD group (85.0% versus 66.7%). These findings merit further exploration as the JAK/STAT pathway has been implicated in response to immune checkpoint blockade.

Estimate the Serum Level of IL-17A and TGF-?1 1 in Iraqi Generalized Vitiligo Patients

Vitiligo is an acquired idiopathic skin disease characterized by white macules result from the destruction ofmelanocytes. Several cytokines have been implicated in the pathogenesis of vitiligo, keeping this in viewthe current study aimed to evaluate the serum levels of IL-17A and TGF-?1 in 25 patients with generalizedvitiligo and compared them with healthy individuals in order to investigate whether these cytokinesimbalances plays a role in the pathogenesis of this depigmentary disorder. Results of the present studyshowed that the serum level of IL-17A in vitiligo patients was increased significantly (p? 0.05) while theserum level of TGF-?1 was decreased significantly (p? 0.05) as compared with healthy control. Accordingto the gender of patients, males had a slightly non-significant increased (p&lt;0.05) in the level of IL-17A andTGF-?1 as compared with females. Patients with early onset vitiligo had non-significant increased (p&lt;0.05)in the level of IL-17A and TGF-?1 as compared with late onset vitiligo patients. No significant differences(p&lt;0.05) were detected in the levels of IL-17A and TGF-?1 in patients regarding the clinical types of vitiligo,family history and Koebner phenomenon. Patients with active disease had a significant increase (p?0.05) inthe level of IL-17A, though a significant decrease (p?0.05) in the level of TGF-?1 was noticed as comparedwith both patients with stable disease and healthy control groups. Serum levels of both IL-17A and TGF-?1have been shown to be negatively correlated with the disease duration (r=-0.174, p=0.405) and (r=-0.057,p=0.788) respectively

Association of lenvatinib plasma concentration with clinical efficacy and adverse events in patients with hepatocellular carcinoma

This study aimed to examine the association between the trough plasma concentration of lenvatinib with the objective response rate (ORR) and adverse events in patients with hepatocellular carcinoma (HCC). Twenty-one patients with HCC who received lenvatinib were enrolled. We examined the median trough concentration (Ctrough median) of plasma lenvatinib until the first clinical response evaluation. The receiver-operating characteristic curve was drawn to show the discrimination potential of the Ctrough median for the ORR, using the modified Response Evaluation Criteria in Solid Tumors. Adverse events were graded based on the Common Terminology Criteria for Adverse Events (ver. 5.0). The Ctrough median values in the complete response and partial response group were significantly higher than those in the stable disease and progressive disease groups. The ORR was significantly higher in the high-Ctrough median group (≥ 42.68ng/mL) than in the low-Ctrough median group (< 42.68ng/mL) (80.0% vs. 18.2%; p = 0.0089). Although there was no difference in the occurrence of most adverse events between the high- and low-Ctrough median groups, the occurrence of any grade anorexia (100.0% vs. 45.5%; p = 0.0124) and grade 3 serious hypertension (70.0% vs. 18.2%; p = 0.0300) was significantly higher in the high-Ctrough median group than in the low-Ctrough median group. Multivariate analysis showed that high-Ctrough median was significantly associated with ORR development (odds ratio, 15.00; 95% confidence interval, 1.63-138.16; p = 0.0168). Maintaining Ctrough median above 42.68ng/mL was crucial for achieving the ORR in patients with HCC.

SRPX2 boosts pancreatic cancer chemoresistance by activating PI3K/AKT axis.

Background and aimThis investigation was aimed at disclosing whether SRPX2 affected pancreatic cancer (PC) chemoresistance by regulating PI3K/Akt/mTOR signaling.MethodsTotally 243 PC patients were recruited, and they were incorporated into partial remission (PR) group, stable disease (SD) group and progressive disease (PD) group in accordance with their chemotherapeutic response. PC cell lines (i.e. AsPC1, Capan2, VFPAC-1, HPAC, PANC-1, BxPC-3 and SW1990) and human pancreatic ductal epithelial cell lines (hTERT-HPNE) were also collected.ResultsPC patients of SD + PD group were associated with higher post-chemotherapeutic SRPX2 level than PR group, and their post-chemotherapeutic SRPX2 level was above the pretherapeutic SRPX2 level (P < 0.05). PR population showed lower SRPX2 level after chemotherapy than before chemotherapy (P < 0.05). Besides high serum SRPX2 level and SRPX2 level change before and after chemotherapy were independent predictors of poor PC prognosis. Additionally, si-SRPX2 enhanced chemosensitivity of PC cell lines, and expressions of p-PI3K, p-AKT and p-mTOR were suppressed by si-SRPX2 (P < 0.05). IGF-1 treatment could changeover the impact of si-SRPX2 on proliferation, migration, invasion and chemoresistance of PC cells (P < 0.05).ConclusionThe SRPX2-PI3K/AKT/mTOR axis could play a role in modifying progression and chemoresistance of PC cells, which might help to improve PC prognosis.

Prognostic Value of Serum Soluble Programmed Death-Ligand 1 and Dynamics During Chemotherapy in Advanced Gastric Cancer Patients.

PurposeThe soluble form programmed death-ligand 1 (sPDL1) has immunosuppressive properties and is being studied as a candidate biomarker for immuno-oncology drug development. We measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in advanced gastric cancer (GC).Materials and MethodsWe prospectively enrolled 68 GC patients who were candidates for palliative standard first-line chemotherapy, and serially collected blood at baseline and after one cycle of chemotherapy, at the best response and after disease progression. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS), progression-free survival (PFS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were obtained. The cut-off value of sPDL1 levels for survival analysis was found using C-statistics.ResultsThe median baseline sPDL1 was 0.8 ng/mL (range, 0.06 to 6.06 ng/mL). The median OS and PFS were 14.9 months and 8.0 months, respectively. sPDL1 and NLR showed a weak positive correlation (Spearman’s rho=0.301, p=0.013). Patients with low levels of sPDL1 at diagnosis (< 1.92 ng/mL) showed a better OS and PFS than patients with a high sPDL1. The baseline sPDL1 before treatment was higher in the progressive disease group than in the stable disease and partial response groups. Patients whose sPDL1 increased after the first cycle of chemotherapy showed worse PFS and OS. Following disease progression, sPDL1 increased compared with the baseline.ConclusionsPDL1 at prechemotherapy confers a prognostic value for PFS and OS in GC patients under palliative first-line chemotherapy. Dynamics of sPDL1 during chemotherapy correlates with disease progression.

The association between monocytic myeloid-derived suppressor cells levels and the anti-tumor efficacy of anti-PD-1 therapy in NSCLC patients.

Monocytic myeloid-derived suppressor cells (M-MDSCs), granulocytic MDSC (G-MDSCs) and regulatory T cells (Tregs) inhibit adaptive anti-tumor immunity and undermine the efficacy of anti-PD-1 therapy. However, the impact of anti-PD-1 treatment on these immunosuppressive cells has not been clearly defined in non-small cell lung cancer (NSCLC). In this retrospective study, 27 advanced NSCLC patients were divided into partial response (PR), stable disease (SD), and progressive disease (PD) groups. The impact of anti-PD-1 therapy on circulating Tregs, G-MDSCs, and M-MDSCs was assessed by flow cytometer. Here, we found that anti-PD-1 treatment boosted circulating Tregs levels, which presented the most remarkable augment during the first two therapeutic cycles, in NSCLC patients. In contrast, anti-PD-1 therapy did not overall change G-MDSCs and M-MDSCs levels. However, the PR group had a higher baseline level of M-MDSCs, which exhibited a significant decrease after the first cycle of anti-PD-1 treatment. Besides, M-MDSCs levels in the PR group were maintained at a low level in the following therapeutic cycles. Consistently, Tregs levels robustly increased in the syngeneic tumor model after anti-mouse PD-1 Ab treatment. Accordingly, M-MDSCs neutralization by anti-mouse ly6c Ab enhanced the anti-tumor efficacy of anti-PD-1 therapy in mice. Finally, the decreased M-MDSCs levels were associated with the enhanced effector CD8+ T cells expansion in the PR group and mice. In conclusion, anti-PD-1 therapy upregulates Tregs levels in NSCLC patients, and the M-MDSC levels are associated with the anti-tumor efficacy of anti-PD-1 treatment. Neutralization of M-MDSCs may be a promising option to augment anti-PD-1 therapy efficacy in NSCLC.

The role of volumetric method in the assessment of chemotherapy response and predicting survival in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a pleural tumor with high mortality rate and short-term survival expectancy after diagnosis. Assessment of the response to chemotherapy, which is the first choice in treatment of MPM, is important for the transition to alternative chemotherapy protocols and immunotherapy. There is no clarity in the response to chemotherapy treatment. Our study aims to compare the assessment of chemotherapy response using the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria and volumetric measurements and to correlate with median survival. Thirty-two patients (16 females and 16 males) were included in the study, and their ages ranged from 28 to 78 years. Chemotherapy response was determined by both mRECIST and volumetric approach. Tumor volume was measured by linear interpolation and semi-automatic segmentation. Log-rank multiple cutoff analysis was used to determine appropriate cutoff values of volumetric response criteria. According to both mRECIST and volumetric approach, median survival times in partial response, stable disease, and progressive disease groups were 24, 15, and 9 months, respectively. The survival times of the three groups were different (logrank: 17.76; P < 0.001) by mRECIST. The survival of the progressive disease group was shorter than that of the other groups (logrank: 18.91; P < 0.001) by volumetric approach. In the assessment of chemotherapy response, even though classifications obtained according to the mRECIST criteria and volumetric measurements are statistically compatible, we think that the measurement of the volumetric values will increase the standardization. In our study, threshold values for volumetric measurements were determined; however, these values should be supported by large-scale multicenter studies.

Comparison of Metabolic and Morphological Response Criteria for Early Prediction of Response and Survival in NSCLC Patients Treated With Anti-PD-1/PD-L1.

Introduction/Aim: Immunotherapy with immune checkpoint inhibitors (ICIs) has positively changed the history of several malignant tumors. In parallel, new challenges have emerged in the evaluation of treatment response as a result of their peculiar anticancer effect. In the current study, we aimed to compare different response criteria, both morphological and metabolic, for assessing response and outcome in patients with advanced non-small cell lung cancer (NSCLC) treated with ICI.Materials and Methods: Overall, 52 patients with advanced NSCLC candidate to ICI were prospectively evaluated. Inclusion criteria comprised whole-body contrast-enhanced CT and 18F-FDG PET/CT at baseline and at the first response evaluation 3 or 4 cycles after ICI. Response assessment on CT was performed according to RECIST 1.1 and imRECIST criteria, whereas metabolic response on PET was computed by EORTC, PERCIST, imPERCIST, and PERCIMT criteria. The concordance between the different tumor response criteria and the performance of each criterion to predict progression-free survival (PFS) and overall survival (OS) were calculated.Results: Inclusion criteria were fulfilled in 35 out of 52 patients. We observed a low agreement between imRECIST and imPERCIST (κ = 0.143) with discordant response in 20 patients, particularly regarding stable disease and progressive disease groups. Fair agreement between imRECIST and EORTC (κ = 0.340), and PERCIST (κ = 0.342), and moderate for PERCIMT (κ = 0.413) were detected. All criteria were significantly associated with PFS, while only PERCIMT and imPERCIST were associated with OS. Of note, in patients classified as immune stable disease (iSD), imPERCIST, and PERCIMT well-differentiated those with longer PFS (p < 0.001, p = 0.009) and OS (p = 0.001, p = 0.002). In the multivariate analysis, performance status [hazard ratio (HR) = 0.278, p = 0.015], imRECIST (HR = 3.799, p = 0.026), and imPERCIST (HR = 4.064, p = 0.014) were predictive factors for PFS, while only performance status (HR = 0.327, p = 0.035) and imPERCIST (HR = 3.247, p = 0.007) were predictive for OS.Conclusions: At the first evaluation during treatment with ICI, imPERCIST criteria correctly evaluated treatment response and appeared able to predict survival. Moreover, in patients with iSD on CT, imPERCIST were able to discriminate those with longer survival. This advantage might allow for earlier therapy modification based on metabolic response.

Systemic inflammatory response and nutritional biomarkers as predictors of nivolumab efficacy for gastric cancer.

To investigate the usefulness of clinicopathological systemic inflammatory response and nutritional biomarkers for predicting the efficacy of nivolumab in patients with advanced gastric cancer. The subjects of this study were 29 patients who received nivolumab treatment for advanced gastric cancer at the Kochi Medical School between 2017 and 2019. Clinicopathological information, including systemic inflammatory response data, were obtained to investigate the associations between baseline cancer-related prognostic variables and survival outcomes. Immune-related adverse events (irAEs) of any grade were identified in 34.5% (10/29) of the patients. The median progression-free survival of patients with irAEs was significantly greater than that of patients without irAEs (5.8months vs. 1.2months, respectively; P = 0.028). The neutrophil to lymphocyte ratio (NLR) after 4weeks of treatment in the complete response (CR) or partial response (PR) group was significantly lower than that in the stable disease (SD) or progression disease (PD) group (2.2 vs. 2.9, respectively; P = 0.044). The prognostic nutrition index (PNI) before treatment in the CR or PR group was significantly higher than that in the SD or PD group (37.1 vs. 32.1, respectively; P = 0.011). The PNI 8weeks after treatment and the Glasgow prognostic score (GPS) before treatment were significantly associated with a poor outcome. The irAE, NLR, PNI, and GPS may be useful predictive markers for nivolumab efficacy in patients with advanced gastric cancer.

Platelet Volume Indices in Patients with Acute Coronary Syndrome

Background &amp; Aims: Acute coronary syndrome is one of the leading causes of morbidity and mortality in the world and platelet hyperactivity with local platelet activation plays a crucial role in its genesis. As there is discrepancy regarding the significance of deranged platelet parameters, we aimed to study the role of platelet volume indices in the spectrum of coronary artery syndrome and to correlate them clinically.&#x0D; Study Design: The study was conducted by collecting the data of patients with Myocardial infarction from the Cardiac care unit registry along with their clinical history and investigations. Stable coronary artery cases were collected from the Catheterization Lab and compared with Age and Sex matched controls. All CBCs of the above groups were processed by a 5-part counter and the data generated was transferred to a master chart for statistical analysis.&#x0D; Place and Duration of study: The study was conducted in the Central Laboratory &amp; Department of Pathology at D.Y. Patil Hospital, Navi Mumbai, India in collaboration with the Cardiac Care Unit and Catheterisation Lab of the hospital for a period of two years.&#x0D; Methods: A total of 122 cases were studied and grouped into 5 groups according to presentation and the platelet volume indices of these were compared with 38 matched controls and statistically analysed.&#x0D; Results: Mean Platelet Volume and Platelet Distribution Width of patients with ST elevation Myocardial Infarction (STEMI) and Non ST elevation Myocardial Infarction(NSTEMI) were increased marginally in number when compared to Stable Coronary Artery Disease(SCAD) and Control group, however this was not statistically significant. Platelet Large Cell Ratio (PLCR) was significantly raised in STEMI cases only (P = 0.09), so it may prove to be a better marker for the disease (P = 0.09). Platelet counts in various groups when compared with controls gave inconsistent results i.e SCAD vs Control significantly decreased (P = 0.07) and STEMI vs Control significantly increased (P = 0.01).&#x0D; Conclusion: The platelet volume indices in suspected acute coronary syndrome cases showed various changes, but present data failed to be diagnostically significant. However this data may later help to characterise further relationship between Acute coronary syndrome and platelet function in subsequent studies.

Correlation analysis of Sema4D with rheumatoid arthritis disease activity, bone destruction and rheumatoid arthritis-related interstitial lung disease

Objective: To explore the correlation between Semaphorin 4D (Sema4D) and rheumatoid arthritis (RA) clinical manifestations, laboratory indexes, bone destruction and rheumatoid arthritis related interstitial lung disease(RA-ILD), and to analyze its significance in evaluating the severity of patients with rheumatoid arthritis. Methods: A total of 108 RA patients and 50 healthy controls from September 2018 to October 2019 were collected from the Department of Rheumatology and Immunology, Peking University People's Hospital and Beijing Haidian Hospital. According to the DAS 28 score, RA patients were divided into active disease group (DAS28>2.6) and stable disease group (DAS28 ≤ 2.6). Fifty healthy controls. The levels of Sema4D in serum were detected by enzyme-linked immunoassay method (ELISA), and their correlation with clinical manifestations of RA, laboratory indicators, degree of bone damage and RA-ILD were analyzed. Results: The level of serum Sema4D in RA active group was significantly higher than that in stable group and healthy control group (P<0.05). The concentration serum Sema4D was positively correlated with C-reactive protein(CRP) (r=0.28, P<0.05), rheumatoid factor(RF) (r=0.25, P<0.05) and the 28-joint disease activity score (DAS28) (r=0.45, P<0.01). The concentration serum Sema4D was positively correlated with β-Crosslaps(r=0.20, P<0.05) and Sharp-van der Heijde score (SHS)(r=0.13, P<0.05). The concentration serum Sema4D was positively correlated with Vascular endothelial growth factor (VEGF)(r=0.25, P<0.05) and Warrick score of chest CT in RA patients(r=0.27, P<0.05). The anti-cyclic citrullinated peptid(CCP) antibody, DAS28, VEGF and the incidence of RA-ILD were significantly higher than that in Sema4D negative group (P<0.05). Conclusions: Serum Sema4D level in RA patients is closely related to the disease activity, bone destruction and RA-ILD. Serum Sema4D can be used as an indicator of disease monitoring and prognosis evaluation in RA patients.

Identification of CCN1 transferred by extracellular vesicles derived from breast cancer cells responsible for doxorubicin-resistance.

e12623 Background: The anthracycline drug, doxorubicin, is one of the most frequently used chemotherapeutic drugs for breast cancer. However, not all patients respond to doxorubicin-containing combination chemotherapy due to chemo-resistance (natural or acquired). Preceding researches have shown that extracellular vesicles (EVs) can be readily harvested from peripheral blood for further biological analysis and thus perform an attractive source of tumor derived materials for identification of chemo-resistance factors. This study aims to provide a theoretical basis to use CCN1-containing EVs as new biomarkers and therapeutic targets for doxorubicin-resistance in breast cancer. Methods: A strategy combining RNA-sequencing technique and bioinformatic analysis was used to determine the level of differential expressed mRNAs in EVs samples from cellular supernatant (n = 4) and blood serum (n = 8) from chemo-resistant and chemo-sensitive patients. Serial gene expression analysis in patients (n = 203) who treated with neoadjuvant (GSE32603) were also employed to identified drug-resistance-related proteins. The expression of CCN1 was detected in doxorubicin-resistant cell lines (MCF-7/DOX),MCF-7 and their EVs by RT-qPCR and western blot. Then, we used cell apoptosis and immunofluorescence stain to confirm the ability of CCN1-containing EVs in conferring drug resistance. Immunohistochemistry stain and RT-qPCR were used to prove the expression level of CCN1 in tumor tissues from breast cancer patients (n = 80) and in serum EVs from patients treated with the whole neoadjuvant chemotherapy. Results: We combined the differentially expressed mRNAs from three datasets and found identified CCN1 as a drug-resistance-related factor in breast cancer. The expression level of CCN1 is much higher in MCF-7/DOX cells and their EVs compared with MCF-7 cells and their EVs. The addition of CCN1-containing EVs has been found significantly increase the resistance to doxorubicin in sensitive cells. Moreover, a higher expression level of CCN1 was detected in the progressive disease (PD)/stable disease (SD) group than in the partial response (PR)/complete response (CR) group both in tissues and serum EVs. Conclusions: All These findings demonstrate that CCN1-containing EVs appear to be essential in conferring resistance to doxorubicin. More importantly, we exhibit the potential applications of CCN1-containing EVs for predicting the efficiency and outcome of patients treated with doxorubicin-based chemotherapy.