Predictive Value For Response Research Articles

Australasian Leukaemia & Lymphoma Group NHL35-Pacific: An Open Label Phase II Study of Pembrolizumab and Chemo-Immunotherapy As First-Line Therapy for Primary Mediastinal B-Cell Lymphoma - Trial in Progress

Background: Primary Mediastinal B-cell Lymphoma (PMBL) comprises 10% of Diffuse large B-cell lymphoma (DLBCL), primarily affecting young adults. Combination chemoimmunotherapy with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) is effective, however up to 10-20% of patients may have either refractory disease or experience relapse within 12 months of completing treatment. Consolidative radiotherapy has often been used following R-CHOP, with retrospective data suggesting a survival benefit compared with R-CHOP alone. However, mediastinal radiotherapy increases risk of breast cancer and cardiovascular disease and the recently reported randomised IELSG37 study demonstrated no improvement in progression free survival (PFS) with the use of consolidative radiotherapy following chemoimmunotherapy. Dose-adjusted Etoposide, Prednisolone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (DA-EPOCH-R) without radiotherapy has demonstrated excellent activity in a small phase II study but with increased chemotherapy toxicity. In IELSG37, PFS was inferior for patients treated with R-CHOP-21 compared with other chemoimmunotherapy regimens, supporting intensification of therapy beyond R-CHOP-21 in this entity. The outcome for patients with relapsed/refractory PMBL is poor, with response rates of around 25% to second line therapy, and a 2-year overall survival of 15%. Therefore, there remains a need to improve initial therapy for patients with PMBL. Programmed-Death-1 (PD-1) ligands PD-L1/PD-L2 are commonly upregulated in PMBL. The PD-1 inhibitor Pembrolizumab blocks the interaction of PD-1 and PD-L1/2, and subsequent signalling, and has encouraging activity in relapsed/refractory PMBL, with an overall response rate of 43% (complete response 23%) and modest toxicity in a phase II study. ‘Window’ induction treatment involving delivery of checkpoint inhibitor therapy to patients with lymphoma, prior to initiation of chemotherapy has been investigated in phase II studies, showing encouraging efficacy and no safety concerns with this ‘chemotherapy-free’ initial treatment approach. The combination of Pembrolizumab and Rituximab is predicted to be synergistic, and in non-randomised trials in other B-cell lymphoma histologies, has demonstrated superior response rates to those expected with Rituximab monotherapy, suggesting synergism of the combination. There is therefore compelling rationale for combining R-CHOP and Pembrolizumab as first-line therapy for PMBL. This study investigates the efficacy and safety of this novel, time-limited, radiotherapy sparing regimen. Methods ALLG-PACIFIC (ANZCTR- ACTRN12621001529831) is a phase II, single arm, open-label study of R-CHOP in combination with Pembrolizumab. The trial is open to recruitment across Australia. Approximately 35 patients with newly diagnosed PMBL, will be enrolled to receive two cycles of Rituximab (375mg/m 2) plus Pembrolizumab (200mg) once every 21 days ('window phase') followed by six cycles of R-CHOP plus Pembrolizumab once every 21 days ('induction phase') followed by five cycles of Pembrolizumab 400mg once every 42 days ('consolidation phase') (Figure 1). Adults (≥18 years) with treatment naïve histologically confirmed PMBL and adequate organ function are eligible. Key exclusion criteria are the presence of active autoimmune disease, requiring recent immunosuppressive therapy, life-threatening or organ-compromising lymphoma symptoms requiring urgent cytoreductive therapy, and other medically significant conditions that preclude eligibility to receive R-CHOP. Patients who require urgent cytoreductive therapy following initiation of window phase treatment may proceed immediately to induction phase chemotherapy. The primary endpoint is 18-month event free survival. Key secondary endpoints include response to window phase treatment, overall survival, requirement for radiotherapy and safety of treatment including rates of early discontinuation due to treatment toxicity. Several biomarkers are also being investigated for their predictive value for treatment response including minimal residual disease status (measured by Adaptive Immunoseq and CAPP-Seq), PET-CT parameters (e.g., Metabolic tumour volume), and PD-1/PD-L1 expression and 9q24 alterations.

Altered threonine tyrosine kinase (TTK) expression is associated with adverse clinical outcomes in breast tumors: An in silico approach

The most common and lethal malignancy in women on a global scale remains breast cancer. Threonine tyrosine kinase (TTK) has been shown to be a critical mitotic spindle assembly checkpoint (SAC) molecule, resulting in correct chromosome segregation and maintenance of genomic stability. Therefore, the present study was carried out to evaluate the expression pattern of threonine tyrosine kinase (TTK) in breast cancer and its potential prognostic and predictive value for therapeutic response using bioinformatics tools. Web platforms containing clinical information and cDNA microarray data were selected to perform in silico analyzes of the potential threonine tyrosine kinase (TTK) marker. The threonine tyrosine kinase (TTK) gene was found to be differentially expressed in tumor samples when compared to healthy breast tissue samples (p<0.0001) and the TNBC subtype exhibited the highest expression of threonine tyrosine kinase (TTK) relative to the other subtypes (p<0.0001). Furthermore, Kaplan-Meier curves revealed that high threonine tyrosine kinase (TTK) levels corresponded to an unfavorable outcome for overall survival (p<0.0001), as well as for recurrence-free survival (p<0.0001) and distant metastasis-free survival (p<0.0001). Finally, differential expression of threonine tyrosine kinase (TTK) was related to the response of breast cancer patients to different therapies. Our cumulative results demonstrate that threonine tyrosine kinase (TTK) may be a promising biomarker for predicting prognosis and therapeutic response in breast cancer patients.

Circulating memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio predict response and outcome to immunotherapy in advanced gastric cancer patients

BackgroundLimited benefit population of immunotherapy makes it urgent to select effective biomarkers for screening appropriate treatment population. Herein, we have investigated the predictive values of circulating CD8+ T cells and CD8+T/CD4+T cell ratio in advanced gastric cancer patients receiving immunotherapy.MethodsA retrospective cohort analysis of 187 advanced gastric cancer patients receiving sintilimab combined with oxaliplatin and capecitabine therapy in The Affiliated Xinghua People’s Hospital, Medical School of Yangzhou University between December 2019 and February 2023 was conducted. The corresponding clinical outcomes of the variables were analyzed by receiver operating characteristic (ROC) curve, chi-square test, Kaplan–Meier methods and Cox proportional hazards regression models.ResultsThe optimal cutoff values for percentages of CD8+ T cells, naive CD8+ T cells (CD8+ Tn) and memory CD8+ T cells (CD8+ Tm) expressing programmed cell death -1(PD-1) as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were 21.0, 21.5, 64.3 and 0.669, respectively. It was found that the mean percentages of CD8+ T and CD8+ Tm expressing PD-1 as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were significantly higher in responder (R) than non-responder (NonR) advanced gastric cancer patients associated with a longer progression free survival (PFS) and overall survival (OS). We also observed this correlation in programmed cell death-ligand 1(PD-L1) combined positive score (CPS) ≥ 5 subgroups. Univariate and multivariate Cox regression analyses demonstrated that lower CD8+ T and CD8+ Tm expressing PD-1 as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were independent risk factors in advanced gastric cancer patients receiving immunotherapy plus chemotherapy.ConclusionThe circulating memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio revealed high predictive values for response and prolonged survival outcomes in advanced gastric cancer patients receiving immunotherapy. Memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio might be effective for screening benefit population of immunotherapy in advanced gastric cancer patients based on this preliminary evidence.

Dynamic blood flow imaging with 99mTc-hydroxymethylene diphosphonate as a therapeutic response marker in patients with Raynaud's phenomenon.

We evaluated the predictive value of dynamic blood flow scintigraphy with 99mTc-HDP (hydroxymethylene diphosphonate) for therapeutic response in patients with Raynaud's phenomenon (RP). Eighty patients who underwent dynamic blood flow scintigraphy using the one-hand chilling method were enrolled. We analyzed the quantitative variables as the ratio of chilled fingers to ambient fingers (CAfinger), that of the chilled hand to ambient hand (CAhand), and that of chilled fingers to ambient palm (FPR) (CAFPR) at 15 and 30s after 99mTc-HDP bolus injection. Total cumulative radioactivity counts for 180s were obtained. We evaluated the clinical utility of these quantitative parameters with other clinical variables, including RP severity, therapeutic compliance, types of RP, and scintigraphic interpretation of findings in patients with RP. Fifty-two patients showed poor therapeutic response. There were significant differences between good- and poor-therapeutic responder groups in RP intensity (p = 0.003), CAfinger15s (p = 0.008), CAfinger30s (p = 0.002), CAfinger180s (p = 0.011), CAhand15s (p = 0.008), CAhand30s (p = 0.007), CAhand180s (p = 0.017), CAFPR30s (p = 0.004), and CAFPR180s (p = 0.002). After multivariate logistic regression analysis, only CAfinger30s (p = 0.002) had an independent predictive value of the therapeutic response. 99mTc-HDP dynamic blood flow scintigraphy could be helpful in predicting the therapeutic response in patients with RP.

Abstract 11832: Carotid Sinus Massage Can Obviate the Need for Tilt Table Testing in Patients With Undiagnosed Vasodepressor Syncope

Introduction: Head-up tilt table (HUTT) testing is typically utilized for patients with syncope where the diagnosis is unclear but suspicion of a vasovagal etiology. Carotid sinus massage (CSM) can be used to elicit a vasopressor response though typically used to diagnose carotid sinus hypersensitivity. The usual protocol of HUTT consists of baseline CSM, 30-mins of HUTT, a repeat of CSM, and drug infusion. This is time-consuming and tedious. Hypothesis: CSM has a high predictive value for a vasodepressor response and may prevent the need for the completion of the HUTT protocol. Methods: Consecutive patients with clinical suspicion of vasovagal syncope underwent HUTT. Protocol consisted of baseline CSM in the supine posture, 30-mins of HUTT at 60 degrees, repeat CSM, and infusion of isoproterenol infusion from 1 to 3 mcg/min. Beat-to-beat blood pressure (BP) monitoring was performed non-invasively and standard cuff BP monitoring every minute. Positive tilt was defined as a drop in BP by more than 20 mmHg with reproducible symptoms (correlation to clinical symptoms). Results: 55 consecutive patients with a history of syncopal episode(s) underwent HUTT. 46 were females and 9 were male with a mean age of 54.4 ± 17.4 years old. They presented symptoms suggestive of a vasovagal etiology but were not diagnostic. 12 out of 55 (21.8%) patients had a positive reproducible response with supine CSM. 11 out of 12 of these patients subsequently had a positive result with protocol completion. This provided a positive predictive value (PPV) of 92%. 36 out of 55 (65.5%) patients had a negative response to CSM. All 36 had a negative result on completion of the HUTT protocol. This provided a negative predictive value (NPV) of 100%. 7 out of 55 (12.7%) patients had a “borderline” positive supine CSM. All 7 had a positive result with the completion of the HUTT protocol. Of note, these patients became positive only with isoproterenol infusion. Conclusions: CSM in the supine posture has a high PPV and NPV in eliciting a possible vasodepressor etiology. A full HUTT protocol may be only required in a patient who presents with a “borderline” CSM response in the supine posture. Therefore, CSM may easily be performed at the bedside with a monitor and a BP apparatus obviating the need for the full HUTT protocol.

Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma

BackgroundPapillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the...

Pretreatment Absolute Immature Platelet Count is a Promising Predictor of Response to Short-Term Dexamethasone Monotherapy or Combination Therapy in Newly Diagnosed Adult Primary Immune Thrombocytopenia.

Reliable indicators that can predict drug responsiveness in primary immune thrombocytopenia (ITP) patients are urgent. We aimed to establish a reference interval of percentage of immature platelet fraction (IPF%) and absolute immature platelet count (A-IPC), and assess their efficacy in discriminating ITP patients from controls, especially their predictive value for responsiveness to drug treatment. We retrospectively studied 72 treatment-naive adult patients with ITP who received Dexamethasone monotherapy or combination therapy. Baseline (pretreatment) information was collected from medical records. Reference intervals for A-IPC and IPF% were established based on controls and their effectiveness in discriminating ITP patients from controls was assessed. Predictive value of pretreatment IPF% and A-IPC at four co-primary endpoints of treatment response in patients were investigated. The 95% reference intervals for A-IPC and IPF% were (2.7-15.6) × 109/L and 1.2%-7.3%, respectively. Both A-IPC and IPF% had excellentdiscrimination ability for ITP patients from controls. It showed highly statistically significantdifferences in pretreatment A-IPC for predicting treatment response at day 7 between responders and non-responders, but not at days 14, 21 and 28. Pretreatment A-IPC had the higher area under the ROC curve with a cut-off of 0.86 than that of IPF% with a cut-off of 14.5% in predicting the treatment response in ITP patients at day 7. Pretreatment A-IPC exhibited acceptable predictive power and could be a promising predictor of response to short-term Dexamethasone monotherapy or combination therapy at day 7 in ITP patients.

Interaction between intratumoral microbiota and tumor mediates the response of neoadjuvant therapy for rectal cancer.

Previous observations have demonstrated that the response to neoadjuvant chemoradiotherapy (nCRT) is highly variable in patients with locally advanced rectal cancer (LARC). Recent studies focusing on the intratumoral microbiota of colorectal cancer have revealed its role in oncogenesis and tumor progression. However, limited research has focused on the influence of intratumoral microbiota on the nCRT of LARC. We explored the microbial profiles in the tumor microenvironment of LARC using RNA-seq data from a published European cohort. Microbial signatures were characterized in pathological complete response (pCR) and non-pCR groups. Multi-omics analysis was performed between intratumor microbiomes and transcriptomes. Microbial α and β diversity were significantly different in pCR and non-pCR groups. Twelve differential microbes were discovered between the pCR and non-pCR groups, six of which were related to subclusters of cancer-associated fibroblasts (CAFs) associated with extracellular matrix formation. A microbial risk score based on the relative abundance of seven differential microbes had predictive value for the nCRT response (AUC = 0.820, p < 0.001). Our study presents intratumoral microbes as potential independent predictive markers for the response of nCRT to LARC and demonstrates the underlying mechanism by which the interaction between intratumoral microbes and CAFs mediates the response to nCRT.

Neoadjuvant Imatinib in Locally Advanced Gastrointestinal Stromal Tumors (GISTs) is Effective and Safe: Results from a Prospective Single-Center Study with 108 Patients.

Neoadjuvant imatinib is considered for gastrointestinal stromal tumors (GISTs) when decreased tumor size provides less extensive surgery and higher R0 resection rates. This study evaluates the effectivity and safety of neoadjuvant imatinib for large or locally advanced GIST. From the prospective database of the Dutch GIST Consortium, all patients who underwent surgery after neoadjuvant imatinib at our center between 2009 and 2022 were selected. Independent and blinded assessment of surgical strategy was performed by two surgeons, based on anonymized computed tomography (CT) scans before and after neoadjuvant imatinib. Of 113 patients that received neoadjuvant imatinib, 108 (95%) [mean age 61.6, standard deviation (SD) 11.5, 54% male] underwent a GIST resection. Of all GISTs, 67% was localized in the stomach and 25% in the duodenum or small intestine. In 74% of the patients with GIST, a KIT exon 11 mutation was found. Decreased tumor size was seen in 95 (88%) patients. Having a KIT exon 11 mutation [odds ratio (OR) 5.64, 95% confidence interval (CI) 1.67-19.1, p < 0.01] or not having a mutation (OR 0.19, 95% CI 0.04-0.89, p = 0.04) were positive and negative predictive values for partial response, respectively. In 55 (51%) patients, there was deescalation of surgical strategy after neoadjuvant imatinib. Surgical complications were documented in 16 (15%) patients (n = 8, grade II; n = 5, grade IIIa; n = 3, grade IIIb) and R0 resection was accomplished in 95 (89%) patients. The 5-year disease-free and overall survival were 80% and 91%, respectively. This study shows that neoadjuvant imatinib is effective and safe for patients with large or locally advanced GIST.

140P Predictive value of DNA damage response and repair gene alterations and neoscore for neoadjuvant immunotherapies in non-small cell lung cancer

140P Predictive value of DNA damage response and repair gene alterations and neoscore for neoadjuvant immunotherapies in non-small cell lung cancer

Pretreatment Neurofilament Light Chain Serum Levels, Early Disease Severity, and Treatment Response in Pediatric Multiple Sclerosis.

High disease activity and frequent therapy failure in pediatric multiple sclerosis (MS) make prognostic biomarkers urgently needed. We investigated whether serum neurofilament light chain (sNfL) levels in treatment-naive pediatric patients with MS are associated with early disease severity and indicate treatment outcomes. A retrospective cohort study of patients seen in the Göttingen Center for MS in Childhood and Adolescence, Germany. Inclusion criteria were MS diagnosis according to the McDonald criteria, MS onset <18 years, and available pretreatment serum sample. sNfL levels were analyzed using a single-molecule array assay. Associations with clinical and MRI evidence of disease severity at sampling were evaluated using the Spearman correlations and nonparametric tests for group comparisons. Correlations between pretreatment sNfL and annualized relapse and new T2 lesion rate on first-line therapy, and odd ratios for switch to high-efficacy therapy were assessed. A total of 178 patients (116 women [65%]) with a mean sampling age of 14.3 years were included in the study. Pretreatment sNfL levels were above the ≥90th percentile reported for healthy controls in 80% of patients (median 21.1 pg/mL) and correlated negatively with age, but no correlation was seen with sex, oligoclonal band status, or body mass index. High pretreatment sNfL levels correlated significantly with a high number of preceding relapses, a shorter first interattack interval, a high T2 lesion count, and recent gadolinium-enhancing lesions. Of interest, sNfL levels reflected more strongly MRI activity rather than clinical activity. Pretreatment sNfL levels also correlated significantly with the relapse rate and occurrence of new/enlarging T2 lesions while on first-line injectable therapy. Odds of future therapy escalation increased from 0.14 for sNfL below 7.5 pg/mL to 6.38 for sNfL above 15 pg/mL. In patients with a recent relapse, higher sNfL levels were associated with poorer recovery 3 months after attack. The results of this study have 3 important implications: First, pretreatment sNfL levels are a valuable biomarker for underlying disease activity in pediatric patients with MS. Second, pretreatment sNfL levels in pediatric patients with MS have a predictive value for the response to first-line therapy and the necessity of future therapy escalation. Third, high sNfL levels during a relapse are associated with poor recovery in this age group.

Immediate hypnosis effects and outcome predictors in chronic nociplastic pain

ABSTRACT This study used data from a randomized controlled trial on the efficacy of hypnosis with analgesic suggestions relative to hypnosis with nonspecific suggestions to explore two areas. The first was the immediate effects of each hypnosis session and their relevance to the treatment induced change in pain intensity. The second was the identification of variables associated with the beneficial effects of hypnosis treatment in the form of reducing pain intensity and pain quality. The predictive value of the initial treatment response, hypnotizability, and the dichotomous variable of pain medication use were examined. Both interventions resulted in similar significant reductions in pain intensity after each session, but without a cumulative effect. The initial response correlated positively and moderately with pain intensity decreases induced by the complete hypnosis treatment. There was only a weak association between hypnotizability and pain quality improvement. Only participants not taking pain medications achieved a meaningful reduction in pain outcomes. Each hypnosis session results in an immediate reduction in chronic nociplastic pain intensity, and a fruitful first session may be a positive signal to continue therapy. Even patients with low hypnotizability can obtain beneficial outcomes. Pain medication use may become a new predictor in hypnosis research, as significant decreases in pain intensity and pain quality occurred only in the absence of pharmacotherapy. However, the results of this study require confirmation in further research with longer treatment periods.

Cutaneous allodynia as predictor for treatment response in chronic migraine: a cohort study

BackgroundCentral sensitisation is an important mechanism in migraine chronification. It is presumed to occur in second and third order neurons sequentially, resulting in an analogous spatial distribution of cutaneous allodynia with cephalic and extracephalic symptoms. We investigated whether allodynia, and its subtypes based on spatial distribution and type of stimulus, predict response to treatment in chronic migraine patients.MethodsThis study was conducted as part of the CHARM study (NTR3440), a randomized, double-blind, placebo-controlled trial in chronic migraine patients with medication overuse. We included 173 patients. The presence of cutaneous allodynia at baseline was established with the Allodynia Symptom Checklist. Primary endpoint was reversion from chronic to episodic migraine.ResultsOf all patients, 74.6% reported cutaneous allodynia. Absence of allodynia compared to presence of allodynia was predictive for reversion from chronic to episodic migraine, odds ratio (OR): 2.45 (95% CI: 1.03–5.84), p = 0.042. The predictive value was more pronounced when subdivided for spatial distribution, for participants without allodynia versus cephalic (OR: 4.16 (95% CI: 1.21–14.30), p = 0.024) and extracephalic (OR: 7.32 (95% CI: 1.98- 27.11), p = 0.003) allodynia. Mechanical, but not thermal, allodynia, was associated with outcome.ConclusionsCutaneous allodynia, an important marker for central sensitization, likely has predictive value for treatment response in chronic migraine.Graphical

Circulating exosomal has-miR-24-3p and has-miR-128-3p reflect early efficacy of sublingual immunotherapy in allergic rhinitis

ObjectiveSublingual immunotherapy (SLIT) can improve the symptoms of allergic rhinitis (AR) and modify its natural course, but its effectiveness varies among individuals. This study aims to analyze miRNAs from serum exosomes and evaluate their predictive values for the early response of SLIT in AR. MethodsRNA sequencing was performed to investigate the differential expressions of serum exosomal miRNAs between ineffective and effective AR patients who treated with SLIT. The identified candidate miRNAs were validated in two independent cohorts, and the predictive capabilities of these miRNAs and alterations of their expression levels between pre- and 1 year post-SLIT were evaluated. ResultsThe serum exosome-derived miRNA profiles were significantly different between the effective and ineffective groups. The five most up-regulated and down-regulated miRNAs were verified in the first validation cohort, and the results demonstrated that serum exosomal has-miR-24-3p and has-miR-206 were reduced, while has-miR-128-3p was increased in the effective group compared to the ineffective group (P < 0.05). Additionally, the receiver operating characteristic (ROC) curves revealed that serum levels of has-miR-24-3p and has-miR-128-3p displayed potential values for predicting the early efficacy of SLIT (P < 0.05). In the second validation cohort, it was observed that the baseline levels of serum exosomal has-miR-24-3p were significantly lower, while has-miR-128-3p levels were significantly higher in the effective group compared to the ineffective group (P < 0.05). After 1 year of SLIT, there was a significant decrease in serum exosomal levels of has-miR-24-3p compared to baseline. On the other hand, effective patients showed a notable increase in serum exosomal levels of has-miR-128-3p (P < 0.05). ConclusionSerum exosome-derived miRNAs have the potential to impact the efficacy of SLIT in AR patients. Among them, serum exosomal has-miR-24-3p and has-miR-128-3p show promise as biomarkers for predicting the early effectiveness of SLIT and monitoring therapeutic outcomes.

Integrated single-cell and bulk sequencing analyses with experimental validation identify the prognostic and immunological implications of CD226 in pan-cancer.

CD226 (DNAM-1) is an activating receptor mainly expressed in CD8 + and NK cells. CD226 deficiency and blockade have been shown to impair tumor suppression, while enhanced CD226 expression positively correlated with the increased efficacy of immune checkpoint blockade (ICB) therapies. However, the detailed function and role of CD226 in pan-cancer are largely unknown and require further in-depth investigation. Therefore, this study aims to investigate the biological functions of CD226, its role in tumor immunity, and its potential to predict prognosis and immunotherapy response in pan-cancer. By taking advantage of single-cell and bulk sequencing analyses, we analyzed the expression profile of CD226, its correlation with patient prognosis, immune infiltration level, immune-related genes, tumor heterogeneity, and stemness in pan-cancer. We also investigated the biological functions of CD226 using gene set enrichment analysis (GSEA) and evaluated its predictive value in response to immunotherapy and small-molecule targeted drugs. In addition, we validated the expression of CD226 in tumor-infiltrating CD8 + and NK cells and studied its association with their functions using a murine B16F10 melanoma model. CD226 exhibited differential expression across most tumor types, and its elevated expression was associated with improved clinical outcomes in multiple cancer types. CD226 is closely correlated with numerous tumor-infiltrating immune cells, tumor stemness, and heterogeneity in most cancers. Furthermore, based on single-cell sequencing analysis, CD226 expression was found to be higher on effector CD4 + T cells than naïve CD4 + T cells, and its expression level was decreased in exhausted CD8 + T cells relative to effector CD8 + T cells in multiple cancer types. Additionally, flow cytometric analysis demonstrated that CD226 was highly correlated with the function of tumor-infiltrating NK and CD8 + T cells in murine B16F10 melanoma. Moreover, GSEA analysis revealed that CD226 was closely associated with T cell activation, natural killer cell mediated immunity, natural killer cell-mediated cytotoxicity, and T cell receptor signaling pathway. Finally, CD226 showed promising predictive potential for responsiveness to both ICB therapies and various small-molecule targeted drugs. CD226 has shown great potential as an innovative biomarker for predicting patient prognosis, immune infiltration levels, and the function of tumor-infiltrating CD8 + T cells, as well as immunotherapy response. Additionally, our findings suggest that the optimal modification of CD226 expression and function, combined with current ICBs, could be a promising strategy for tumor immunotherapy.

Immuno markers in newly diagnosed glioblastoma patients underwent Stupp protocol after neurosurgery: a retrospective series

PurposeThe aims of our retrospective study investigated the role of immune system in glioblastoma (GBM), which is the most aggressive primary brain tumor in adults characterized by a poor prognosis. The recurrence rate remains high, probably due to “immune-desert” tumor microenvironment (TME) making GBM hidden from the anti-tumoral immune clearance. Considering this, we aimed to create a panel of prognostic markers from blood and tumor tissue correlating with overall survival (OS) and progression-free survival (PFS).MethodsFirstly, we analyzed the inflammatory markers NLR and PLR as the ratio of the absolute neutrophil count and absolute platelet count by the absolute lymphocyte count respectively, collected at different time points in the peripheral blood of 95 patients. Furthermore, in 31 patients of the same cohort, we analyzed the formalin-fixed paraffin embedded samples to further compare the impact of circulating and inflammatory markers within the TME.ResultsPatients aged < 60 years and with methylated MGMT showed better OS. While, pre-chemotherapy Systemic Inflammatory Index (SII) < 480 was related to a better OS and PFS, we observed that only CD68+macrophage and CD66b+neutrophils expressed in vascular/perivascular area (V) showed a statistically significant prognostic role in median OS and PFS.ConclusionsThus, we underscored a role of SII as predictive value of response to STUPP protocol. Regarding the TME-related markers, we suggested to take into consideration for future studies with new immunotherapy combinations, each component relating to expression of immune infiltrating subsets.

Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer.

The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC). Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests. A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε (POLEmut EC). In mismatch repair-deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001). The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLEmut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.

Pretreatment dual-energy CT for predicting early response to induction chemotherapy and survival in nasopharyngeal carcinoma.

To evaluate the predictive performance of pretreatment dual-energy CT (DECT) for early response to induction chemotherapy and survival in nasopharyngeal carcinoma (NPC). In this retrospective study, 56 NPC patients who underwent pretreatment DECT scans with posttreatment follow-up were enrolled. The DECT-derived normalised iodine concentration (nIC), effective atomic number (Zeff), 40-180keV (20keV interval), and Mix-0.3 value of the tumour lesions were measured to predict the early response to induction chemotherapy and survival in nasopharyngeal carcinoma. The Mann‒Whitney U test, ROC analysis, Kaplan‒Meier method with log-rank test, and Cox proportional hazards model were performed to evaluate the predictive performance of DECT parameters, respectively. Among all DECT-derived parameters, ROC analysis showed the predictive performances of nIC and Zeff values for early objective response to induction chemotherapy (AUCs of 0.803 and 0.826), locoregional failure-free survival (AUCs of 0.786 and 0.767), progression-free survival (AUCs of 0.856 and 0.731) and overall survival (AUCs of 0.765 and 0.799) in NPC patients, respectively (all p < 0.05). Moreover, multivariate analysis showed that a high nIC value was an independent predictor of poor survival in NPC. In addition, survival analysis indicated that NPC patients with higher nIC values in primary tumours tend to have lower 5-year locoregional failure-free survival, progression-free survival and overall survival rates than those with lower nIC values. DECT-derived nIC and Zeff values can predict early response to induction chemotherapy and survival in NPC; in particular, a high nIC value is an independent predictive factor of poor survival in NPC. Preoperative dual-energy computed tomography may provide predictive value for early response and survival outcomes in patients with nasopharyngeal carcinoma, and facilitate their clinical management. • Pretreatment dual-energy computed tomography helps to predict early response to therapy and survival in NPC. • NIC and Zeff values derived from dual-energy computed tomography can predict early objective response to induction chemotherapy and survival in NPC. • A high nIC value is an independent predictive factor of poor survival in NPC.

The Association of Urinary MCP-1 with Disease Activity of Lupus Nephritis

Background: The association of urinary MCP-1 (Monocyte Chemoattractant Protein-1) with disease activity in lupus nephritis (LN) has been a subject of significant interest. MCP-1 is a chemokine involved in the recruitment and activation of monocytes, which play a critical role in the pathogenesis of LN. Objective: To assess association of Urinary MCP-1 with disease activity of lupus nephritis. Method: This cross sectional study was conducted in the Department of Nephrology, Dhaka Medical College Hospital, Dhaka from January, 2017 to June, 2018. This cross sectional study was performed on 60 biopsy proven lupus nephritis patients and 30 age and sex matched apparently healthy control subjects. All the patients were recruited as per inclusion and exclusion criteria. Diagnosed SLE patients who had renal involvement and undergone renal biopsy for standard clinical indications were recruited by purposive sampling and divided into two groups of active and inactive LN as per operational definition. Results: During the study, The urinary MCP-1 was higher in active LN patients compared to the inactive group and both were higher than the level in the control. Plus, highest Sensitivity and specificity of uMCP-1 observed at cutoff value 433 pg/ml, where sensitivity was 0.967 and specificity was 0.900. Among 30 active lupus nephritis cases raised uMCP-1 was found in 29 cases and among 30 inactive lupus nephritis cases raised uMCP-1 was found in 3 cases. uMCP-1 showed very good agreement in diagnosis of lupus nephritis activity according to Kappa statistics. uMCP-1 in diagnosis of lupus nephritis activity showed accuracy, sensitivity, specificity, PPV and NPV were 0.933, 0.967, 0.900, 0.906 and 0.964 respectively. Conclusion: In conclusion, urinary MCP-1 holds great promise as a useful biomarker for the determination of lupus nephritis activity. Its association with disease activity, predictive value for treatment response and renal outcomes, and non-invasive nature make it an ...

The gut microbiota composition has no predictive value for the endotoxin-induced immune response or development of endotoxin tolerance in humans invivo

BackgroundIt is largely unknown whether the gut microbiome regulates immune responses in humans. We determined relationships between the microbiota composition and immunological phenotypes in 108 healthy volunteers, using 16S sequencing, an ex vivo monocyte challenge model, and an in vivo challenge model of systemic inflammation induced by lipopolysaccharide (LPS). ResultsSignificant associations were observed between the microbiota composition and ex vivo monocytic cytokine responses induced by several stimuli, most notably IL-10 production induced by Pam3Cys, Pseudomonas aeruginosa and Candida albicans, although the explained variance was rather low (0.3–4.8%). Furthermore, a number of pairwise correlations between Blautia, Bacteroides and Prevotella genera and cytokine production induced by these stimuli were identified. LPS administration induced a profound transient in vivo inflammatory response. A second LPS challenge one week after the first resulted in a severely blunted response, reflecting endotoxin tolerance. However, no significant relationships between microbiota composition and in vivo parameters of inflammation or tolerance were found (explained variance ranging from 0.4 to 1.5%, ns). ConclusionsThe gut microbiota composition explains a limited degree of variance in ex vivo monocytic cytokine responses to several pathogenic stimuli, but no relationships with the LPS-induced in vivo immune response or tolerance was observed.