Higher Clinical Benefit Research Articles

Development of a Risk Predictive Model for Evaluating Immune Infiltration Status in Invasive Thyroid Carcinoma.

Aims This study aimed to reveal the molecular characteristics and potential biomarker of immune-activated and immunosuppressive invasive thyroid carcinoma. Methods Expression and clinical data for invasive thyroid carcinoma were obtained from the TCGA database. Tumor samples were divided into immune-activated or immunosuppressive groups based on the immune enrichment score calculated by ssGSEA. Differentially expressed genes (DEGs) between tumor vs. normal groups or between immune-activated vs. immunosuppressive groups were screened, followed by functional enrichment. Immune infiltration was evaluated using the ESTIMATE, CIBERSORTx, and EPIC algorithms, respectively. A random forest algorithm and Lasso cox analysis were used to identify gene signatures for risk model construction. Results Totally 1171 DEGs were screened between tumor vs. normal groups, and multiple tumorigenesis-associated pathways were significantly activated in invasive thyroid carcinoma. Compared to immune-activated samples, immunosuppressive samples showed higher tumor purity, lower immune/stromal scores, and lower expression of immune markers, as well as lower infiltration abundance of CD4+ T cells and CD8+ T cells. A risk model based on a 12-immune signature (CCR7, CD1B, CD86, CSF2RB, HCK, HLA-DQA1, LTA, LTB, LYZ, NOD2, TNFRSF9, and TNFSF11) was developed to evaluate the immune infiltration status (AUC = 0.998; AUC of 0.958 and 0.979 in the two external validation datasets), which showed a higher clinical benefit and high accuracy. Immune-activated samples presented lower IC50 value for bortezomib, MG.132, staurosporine, and AZD8055, indicating sensitivity to these drugs. Conclusion A 12-gene-based immune signature was developed to predict the immune infiltration status for invasive thyroid carcinoma patients and then to identify the subsets of invasive thyroid carcinoma patients who might benefit from immunotherapy.

A decision curve analysis of the clinical usefulness of a two-step frailty assessment strategy in older patients with prostate, breast, colorectal, or lung cancer.

12011 Background: Geriatric Assessment (GA) is recommended to assess the health status and select the most appropriate cancer treatment in older patients. However, GA is resource- and time-consuming. Thus, a two-step approach using frailty screening has been recommended. We aimed to evaluate the usefulness of frailty screening over GA for identifying unfit individuals who need GA and reducing unnecessary GA in fit individuals in a population of older outpatients with cancer. Methods: We analyzed patients age 70 and older with prostate, breast, colorectal, or lung cancer included in the multicenter, prospective ELCAPA cohort study (NCT02884375) between February 2007 and December 2019. All patients had a GA at inclusion. GA was the reference test. We defined unfit patients as those having at least one abnormal score in the following domains: functional status, mobility, comorbidity, cognition, mental health status, nutrition, and polypharmacy. We defined unfit patients according to the G8 and modified G8 scores using the recommended cut-offs (≤ 14 out of 17 points and ≥ 6 out of 35 points, respectively). We calculated each screening tool's sensitivity, specificity, and positive and negative predictive values. We used decision curve analysis to estimate the net benefit (the percentage of patients found to be unfit) of screening over GA. We assessed the avoided unnecessary GAs for each screening tool (reducing unnecessary GA in fit patients without decreasing the number of unfit patients undergoing [necessary] GA). We calculated these estimates across different threshold probabilities corresponding to the value of missing an unfit patient compared to exposing a fit patient to an unnecessary GA. A probability of 0.33 indicated that missing an unfit patient was two times worse than referring a fit patient to an unnecessary GA. A probability of 0.50 indicated that missing an unfit patient was the same as exposing a fit patient to an unnecessary GA. Results: We analyzed 1,648 patients with prostate (15%), breast (52%), colorectal (22%), or lung cancer (11%). The median age was 81 years, 559 patients (34%) had metastatic disease, and 1,428 patients (87%) were unfit. The sensitivity (95% CI) and specificity were 85% (84-87) and 59% (57-61) for the G8 score, and 86% (84-87) and 60% (58-63) for the modified G8 score. With a threshold probability of 0.33, the net benefit was 0.71 for the G8 score, 0.72 for the modified G8 score, and 0.80 for GA. With a threshold probability of 0.50, the net benefit was 0.68 for the G8 score, 0.69 for the modified G8 score, and 0.73 for GA. We did not observe a reduction in unnecessary GA of screening tools over GA. Conclusions: Frailty screening tools showed good diagnostic performances. However, our findings suggest that the GA-for-all strategy provides the higher clinical benefit in older patients with cancer.

Genomic characterization and translational immunotherapy of microsatellite instability-high (MSI-H) in cholangiocarcinoma.

4101 Background: Microsatellite instability-high (MSI-H) status is a unique genomic state with encouraging effects of PD-1-based therapy in patients with advanced cancer. Cholangiocarcinoma is often driven by genetic mutations. However, the genomic characterization and translational medicine of MSI-H are not clear. Methods: In this study, 881 Chinese patients with cholangiocarcinoma (582 intrahepatic cholangiocarcinoma and 299 extrahepatic cholangiocarcinoma) were enrolled and their genomes were investigated using panel sequencing or whole-exome sequencing. Clinicopathological and genomic features as well as PD-1 inhibitor-based immunotherapy were analyzed by MSI status in patients with cholangiocarcinoma. Results: Overall, 47 (5.3%) cholangiocarcinoma patients were identified as MSI-H patients after enrichment enrollment. Intrahepatic cholangiocarcinoma (ICC) accounted for 74.47% (35/47) of MSI-H patients. Clinicopathological parameters showed younger, ICC-dominated, and more positive PD-L1 expression in MSI-H patients. In the genome of MSI-H cholangiocarcinoma, ACVR2A (75.00%), ARID1A (75.0%), KMT2D (72.2%), TGFBR2 (63.9%), PBRM1 (58.3%), RNF43 (55.6%), TP53 (52.8%) ), ARID1B (47.2%) had a higher mutation frequency. Comparing the SNV and INDEL mutation in the genome, the differential genes between MSI-H and MSS were ARID1A, ACVR2A, KMT2D, TGFBR2, PBRM1, RNF43, LRP1B, ARID1B, etc., respectively. In addition, the differential mutation pathways of MSI-H showed that the mutation rate of DDR, SWI/SNF CellCycle, HRD and other pathways was significantly higher than that of MSS samples. The tumor mutation burden (TMB) in MSI-H patients was significantly higher than that in MSS (P<0.001). In a cohort of 151 CCA patients who received PD-1 inhibitor-based immunotherapy, 19 patients with MSI-H cholangiocarcinoma were found to have a favorable prognosis (1-year survival rate 68.4%). Compared with 132 MSS cholangiocarcinoma patients, Patients with MSI-H cholangiocarcinoma had significantly prolonged OS (Not reach vs. 13.4m, P<0.001, HR=0.17, P <0.001) and high clinical benefit (CBR) (OR=8.16, P <0.001). In this immunotherapy cohort, ≥2 DDR pathway genes and ≥2 SWI/SNF pathway genes mutations, positive PD-L1 expression and TMB-H were also associated with better OS and CBR (both P<0.05). Conclusions: MSI-H cholangiocarcinoma has distinct genomic features, and the effect of PD-1 inhibitors immunotherapy is excellent to these patients. Clinical trial information: NCT03892577.

Safety, efficacy, and clinical outcomes of the anti-CCR5 inhibitor (Leronlimab): A pooled analysis of three clinical trials in patients with mTNBC.

e13062 Background: Metastatic triple negative breast cancer (mTNBC) is a highly invasive BC subtype with limited treatment options and poor clinical outcomes. Leronlimab, a humanized IgG4κ antibody, competitively inhibits CCR5, a cancer motility receptor and target for cancer inhibition. We report on a pooled analysis of n = 28 mTNBC patients (pts) showing that leronlimab has potent antitumor activity with improved 1 year progression free (PFS) & overall survival (OS) with few treatment emergent adverse events (TEAEs). Further, we explored the effect of leronlimab on circulating tumor associated cells (TACs) from peripheral blood as a surrogate and early predictor of drug response. Methods: mTNBC pts results from 3 blinded prospective clinical drug studies, Phase 1b/2 dose escalation (NCT03838367), Compassionate Use (NCT04313075), and Basket Study (NCT04504942) were pooled to evaluate leronlimab’s safety & efficacy at 12 months (mos). Pts received ≥1 dose of leronlimab alone (n = 2), with carboplatin (n = 11) or with physician’s choice (n = 15). Pts received 1-33 doses, ranging from 350mg (n = 9), 525mg (n = 16) or 700mg (n = 3). In addition, anonymized pt peripheral blood was procured before and after (̃30 days) induction as an exploratory biomarker, to evaluate TACs in predicting efficacy. Progressive disease, stable disease or partial response was determined by RESICT v1.1, and univariate analysis was used evaluate PFS & OS. Results: mTNBC pts were pooled from Phase 1b/2 (n = 10), Compassionate Use (n = 16), and Basket Study (n = 2) treated with 350-700mg doses, 4 pts escalating 350 to 525mg. Pts had 1-5+ prior systemic therapies for mTNBC (median = 2), median age 52 (range 33-84), ECOG 0 (n = 18) or ECOG 1 (n = 10), n = 17 had visceral mets, and n = 6 had brain mets. A total of n = 68 TEAEs were reported, with n = 7 grade I/II & n = 1 grade III related to leronlimab. At 12 mos, pts had a mPFS = 3.8 mos (95%CI 2.3-6.2) and mOS = 6.6 mos (CI95% 4.9-12+). However, pts treated with 525-700 mg doses (n = 19) had a > 75% improved mPFS = 6.1 mos (95%CI 2.3-7.5) and mOS 12+ mos (95%CI 5.5-12+). Further, a drop in circulating TACs was identified in 75% (n = 21/28) pts and predicted for significantly better clinical outcomes, mPFS = 6.2 and mOS > 12 mos. Conclusions: These studies suggest that mTNBC pts dosed with leronlimab had high clinical benefit, i.e. longer PFS & OS with few TEAEs, and leronlimab resulted in a drop in circulating TACs in the majority of pts correlating with early therapy response. Clinical trial information: NCT03838367, NCT04313075, NCT04504942.

Health-related quality of life in patients treated with gemcitabine/cisplatin and durvalumab ± tremelimumab in chemotherapy-naïve advanced biliary tract cancer.

4117 Background: In the phase 2 (NCT03046862), gemcitabine/cisplatin (GemCis) and durvalumab (D) ± tremelimumab (T) in chemotherapy-naïve advanced biliary tract cancer (BTC) showed a high objective response rate and durable clinical benefit. Based on this study, phase 3 trial (TOPAZ-1, NCT03875235) has been conducted and the positive result for adding D to GemCis has been reported. Health-related quality of life (HRQoL) for adding immunotherapy to cytotoxic chemotherapy in BTC has not been reported yet. We present HRQoL results from the phase 2 study. Methods: In this study, treatment-naïve patients with unresectable or recurrent BTC were enrolled into three cohorts. Patients received one cycle of GemCis followed by GemCis plus D and T (cohort 1) or, starting with the first cycle, received GemCis plus D (cohort 2) or GemCis plus D and T (cohort 3). The EORTC Quality of Life Questionnaire (QLQ)-C30 and BIL21 were administered at baseline and every cycle throughout treatment. Change from baseline to post-2 cycles and deterioration of HRQoL (≥10 points change) were analysed. Results: At data cut-off (March 22, 2021), 126 patients (32 in cohort 1, 47 in cohort 2, 47 in cohort 3) were included for this analysis. Compliance for QLQ was very high ( > 90 %) at all time points. C30 global health status (GHS) scores remained stable at all time points and from baseline to post 2 cycles (mean [95% CI] change, 2.66 [-1.10‒6.42]), with greater improvements observed in patients with responder (a best response of complete response (CR) or partial response (PR)) (3.60 [-1.27 to 8.47]) compared to non-responder (stable disease (SD) or progressive disease (PD) (0.66 [-5.19 to 6.51]). For the overall cohort, functioning scales also remained stable from baseline to post 2 cycles. Nausea/vomiting (8.4 [4.45 to 12.36]), dyspnea (7.28 [2.17 to 12.4]), constipation (9.24 [3.35 to 15.13]), financial difficulties (5.53 [1.65 to 9.41]) in C30 and eating (5.53 [1.65 to 9.41]), tiredness (5.42 [1.23 to 9.6]), treatment side effects (7.98 [1.15 to 14.81] in BIL21 were worse at post 2 cycles. However, pain (-7.14 [-12.24 to -2.04]), diarrhea (-4.48 [-8.86 to -0.1]) in C30 and jaundice (-5.51 [-9.26 to -1.76]), pain (-6.02 [-9.7 to -2.34] in BIL21 were improved and more improvement was shown in responder compared to non-responder. Regarding deterioration of C30 GHS, median deterioration-free survival (months [95% CI]) was 4.14 (2.66-6.47) in all cohorts and there was no difference between responder (3.68 [2.27-7.92]) and non-responder (5.59 [2.73-9.46], Hazard ratio = 1.00 [95% CI, 0.62-1.61], p = 0.997). There was no difference among 3 cohorts. Conclusions: GemCis plus D ± T in chemotherapy-naïve advanced BTC generally preserved HRQoL and improved some symptom scales such as jaundice and pain although chemotherapy related symptom scales were worse.

Time to access to novel anticancer drugs in Europe, a case study in seven European countries.

1586 Background: After European Medicines Agency Marketing Authorization (EMA-MA) different national reimbursement processes may contribute to unequal access throughout the EU. The aim of this study is to investigate the access time to new anticancer medicines in seven high-income Northern European countries and factors influencing the reimbursement process. Methods: We performed a retrospective database study. New anticancer medicines were included with a positive CHMP advice between January 2016 and January 2020, leading to EMA-MA followed by an application for national reimbursement approval in Germany, UK, France, The Netherlands, Belgium, Norway and Switzerland. The relevant Health Technology Assessment (HTA) - and reimbursement websites for each country were used to identify reimbursement dates. Time to access was defined as the time between EMA-MA and date of inclusion in the relevant reimbursement list. In addition we investigated the differences in national approval process and study-, medication- and patient- related factors which might influence the time to reimbursement. Results: We found that for the thirty-six new anticancer medicines, national reimbursement came on average 289 days after EMA-MA, with a variety of -125 in Switzerland (i.e. non EU-member) to 1415 days. Of these EMA-MA new anticancer medicines 42% were reimbursed in all countries. The average number of cancer medicines reimbursed in the examined countries was 27 (75%), with a range of 24 (67%) in Belgium to 36 (100%) in Germany. The shortest average time from EMA-MA to reimbursement were in Germany, 2.33 days, France and Switzerland following with 207 days and 279 days respectively. The median time to reimbursement was 227 days with a range of 3 days in Germany to 553 days in Belgium. In Germany, where there is no pricing and reimbursement approval required when launching a pharmaceutical, 100% of the cancer medicines are reimbursed within five days. After one year, In the UK 56% of the medicines are reimbursed, followed by 53% in the Netherlands, France and Switzerland. Belgium and Norway have a one year reimbursement rate of 14% and 11% respectively. Access to anticancer medicines is dependent on regulatory procedures, HTA and price regulations. Germany has a fast market access for anticancer medicines with a price regulation one year after launching the medicines. In the other countries, price regulation is part of the launching process. Other factors which might accelerate the time to reimbursement we are examining are high clinical benefit score (ESMO-MCBS), (non-)orphan status of the medicines and submission by big pharmaceuticals. Conclusions: This study shows that after EMA-MA, except for Germany, on average it takes a long time for anticancer medicines to be reimbursed in Northern European countries. There is a considerably variety both within and among countries.

Health-related quality of life in patients treated with pembrolizumab for microsatellite instability–high/mismatch repair–deficient advanced solid tumours: Results from the KEYNOTE-158 study

BackgroundIn the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite instability−high (MSI-H)/mismatch repair‒deficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K). Patients and methodsEligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score. ResultsAt data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean [95% CI] change, 3.07 [0.19–5.94]), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 [6.36–15.35]). Patients with CR/PR showed improvements in physical (5.58 [1.91–9.25]), role (9.88 [3.80–15.97]), emotional (5.62 [1.56–9.68]), and social (8.33 [2.70–13.97]) functioning, and stable cognitive functioning (1.74 [−1.45 to 4.94]). ConclusionsPembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours.

Molecular reactivity profiling upon immunotherapy with a 300 IR sublingual house dust mite tablet reveals marked humoral changes towards major allergens.

Molecular antibody reactivity profiles have not yet been studied in depth in patients treated by sublingual house dust mite (HDM) tablet immunotherapy. Humoral immune responses to a large panel of HDM mite allergens were studied using allergen microarray technology in a subset of clinically defined high and low responder patients from a double-blind placebo-controlled allergen-specific immunotherapy (AIT) trial using sublingual 300IR HDM tablets. Serum levels of IgE, IgG and IgG4 to 13 Dermatophagoides pteronyssinus molecules were measured at baseline and after 1-year AIT, using allergen microarrays in 100subjects exhibiting high or low clinical benefit. Derp1, Derp2 and Derp23 were the most frequently recognized allergens in the study population. Patients with HDM-related asthma had significantly higher allergen-specific IgE levels to Derp1 and Derp23. No significant difference in the distribution of allergen sensitization pattern was observed between high and low responders. An increase in serum allergen-specific IgG and IgG4 occurred upon AIT, in particular to allergens Derp1, Derp2 and Derp23 (p<0.0001). We confirm for our study population that Derp1- and Derp23-specific IgE levels are associated with asthma. IgE reactivity profiles were not predicitive of sublingual AIT outcomes, with 300 IR tablets as efficacious in pauci- and multi-sensitized subjects. Our study is the first to demonstrate the induction of IgG and IgG4 specific for the HDM allergens Derp1, Derp2 and Derp23 by sublingual AIT.

Effect of FBXW7 gene mutation on the prognosis of immunotherapy in patients with non-small cell lung cancer

Objective: To explore the effect of F-box and WD-40 domain protein 7 (FBXW7) gene mutation on the prognosis of immunotherapy in patients with non-small cell lung cancer (NSCLC). Methods: (1) The clinical data of 125 patients with advanced NSCLC in the First Affiliated Hospital of Nanjing Medical University from January 2019 to June 2021 were collected. There were 70 males and 55 females, with a median age [M (Q1, Q3)] of 64(57, 70) years. The correlation of FBXW7 mutation with immunotherapy efficacy and prognosis was analyzed. (2) The Data set of NSCLC patients treated with immunotherapy from cBioPortal database was downloaded. A total of 261 patients were included as immunotherapy group. There were 120 males and 141 females, with a median age of 66(57, 73) years. The association of FBXW7 mutation with clinical characteristics and prognosis of NSCLC patients was investigated. (3) The data of patients with NSCLC from the cancer genome atlas (TCGA) database were downloaded. A total of 1 030 patients were included as TCGA group. There were 633 males and 397 females, with a median age of 67(60, 73) years. The effect of FBXW7 mutation on the efficacy of immunotherapy was analyzed. The key molecules and their biological functions were also determined Results: Among the 125 NSCLC patients, the FBXW7 mutation rate was 5.6% (7/125). All FBXW7 mutation types was truncating mutation. In these FBXW7 mutation patients who received immunotherapy, 4 had partial response, 2 had stable disease, and 1 had progressive disease. The objective response rate (ORR) and disease control rate (DCR) were 4/7 and 6/7, respectively. The median progression-free survival (PFS) was 13.0 months (95%CI: 7.0-22.0 months) for patients with FBXW7 mutation and 4.0 months (95%CI: 2.0-11.5 months) for patients with FBXW7 wild type, with a statistically significant difference (P=0.046). The bioinformatics analysis indicated that patients with FBXW7 mutation have higher clinical benefits from immunotherapy. Moreover, patients with FBXW7 mutation in immunotherapy group had higher tumor mutational burden (TMB) [M (Q1, Q3): 17.8 (11.5, 29.3)/Mb] than those with FBXW7 wild type [5.7 (3.0, 10.4)/Mb, P=0.001]. The TMB of patients with FBXW7 mutation in TCGA group was 15.9 (4.2, 28.1)/Mb, insertion-deletion (Indel) neoantigen was 192.5 (70.8, 535.0) and single nucleotide variant (SNV) neoantigen was 363.0 (194.8, 534.8), which were significantly higher than those of patients with FBXW7 wild type [5.6 (3.2, 8.9)/Mb, 53.0 (12.0, 131.0), 83.5 (34.0, 178.0), respectively] (P=0.002, P=0.008, P<0.001). The results indicated that FBXW7 mutated tumors had stronger immunogenicity, which might generate anti-tumor immunity. FBXW7 mutation was also related to the activation of T cells (T lymphocyte receptor complexes and signaling). In addition, FBXW7 mutation was correlated with increased infiltration of CD8+T cells and M1 macrophages. CD8+T cells and M1 macrophages infiltration level was significantly up-regulated in FBXW7 mutation group than wild-type group [10% (8%, 14%) vs 7%(4%, 12%), P=0.049; 8%(4%, 11%) vs 4%(1%, 8%), P=0.046]. Conclusions: NSCLC patients with FBXW7 mutant have higher clinical benefits from immunotherapy. FBXW7 mutation has the potential as a predictive marker for the efficacy of immunotherapy in NSCLC patients.

A Predictive Model for the Risk of Posterior Circulation Stroke in Patients with Intracranial Atherosclerosis Based on High Resolution MRI.

Intracranial vertebrobasilar atherosclerosis is the main cause of posterior circulation ischemic stroke. We aimed to construct a predictive model for the risk of posterior circulation ischemic stroke in patients with posterior circulation atherosclerosis based on high-resolution MRI (HR-MRI). A total of 208 consecutive patients with posterior circulation atherosclerosis confirmed by HR-MRI, from January 2020 to July 2021, were retrospectively assessed. They were assigned to the posterior circulation stroke (49 patients) and non-posterior circulation stroke group (159 patients) based on clinical presentation and diffusion-weighted imaging (DWI). Demographic data, risk factors of atherosclerosis, laboratory findings, and imaging characteristics were extracted from electronic health records. Plaque features were investigated by HR-MRI. Fifty-three clinical or imaging features were used to derive the model. Multivariable logistic regression analysis was employed to construct the prediction model. The nomogram was evaluated for calibration, differentiation, and clinical usefulness. Plaque enhancement, plaque irregular surface morphology, artery location of plaque, and dorsal quadrant of plaque location were significant predictors for posterior circulation stroke in patients with intracranial atherosclerosis. Subsequently, these variables were selected to establish a nomogram. The model showed good distinction (C-index 0.830, 95% CI 0.766-0.895). The calibration curve also showed excellent consistency between the prediction of the nomogram and the observed curve. Decision curve analysis further demonstrated that the nomogram conferred significantly high clinical net benefit. The nomogram calculated from plaque characteristics in HR-MRI may accurately predict the posterior circulation stroke occurrence and be of great help for stratification of stroke decision making.

A Novel mRNA Signature Related to Immunity to Predict Survival and Immunotherapy Response in Hepatocellular Carcinoma.

Background and AimsHepatocellular carcinoma (HCC) is the most common primary liver cancer and the incidence and mortality rates are increasing. Given the limited treatments of HCC and promising application of immunotherapy for cancer, we aimed to identify an immune-related prognostic signature that can predict overall survival (OS) rates and immunotherapy response in HCC.MethodsThe initial signature development was conducted using a training dataset from the Cancer Genome Atlas followed by independent internal and external validations from that resource and the Gene Expression Omnibus. A signature based nomogram was generated using multivariate Cox regression analysis. The associations of signature score with tumor immune phenotype and response to immunotherapy were analyzed using single-sample gene set enrichment analysis and tumor immune dysfunction and exclusion algorithm. A cohort from Zhongshan Hospital was employed to verify the predictive robustness of the signature regarding prognostic risk and immunotherapy response.ResultsThe prognostic signature, IGSHCC, consisting of 22 immune-related genes, had independent prognostic ability, with training and validation cohorts. Also, IGSHCC stratified HCC patients with different outcomes in subgroups. The prognostic accuracy of IGSHCC was better than three reported prognostic signatures. The IGSHCC-based nomogram had high accuracy and significant clinical benefits in predicting 3- and 5-year OS. IGSHCC reflected distinct immunosuppressive phenotypes in low- and high-score groups. Patients with low IGSHCC scores were more likely than those with high scores to benefit from immunotherapy.ConclusionsIGSHCC predicted HCC prognosis and response to immunotherapy, and contributed to individualized clinical management.

Construction and Validation of a Risk Prediction Model for Acute Kidney Injury in Patients Suffering from Septic Shock.

Background Acute kidney injury (AKI) is an important complication in critically ill patients, especially in sepsis and septic shock patients. Early prediction of AKI in septic shock can provide clinicians with sufficient information for timely intervention so that improve the patients' survival rate and quality of life. The aim of this study was to establish a nomogram that predicts the risk of AKI in patients with septic shock in the intensive care unit (ICU). Methods The data were collected from the Medical Information Mart for Intensive Care III (MIMIC-III) database between 2001 and 2012. The primary outcome was AKI in the 48 h following ICU admission. Univariate and multivariate logistic regression analyses were used to screen the independent risk factors of AKI. The performance of the nomogram was evaluated according to the calibration curve, receiver operating characteristic (ROC) curve, decision curve analysis, and clinical impact curve. Results A total of 2415 patients with septic shock were included in this study. In the training and validation cohort, 1091 (64.48%) of 1690 patients and 475 (65.52%) of 725 patients developed AKI, respectively. The predictive factors for nomogram construction were gender, ethnicity, congestive heart failure, diabetes, obesity, Simplified Acute Physiology Score II (SAPS II), angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs), bilirubin, creatinine, blood urea nitrogen (BUN), and mechanical ventilation. The model had a good discrimination with the area under the ROC curve of 0.756 and 0.760 in the training and validation cohorts, respectively. The calibration curve for probability of AKI in septic shock showed optimal agreement between prediction by nomogram and actual observation. Decision curve and clinical impact curve analysis indicated that the nomogram conferred high clinical net benefit. Conclusion The proposed nomogram can quickly and effectively predict the risk of AKI at an early stage in patients with septic shock in ICU, which can provide information for timely and efficient intervention in patients with septic shock in the ICU setting.

Examining the association between oncology drug clinical benefit and the time to public reimbursement.

BackgroundWe examined if oncology drug indications with high clinical benefit, as measured by the American Society of Clinical Oncology Value Framework (ASCO‐VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO‐MCBS), received public reimbursement status faster than those with lower clinical benefit from the time of pan‐Canadian Oncology Drug Review (pCODR) recommendation.MethodsOncology drug indications submitted to pCODR between July 2011 and October 2018 were examined. Included indications had a regulatory approval date, completed the pCODR review process, received a positive pCODR recommendation, and been funded by at least one province. Trials cited for clinical efficacy were used to determine the clinical benefit (per ASCO‐VF and ESMO‐MCBS) of drug indications.ResultsEighty‐four indications were identified, yielding 65 ASCO‐VF and 50 ESMO‐MCBS scores. The mean ASCO‐VF and ESMO‐MCBS scores were 44.9 (SD = 21.1) and 3.3 (SD = 1.0), respectively. The mean time to provincial reimbursement from pCODR recommendation was 13.2 months (SD = 9.3 months). Higher ASCO‐VF and ESMO‐MCBS scores had low correlation with shorter time to reimbursement, (ρ = −0.21) and (ρ = 0.24), respectively. In the multivariable analyses, ASCO‐VF (p = 0.40) and ESMO‐MCBS (p = 0.31) scores were not significantly associated with time to reimbursement. Province and year of pCODR recommendation were associated with time to reimbursement in both ASCO and ESMO models.ConclusionsOncology drug indications with higher clinical benefit do not appear to be reimbursed faster than those with low clinical benefit. This suggests the need to prioritize oncology drug indications based on clinical benefit to ensure quicker access to oncology drugs with the greatest benefits.

Establishment and validation of prognosis model for patients with cerebral contusion

Background And ObjectiveCerebral Contusion (CC) is one of the most serious injury types in patients with traumatic brain injury (TBI). In this study, the baseline data, imaging features and laboratory examinations of patients with CC were summarized and analyzed to develop and validate a prediction model of nomogram to evaluate the clinical outcomes of patients.MethodsA total of 426 patients with cerebral contusion (CC) admitted to the People’s Hospital of Qinghai Province and Affiliated Hospital of Qingdao University from January 2018 to January 2021 were included in this study, We randomly divided the cohort into a training cohort (n = 284) and a validation cohort (n = 142) with a ratio of 2:1.At Least absolute shrinkage and selection operator (Lasso) regression were used for screening high-risk factors affecting patient prognosis and development of the predictive model. The identification ability and clinical application value of the prediction model were analyzed through the analysis of receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA).ResultsTwelve independent prognostic factors, including age, Glasgow Coma Score (GCS), Basal cistern status, Midline shift (MLS), Third ventricle status, intracranial pressure (ICP) and CT grade of cerebral edema,etc., were selected by Lasso regression analysis and included in the nomogram. The model showed good predictive performance, with a C index of (0.87, 95% CI, 0.026–0.952) in the training cohort and (0.93, 95% CI, 0.032–0.965) in the validation cohort. Clinical decision curve analysis (DCA) also showed that the model brought high clinical benefits to patients.ConclusionThis study established a high accuracy of nomogram model to predict the prognosis of patients with CC, its low cost, easy to promote, is especially applicable in the acute environment, at the same time, CSF-glucose/lactate ratio(C-G/L), volume of contusion, and mean CT values of edema zone, which were included for the first time in this study, were independent predictors of poor prognosis in patients with CC. However, this model still has some limitations and deficiencies, which require large sample and multi-center prospective studies to verify and improve our results.

Validation of a clinicopathological and gene expression profile model to identify patients with cutaneous melanoma where sentinel lymph node biopsy is unnecessary

BackgroundIn patients with cutaneous melanoma, sentinel lymph node biopsy (SLNB) serves as an important technique to asses disease stage and to guide adjuvant systemic therapy. A model using clinicopathologic and gene expression variables (CP-GEP; Merlin Assay) has recently been introduced to identify patients that may safely forgo SLNB. Herein we present data from an independent validation cohort of the CP-GEP model in Swedish patients. MethodsArchival histological material (primary melanoma tissue) from a prospectively collected cohort of 421 consecutive patients with pT1-T4 melanoma undergoing SLNB between 2006 and 2014 was analyzed using the CP-GEP model. CP-GEP combines Breslow thickness and patient age with the expression levels of eight genes from the primary melanoma. Stratification is based on their risk for nodal metastasis: CP-GEP Low Risk or CP-GEP High Risk. ResultsThe SLNB positivity rate was 13%. Of 421 primary melanomas, the CP-GEP model identified 86 patients as having a low risk for nodal metastasis. In patients with pT1-2 melanomas, the SLNB reduction rate was 35.4% (95% CI: 29.4–41.8) with a negative predictive value (NPV) of 96.5% (95% CI: 90.0–99.3). Among patients with pT1-3 melanomas, CP-GEP suggested a SLNB reduction rate of 24.0% (95% CI: 19.7–28.8) and a NPV of 96.5% (95% CI: 90.1–99.3). Only one of 118 pT3 tumors was classified as CP-GEP Low Risk, and all pT4 tumors were classified as being high risk for nodal metastasis. ConclusionThis study demonstrates that CP-GEP can identify patients with a low risk for nodal metastasis. Patients with pT1-2 melanomas have the highest clinical benefit from using the test, where 35% of the patients could forgo a SLNB procedure.

A brief report on incidence, radiographic feature and prognostic significance of brain MRI changes after anti-PD-1/PD-L1 therapy in advanced non-small cell lung cancer.

Neurologic immune-related adverse events (nirAEs) are uncommon but potentially lethal complications of immune checkpoint inhibitor (ICI) treatment. However, the incidence, radiographic features and prognostic significance of brain magnetic resonance imaging (MRI) changes after ICI treatment remain largely unknown. Consecutive patients with advanced non-small cell lung cancer (NSCLC) at three participating institutions receiving anti-PD-1/PD-L1 therapy from June 2017 to September 2020 were screened, and those who received brain MRI within 6weeks before ICI initiation and at least one follow-up brain MRI after ICI treatment were included. Serial brain MRI images were independently reviewed by two experienced radiologists. With a median follow-up of 13.2months, 27 (20.0%) of the 135 enrolled patients developed certain kind of brain MRI aberration. The 1-, 2- and 3-year cumulative incidence of brain MRI aberration was 17.1%, 36.3% and 52.2%, respectively. Brain MRI aberration indicative of stroke, mimicking typical white matter lesions and presenting as T2-hyperintensity suggestive of CNS vasculitis or encephalitis, was documented in 11, 9 and 4 patients, respectively. Patients with brain MRI aberration had higher clinical benefit rate (p = 0.030), longer progression-free survival (p = 0.015) and a tendency of improved overall survival (p = 0.054). Brain MRI aberrations developed after ICI treatment are not uncommon, and their manifestations vary a lot. Patients developing brain MRI aberrations tended to have better prognosis, which needed to be further investigated.

Coordinated IgG2 and IgE responses as a marker of allergen immunotherapy efficacy.

IgG2 responses are associated with repeated antigen exposure and display highly mutated variable domains. A recent study highlighted a role of IgG2+ memory B cells and allergen-specific IgG2levels after a 3rd consecutive pre-seasonal sublingual allergen immunotherapy (AIT) with grass pollen tablet. Herein, we aim to explore changes in allergen-specific IgG2 in individuals undergoing house dust mite immunotherapy (HDM-AIT) and explore whether the interrelationship with other humoral responses (i.e., IgG4 and IgE) may discriminate between high and low responders. Levels of serum Dermatophagoides pteronyssinus and Dermatophagoides farinae-specific IgG2, IgG4, and IgE antibodies were measured by ELISA or ImmunoCap in a sub-group of individuals enrolled in a randomized, double-blind, placebo-controlled, sublingual AIT study evaluating the safety and efficacy of a 300IR HDM tablet. After 1-year sublingual AIT, HDM-specific serum IgG2 responses increase mostly in high versus low responders and are distinctive according to the clinical benefit. Higher correlation between HDM-specific IgG2, IgE, and/or IgG4 responses is seen in subjects benefiting the most from HDM-AIT as indicated by changes in Average Total Combined Scores. More strikingly, statistically significant correlation between HDM-specific IgG2 and IgE responses is only observed in individuals stratified as high responders. We provide evidence for coordinated serum immune responses upon AIT in HDM-allergic subjects exhibiting high clinical benefit when compared with low responders. Assessing HDM-specific IgE, IgG2, and IgG4 in serum could be used as follow-up combined markers to support decision as to AIT continuation and/or adaptation.

Differentiating T1a\u2013T1b from T2 in gastric cancer lesions with three different measurement approaches based on contrast-enhanced T1W imaging at 3.0\xa0T

BackgroundTo explore the diagnostic value of three different measurement approaches in differentiating T1a–T1b from T2 gastric cancer (GC) lesions.MethodsA total of 95 consecutive patients with T1a–T2 stage of GC who performed preoperative MRI were retrospectively enrolled between January 2017 and November 2020. The parameters MRI T stage (subjective evaluation), thickness, maximum area and volume of the lesions were evaluated by two radiologists. Specific indicators including AUC, optimal cutoff, sensitivity, specificity, accuracy, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV) and negative predictive value (NPV) of MRI T stage, thickness, maximum area and volume for differentiating T1a–T1b from T2 stage lesions were calculated. The ROC curves were compared by the Delong test. Decision curve analysis (DCA) was used to evaluate the clinical benefit.ResultsThe ROC curves for thickness (AUC = 0.926), maximum area (AUC = 0.902) and volume (AUC = 0.897) were all significantly better than those of the MRI T stage (AUC = 0.807) in differentiating T1a–T1b from T2 lesions, with p values of 0.004, 0.034 and 0.041, respectively. The values corresponding to the thickness (including AUC, sensitivity, specificity, accuracy, PPV, NPV, PLR and NLR) were all higher than those corresponding to the MRI T stage, maximum area and volume. The DCA curves indicated that the parameter thickness could provide the highest clinical benefit if the threshold probability was above 35%.ConclusionsThickness may provide an efficient approach to rapidly distinguish T1a–T1b from T2 stage GC lesions.

Identification and utilization of solid tumor genomic sequencing in the treatment of ovarian and endometrial cancer

Identification and utilization of solid tumor genomic sequencing in the treatment of ovarian and endometrial cancer

SO-8 Health-related quality of life in patients treated with pembrolizumab for microsatellite instability-high/mismatch repair deficient advanced solid tumors: Results from the KEYNOTE-158 study

Approval of pembrolizumab (200 mg Q3W) for the treatment of unresectable or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors that progressed on prior therapy was based on results from the phase 2, open-label, multicohort, KEYNOTE-158 study (NCT02628067). Pembrolizumab demonstrated a high ORR (primary endpoint) and durable clinical benefit in this population. We present Health-related quality of life (HRQoL) results (exploratory endpoints) from the MSI-H/dMMR population (cohort K).