Disease Progression In Group Research Articles

Response monitoring with ctDNA in metastatic pancreatic cancer.

e16284 Background: Various studies about clinical usefulness of serial monitoring with liquid biopsy are being conducted actively in many types of cancer. However, there is not much in pancreatic cancer. We explored whether serial ctDNA monitoring in metastatic pancreatic cancer (MPC) can be beneficial for evaluating treatment response and predicting prognosis. Methods: A total of 51 MPC patients were prospectively enrolled. Blood samples were collected at every response evaluation until progression of disease (PD) or 5th evaluation. Quantitative ctDNA were measured by droplet digital polymerase chain reaction using KRAS G12/G13 screening multiplex Kit (Bio-Rad) and reported as variant allele fraction (VAF). Percent change of ctDNA VAF (DctDNA(%) = (current VAF - previous VAF)/previous VAF*100) were correlated to radiographic responses by RECIST 1.1. Furthermore, Progression free survival (PFS) and overall survival (OS) were analyzed by DctDNA. Results: Among the 51 enrolled patients, baseline ctDNA were detected in 35 patients. During a median follow-up of 9.4 months, PD by radiographic response was observed in 24 patients. As expected, PD group showed higher DctDNA compared with non-PD group (p<0.001). DctDNA for PD yielded Area Under Curve of 0.914 (p<0.001) with 83.3% sensitivity at 90% specificity. Patients who showed early ctDNA clearance (undetectable level at first response evaluation) had longer PFS (8.1 m vs 4.7 m; HR 0.46; 95% CI 0.20 to 1.03; p=0.059) and OS (not reached vs 8.0 m; HR 0.20; 95% CI 0.06 to 0.74; p=0.009) than those who did not. In multivariable analysis, early ctDNA clearance was still associated with significantly longer PFS (HR 0.27; 95% CI 0.08 to 0.92, p=0.036) and OS (HR 0.08; 95% CI 0.02 to 0.54, p=0.007). Conclusions: Serial monitoring with ctDNA in MPC has considerable clinical potential in monitoring treatment response and predicting prognosis.

Combined systemic immune-inflammatory index and prognostic nutritional index predict outcomes in advanced non-small cell lung cancer patients receiving platinum-doublet chemotherapy.

Systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) could evaluate the therapeutic efficacy and prognosis in different tumors. However, no studies investigated the SII-PNI score to predict outcomes in non-small cell lung cancer (NSCLC) patients treated with platinum-doublet chemotherapy. The aim of this study was to investigate the SII-PNI score in predicting outcomes in non-small cell lung cancer (NSCLC) patients treated with platinum-doublet chemotherapy. Our study retrospectively analyzed clinical data from 124 patients with advanced NSCLC receiving platinum-doublet chemotherapy. The SII and PNI were calculated based on peripheral blood cell counts and serum albumin, and the optimal cut-off values were determined using receiver operating characteristic (ROC). All patients were divided into three groups according to the SII-PNI score. The association between the SII-PNI score and the clinicopathological characteristics of the patients was examined. The Kaplan-Meier and Cox regression models were used to assess progression-free survival (PFS)and overall survival (OS). There was no significant correlation between SII, PNI at baseline and chemotherapy response in patients with advanced NSCLC (p>0.05). However, after receiving 4 cycles of platinum-doublet chemotherapy, the SII of the SD group (p=0.0369) and PD group (p=0.0286) was significantly higher than that of the PR group. At the same time, the PNI of the SD group (p=0.0112) and the PD group (p=0.0007) was significantly lower than that of the PR group. The PFS of patients with SII-PNI scores of 0, 1, and 2 were 12.0, 7.0, and 5.0 months, and the OS of patients with SII-PNI scores of 0, 1, and 2 were 34.0, 17.0, and 10.5 months, respectively. There was statistical significance among the three groups (all p <0.001). Multivariate analyses showed that the chemotherapy response of progressive disease (PD) (HR, 3.508; 95% CI, 1.546-7.960; p=0.003) and SII-PNI score of 2 (HR, 4.732; 95% CI, 2.561-8.743; p < 0.001) were independently associated with a shorter OS. The uses of targeted drugs (HR, 0.543; 95% CI, 0.329-0.898; p=0.017) and immune checkpoint inhibitors (HR, 0.218; 95% CI, 0.081-0.584; p=0.002) were protective factors for OS in patients with NSCLC. Compared with baseline parameters, the correlation between SII, PNI after 4 cycles of chemotherapy and the chemotherapy effect was more significant. The SII-PNI score after 4 cycles of chemotherapy is an effective prognostic biomarker for advanced NSCLC patients treated with platinum-doublet chemotherapy. Patients with a higher SII-PNI score had a worse prognosis.

Chemical Exchange Saturation Transfer MRI: Capability for Predicting Therapeutic Effect of Chemoradiotherapy on Non-Small Cell Lung Cancer Patients.

Amide proton transfer (APT) weighted chemical exchange saturation transfer CEST (APTw/CEST) magnetic resonance imaging (MRI) has been suggested as having the potential for assessing the therapeutic effect of brain tumors or rectal cancer. Moreover, diffusion-weighted imaging (DWI) and positron emission tomography fused with computed tomography by means of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG-PET/CT) have been suggested as useful in same setting. To compare the capability of APTw/CEST imaging, DWI, and FDG-PET/CT for predicting therapeutic effect of chemoradiotherapy (CRT) on stage III non-small cell lung cancer (NSCLC) patients. Prospective. Eighty-four consecutive patients with Stage III NSCLC, 45 men (age range, 62-75 years; mean age, 71 years) and 39 women (age range, 57-75 years; mean age, 70 years). All patients were then divided into two groups (Response Evaluation Criteria in Solid Tumors [RECIST] responders, consisting of the complete response and partial response groups, and RECIST non-responders, consisting of the stable disease and progressive disease groups). 3 T, echo planar imaging or fast advanced spin-echo (FASE) sequences for DWI and 2D half Fourier FASE sequences with magnetization transfer pulses for CEST imaging. Magnetization transfer ratio asymmetry (MTRasym ) at 3.5 ppm, apparent diffusion coefficient (ADC), and maximum standard uptake value (SUVmax, ) on PET/CT were assessed by means of region of interest (ROI) measurements at primary tumor. Kaplan-Meier method followed by log-rank test and Cox proportional hazards regression analysis with multivariate analysis. A P value <0.05 was considered statistically significant. Progression-free survival (PFS) and overall survival (OS) had significant difference between two groups. MTRasym at 3.5 ppm (hazard ratio [HR] = 0.70) and SUVmax (HR = 1.41) were identified as significant predictors for PFS. Tumor staging (HR = 0.57) was also significant predictors for OS. APTw/CEST imaging showed potential performance as DWI and FDG-PET/CT for predicting the therapeutic effect of CRT on stage III NSCLC patients. 2 TECHNICAL EFFICACY: Stage 1.

Circulating Tumor Cells Predict Response of Neoadjuvant Chemotherapy in Patients with Bladder Cancer: A Preliminary Study.

This study aimed to explore the existence of circulating tumor cells (CTCs) in patients with muscle-invasive bladder cancer (MIBC) and their predictive potential for response to neoadjuvant chemotherapy (NAC). From 33 blood samples of MIBC patients, CTCs were isolated by cell surface markers and enriched by the IsoFlux™ device, followed by morphological and immunofluorescent identification. CTCs were detected at baseline in all samples. Immunofluorescence confirmed the tumor origin. MIBC patients were stratified by NAC response into the disease control (DC) and progressive disease (PD) groups. In the DC group, the number of CTCs decreased significantly after four courses of NAC (p < 0.0001). CTC counts in 7.5 mL after four NAC cycles were highly correlated with postoperative pathological T stage (p < 0.0001). Our study demonstrated that CTCs might represent a valuable predictive marker for NAC response in MIBC. CTC detection in MIBC patients could allow early arrangement of radical cystectomy for NAC non-responders to prevent disease progression while receiving the NAC courses.

Cerebrospinal fluid exosomal microRNAs as biomarkers for diagnosing or monitoring the progression of non-small cell lung cancer with leptomeningeal metastases

ABSTRACT Non-small-cell lung cancer (NSCLC) has a terrible consequence called leptomeningeal metastases (LM). It is crucial to look for novel biomarkers because none of the known biomarkers could effectively reflect the oncogenesis, progression and therapeutic responses of LM. Exosomal miRNAs from plasma have a critical function in lung cancer, according to growing data. However, unique biomarkers of cerebrospinal fluid (CSF) are more representative for patients with LM, which have not been reported. Here, we explore the possibility of using CSF-derived exosomal microRNAs as potential biomarkers for NSCLC-LM. Nine NSCLC-LM patients who received regular intrathecal chemotherapy with permetexed were divided into a partial response (PR) group and a progressive disease (PD) group. CSF samples were taken from all patients before and after intrathecal treatment and five non-cancerous controls. Using the size exclusion chromatography (SEC) method, the exosome microRNAs were isolated and profiled. Between LM patients and controls, 56 differentially expressed genes (DEGs) were found, of which three highly elevated diagnostic biomarkers (hsa-miR-183-5p, hsa-miR-96-5p and hsa-miR-182-5p) were ruled out. The two most significant DEGs between the untreated PR group and the PD group were determined to be upregulated hsa-miR-509-3p and downregulated hsa-miR-449a, and they may serve as potential indicators of intrathecal anti-pemetrexed treatment. Hsa-miR-1-3p increased gradually with the intrathecal chemotherapy in the PR group, which might offer a new approach to screen optimal patients and estimate the efficacy. This study revealed specific CSF exosomal miRNAs profile and dynamic changes of patients with NSCLC-LM for the first time and identified several potential exosomal miRNA biomarkers in diagnosis, drug resistance and prognosis.

Biomarker analysis from a phase I/I1b study of regorafenib and nivolumab (rego/nivo) in microsatellite stable (MSS) colorectal cancer (CRC).

188 Background: Our previous phase I/Ib study revealed modest clinical efficacy of rego/nivo in refractory MSS-CRC, implying benefits in selected populations. This has prompted us to investigate predictive biomarkers. Methods: Pre-treatment tumor samples from the previous phase Ib rego/nivo study were obtained and assessed for mRNA sequencing (RNAseq). Response-associated transcripts were identified using DESeq2 method and annotated using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Results: A total of 19 pretreatment tumor samples were analyzed including 14 patients (pts) with disease control (DC) (2 partial response and 12 stable disease) and 5 pts with progression disease (PD). We observed significant upregulation of 89 genes including SFTPB ( P&lt;0.001), SFTPA1 ( P&lt;0.001), ERICH6B ( P&lt;0.001) , XIST ( P&lt;0.001), IGHV2-26 ( P&lt;0.001), RETNLB ( P=0.005), VWA5B1 ( P=0.033), IGHV3-53 ( P&lt;0.001), POTEH ( P=0.015), IGHV1-3 ( P=0.001) and downregulation of 70 genes including AFAP1-AS1 ( P=0.022), PRSS21( P&lt;0.001), NTSR1 ( P&lt;0.001), CALB1 ( P=0.033), FAM83A ( P=0.013), TBL1Y ( P=0.045), WNT7A ( P=0.022), PADI1 ( P&lt;0.001), KRT6A ( P=0.030), KRT17 ( P=0.002) on RNA sequencing in the DC compared to PD. GO pathway enrichment analyses revealed 44 significantly upregulated pathways including positive regulation of B cell activation ( P&lt;0.001), B cell receptor signaling pathway ( P&lt;0.001), Phagocytosis engulfment ( P&lt;0.001), Fc-gamma receptor signaling pathway involved in phagocytosis ( P&lt;0.001), endocytosis ( P&lt;0.001), immunoglobulin receptor binding ( P&lt;0.001), serine-type endopeptidase activity ( P&lt;0.001) in the DC compared with PD group. Nine downregulated pathways including cell-substrate junction assembly ( P&lt;0.001), extracellular matrix (ECM) organization ( P=0.030), and ephrin receptor activity ( P=0.046) were observed in the DC compared with PD. KEGG pathway enrichment analysis revealed 8 significantly downregulated pathways including PI3K-Akt signaling ( P=0.009), ECM-receptor interaction ( P=0.006), Focal adhesion ( P=0.028), and Glycine, serine and threonine metabolism ( P=0.007) pathways in the DC compared with PD. Conclusions: RNAseq and following gene set enrichment analysis between pts with DC and PD revealed several dysregulated pathways involving immune regulation including macrophage and B cell activation, and also PI3-Akt signaling, ECM organization/receptor interaction, and adhesion, which are consistent with previous translational studies in other solid tumors. These dysregulated genes and pathways related to differentially expressed genes may need to be further evaluated as potential predictive biomarkers for rego/nivo or other tyrosine kinase inhibitor plus PD-1 blockade in MSS-CRC.

Clinical significance of D-amino acid profile for cancer detection in early stage and prediction of efficacy of nivolumab in gastric cancer.

453 Background: Some metabolites from gut microbiota are reported to associate with immunotherapy response. D-amino acids (D-AAs), enantiomer of L-amino acids (L-AAs), mainly produced by gut microbe and brain, are rare but important metabolite in mammals. Little is known about their biological and immunological significance in cancer patients (pts) as its difficulty of stable measurement. Methods: We first analyzed L/D-AAs in plasma of pts with each disease stage of gastric cancer (GC) before treatment, then compared with healthy control (HC). Second, we analyzed L/D-AAs in plasma of advanced GC pts planned nivolumab (NIVO) monotherapy, and compared among two groups divided based on treatment efficacy of progressive disease (PD) or non-PD. All pts with GC and HC were recruited in Keio University Hospital from October 2017 till March 2022. Concentration of L/D-AAs was measured with Two-Dimensional HPLC-MS/MS System. Results: In the first part, 108 pts with GC before treatment and 87 HC were recruited. D-Ser, D-Asn, D-Ala, D-Pro were detected in plasma of both pts with GC and HC, and their concentration was significantly higher in GC pts rather than in HC, even in pStage 1 ( p&lt;0.0001 of each D-AA, values in table). D-Ser showed an increasing trend as the disease stage progressed. The AUC value of ROC curve to discriminate Stage 1 GC pts from HC were 0.976 with D-AAs. In the second part, 28 pts with advanced GC before NIVO monotherapy were recruited. The best response was PD in 10 pts, and non-PD in 18 pts. D-Ser and D-Asn in plasma were significantly higher in PD group rather than non-PD group ( p=0.0025 and p=0.0158, respectively). The AUC value of the ROC curve discriminating NIVO PD was highest for the equation mainly with D-Ser at 0.933. Pts with poor progression free survival (PFS) and overall survival (OS) could be distinguished by the determined cutoff value of the equation [median PFS: 1.1m vs 3.8m, HR 5.1 ( p=0.0003), median OS: 3.4m vs 18.9m, HR 7.1( p=0.0010)]. Conclusions: D-AAs in plasma significantly increased in pts with GC rather than HC even in early stage. Moreover, higher D-Ser in plasma associated with poor efficacy and prognosis of NIVO in GC pts. We firstly reported D-AA is a novel biomarker of both cancer detection and efficacy of NIVO.[Table: see text]

Evaluating the Gray Level Co-Occurrence Matrix-Based Texture Features of Magnetic Resonance Images for Glioblastoma Multiform Patients' Treatment Response Assessment.

Medical images of cancer patients are usually evaluated qualitatively by clinical specialists which makes the accuracy of the diagnosis subjective and related to the skills of clinicians. Quantitative methods based on the textural feature analysis may be useful to facilitate such evaluations. This study aimed to analyze the gray level co-occurrence matrix (GLCM)-based texture features extracted from T1-axial magnetic resonance (MR) images of glioblastoma multiform (GBM) patients to determine the distinctive features specific to treatment response or disease progression. 20 GLCM-based texture features, in addition to mean, standard deviation, entropy, RMS, kurtosis, and skewness were extracted from step I MR images (obtained 72 h after surgery) and step II MR images (obtained three months later). Responded and not responded patients to treatment were classified manually based on the radiological evaluation of step II images. Extracted texture features from Step I and Step II images were analyzed to determine the distinctive features for each group of responsive or progressive diseases. MATLAB 2020 was applied to feature extraction. SPSS version 26 was used for the statistical analysis. P value < 0.05 was considered statistically significant. Despite no statistically significant differences between Step I texture features for two considered groups, almost all step II extracted GLCM-based texture features in addition to entropy M and skewness were significantly different between responsive and progressive disease groups. GLCM-based texture features extracted from MR images of GBM patients can be used with automatic algorithms for the expeditious prediction or interpretation of response to the treatment quantitatively besides qualitative evaluations.

Can Brain-derived Neurotrophic Factor (BDNF) Mimetics be a Way Out for Neurodegenerative Diseases?

Neurodegenerative diseases are chronic and progressive disease groups characterized by the decline of neural transmission because of the loss of structure and function of neurons. Although there is currently no effective treatment for neurodegenerative diseases, new treatment strategies need to be developed urgently. Among neurotrophins, BDNF has been extensively investigated, and it has emerged as an important regulator of synaptic plasticity, neuronal survival, and differentiation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases. Moreover, promising results have been obtained for BDNF in many experimental studies on animal models. In addition, BDNF serves as a crucial molecular target for developing drugs to treat neurological diseases. However, several pharmacokinetic difficulties have limited its use in clinical practice, such as its inability to cross the blood-brain barrier, short half-life, and potential adverse effects. To avoid these difficulties, several approaches have been explored, but they have led to disappointing results. One way to overcome the limitations of BDNF may be with mimetic molecules that can effectively stimulate the receptors it has an affinity with and thus activates BDNF pathways. In this perspective article, an evaluation of the efficacy of different BDNF mimetics against neurodegenerative diseases was made.

The impact of chemotherapy on quality of life in advanced-stage lung cancer patients.

Most patients with lung cancer are diagnosed at advanced stages of the disease, where chemotherapy plays an important role. This prospective study was conducted to determine the impact of palliative chemotherapy on quality of life (QOL) in advanced-stage lung cancer patients. QOL in lung cancer out-patients was assessed at diagnosis and end of treatment using the EORTC QLQ-C30 questionnaire. Changes in mean QOL scores were calculated. The correlation between patients' tumor response and change in QOL scores was also studied. Scoring was done according to the EORTC manual and results were analyzed using SPSS statistical package. Out of 52 patients, 46 (88.46%) were men and six (11.54%) were women. After chemotherapy, patients' overall QOL score improved significantly (P = 0.005). Cognitive functioning significantly worsened (P = 0.01). Physical functioning (PF) and emotional functioning (EF) scores improved, while role functioning (RF) and social functioning (SF) scores worsened. Pain, dyspnea, and sleep significantly improved (P = 0.001, P = 0.001, and P = 0.005 respectively). On the other hand, nausea, vomiting (P = 0.000), diarrhea (P = 0.004), and financial difficulties (P = 0.009) worsened. Overall QOL improved in patients with partial tumor response (PR) and stable disease (SD) (P = 0.044 and P = 0.000, respectively), but worsened in progressive disease group (PD) (P = 0.648). Symptom scores improved markedly in PR and SD groups. Chemotherapy toxicity was maximum in PD group (P = 0.028). Global quality of life and symptom control significantly improved in lung cancer patients after chemotherapy. Deterioration of cognitive functioning, increased financial burden, and chemotherapy-related toxicity were noteworthy. Changes in QOL were coherent with patients' tumor response.

Tumor thickness in mesothelioma predicts differential response to neoadjuvant therapy and survival

ObjectiveNeoadjuvant systemic therapy in resectable malignant pleural mesothelioma remains controversial and demonstrates variable responses. We sought to evaluate tumor thickness as a predictor of response to neoadjuvant therapy and as a prognostic marker for overall survival. MethodsData from patients who underwent neoadjuvant therapy followed by cytoreductive surgery from 2002 to 2019 were reviewed. Baseline and postneoadjuvant therapy tumor thickness were measured on computed tomography. Radiological tumor response was categorized as progressive disease (≥20% increase), partial response (≥30% decrease), or stable disease (in between). Tumor response outcomes were modeled using logistic regression and multinomial regression models. Overall survival was evaluated based on tumor thickness and tumor response. ResultsOf the 143 patients reviewed, 36 (25%) had progressive disease, 54 (38%) had stable disease, and 56 (39%) had partial response. The baseline tumor thickness of the progressive disease group (36 mm) was lower than in both stable disease and partial response groups (both 63 mm; P < .001). Both logistic regression and multinomial regression analyses demonstrated that thicker baseline tumor thickness was associated with decreased probability of progressive disease and increased probability of partial response. In a multivariable Cox model, thicker postneoadjuvant therapy tumor thickness was associated with worse overall survival (hazard ratio, 1.01, 95% confidence interval, 1.00-1.01, P = .008). The same trend was observed for thicker baseline tumor thickness (hazard ratio, 1.02, 95% confidence interval, 1.01-1.04, P = .008), and the risk was decreased in tumors with partial response (hazard ratio, 0.98, 95% confidence interval, 0.96-0.100, P = .014). ConclusionsWe present the first study demonstrating the relationship between baseline tumor thickness and differential radiographic response to neoadjuvant therapy and survival. Further studies are needed to validate tumor thickness as both a prognostic and predictive biomarker.

Blood Krebs von den Lungen-6 levels predict treatment response to antifibrotic therapy in patients with idiopathic pulmonary fibrosis

Antifibrotic therapy can slow disease progression (DP) in patients with idiopathic pulmonary fibrosis (IPF). However, the prognostic biomarkers for DP in patients with IPF receiving antifibrotic therapy have not been identified. Therefore, we aimed to evaluate the prognostic efficacy of serum Krebs von den Lungen-6 (KL-6) for DP in patients with IPF receiving antifibrotic therapy. The clinical data of 188 patients with IPF who initiated antifibrotic therapy at three tertiary hospitals was retrospectively analyzed. DP was defined as a relative decline in forced vital capacity (FVC) ≥ 10%, diffusing capacity for carbon monoxide ≥ 15%, acute exacerbation, or deaths during 6 months after antifibrotic therapy. The mean age of patients was 68.9 years, 77.7% were male, and DP occurred in 43 patients (22.9%) during follow-up (median, 7.6 months; interquartile range, 6.2-9.8 months). There was no difference in baseline KL-6 levels between the DP and no-DP groups; however, among patients with high baseline KL-6 levels (≥ 500 U/mL), changes in KL-6 levels over 1 month were higher in the DP group than those in the non-DP group, and higher relative changes in KL-6 over 1 month were independently associated with DP (odds ratio, 1.043; 95% confidence interval 1.005-1.084) in the multivariable logistic analysis adjusted for age and FVC. In the receiver operating characteristic curve analysis, the 1-month change in KL-6 was also useful for predicting DP (area under the curve = 0.707; P < 0.012). Our data suggest that the relative change in KL-6 over 1 month might be useful for predicting DP in patients with IPF receiving antifibrotic therapy when baseline KL6 is high.

Dual-energy CT iodine map in predicting the efficacy of neoadjuvant chemotherapy for hypopharyngeal carcinoma: a preliminary study

Neoadjuvant chemotherapy has become one of the important means for advanced hypopharyngeal carcinoma. So far, there is no effective index to predict the curative effect. To investigate the value of iodine map of dual-energy computed tomography (CT) in predicting the efficacy of neoadjuvant chemotherapy for hypopharyngeal carcinoma. A total of 54 hypopharyngeal carcinomapatients who underwent two courses of TPF neoadjuvant chemotherapy were recruited in this study. Three cases had a complete response (CR), thirty-six cases had a partial response (PR), eleven cases had stable disease (SD), and four cases had a progressive disease (PD) after the chemotherapy. All patients underwent a dual-source CT scan before chemotherapy and rescanned after chemotherapy. The normalized iodine-related attenuation (NIRA) of the mean of maximum slice and most enhanced region of lesion at arterial and parenchymal phase were measured: NIRAmean-A, NIRAmax-A, NIRAmean-P, and NIRAmax-P, respectively. Correlation analysis was conducted between different metrics of NIRA and the diameter change rate of lesions, and the curative effect was evaluated based on the receiver operating characteristic (ROC) curve. There were a significant correlation between NIRAmean-A, NIRAmax-A, NIRAmean-P, NIRAmax-P and the change rate of lesion's maximum diameter (ΔD%) (all P < 0.01). The NIRAmax-A, NIRAmean-P, NIRAmax-P had significant differences between CR, PR, SD, PD groups, but NIRAmean-A did not reach a significant difference. All NIRAmean-A, NIRAmax-A, NIRAmean-P, NIRAmax-P had significant differences between effective (CR + PR) and ineffective (SD + PD) groups. The ROC analysis revealed that NIRAmean-P had the largest AUC and prediction efficacy (AUC = 0.809). Dual-energy CT iodine map could predict the efficacy of neoadjuvant chemotherapy and provides imaging evidence to assist in treatment decisions for hypopharyngeal carcinoma patients.

Neoadjuvant chemotherapy for patients with international federation of gynecology and obstetrics stages IB3 and IIA2 cervical cancer: a multicenter prospective trial

BackgroundPreoperative neoadjuvant chemotherapy (NACT) has been widely used in developing countries for the treatment of patients with International Federation of Gynecology and Obstetrics (FIGO) stages IB3 and IIA2 cervical cancer. However, the effectiveness of NACT and treatment options for NACT-insensitive patients have been concerning. This study will assess prognostic differences between NACT and primary surgery treatment (PST), determine factors associated with prognosis, and explore better adjuvant treatment modalities for NACT-insensitive patients.MethodsThis study analyzed clinical characteristics, pathological characteristics, treatment options, and follow-up information of 774 patients with FIGO stages IB3 and IIA2 cervical cancer from 28 centers from January 2016 to October 2019 who participated in a multicenter, prospective, randomized controlled trial.ResultsFor patients undergoing NACT, the 5-year OS and PFS rate was 85.8 and 80.5% respectively. They were similar in the PST group. There was no significant difference in OS and PFS between clinical response (CR)/partial response (PR) groups and stable disease (SD)/progressive disease (PD) groups. Apart from deep cervical invasion (p = 0.046) affecting OS for patients undergoing NACT, no other clinical and pathological factors were associated with OS. 97.8% of NACT-insensitive patients opted for surgery. If these patients did not have intermediate- or high-risk factors, whether they had undergone postoperative adjuvant therapy was irrelevant to their prognosis, whereas for patients with intermediate- or high-risk factors, adjuvant chemotherapy resulted in better PFS (chemotherapy vs. no therapy, p < 0.001; chemotherapy vs. radiotherapy, p = 0.019) and OS (chemotherapy vs. no therapy, p < 0.001; chemotherapy vs. radiotherapy, p = 0.002).ConclusionsNACT could be a choice for patients with FIGO stages IB3 and IIA2 cervical cancer. The main risk factor influencing prognosis in the NACT group is deep cervical invasion. After systematic treatment, insensitivity to NACT does not indicate a poorer prognosis. For NACT-insensitive patients, Chinese prefer surgery. Postoperative adjuvant therapy in patients with no intermediate- or high-risk factors does not improve prognosis, and chemotherapy in patients with intermediate- and high-risk factors is more effective than radiation therapy and other treatments.Trial registrationThe study was prospectively registered on ClinicalTrials.gov (NCT03308591); date of registration: 12/10/2017.

Improving the prediction for the response to radiotherapy of clinical tumor samples by using combinatorial model of MicroRNA expression.

Purpose: Radiation therapy (RT) is one of the main treatments for cancer. The response to radiotherapy varies widely between individuals and some patients have poor response to RT treatment due to tumor radioresistance. Stratifying patients according to molecular signatures of individual tumor characteristics can improve clinical treatment. In here, we aimed to use clinical and genomic databases to develop miRNA signatures that can predict response to radiotherapy in various cancer types. Methods: We analyzed the miRNAs profiles using tumor samples treated with RT across eight types of human cancers from TCGA database. These samples were divided into response group (S, n = 224) and progressive disease group (R, n = 134) based on RT response of tumors. To enhance the discrimination for S and R samples, the predictive models based on binary logistic regression were developed to identify the best combinations of multiple miRNAs. Results: The miRNAs differentially expressed between the groups S and R in each caner type were identified. Total 47 miRNAs were identified in eight cancer types (p values <0.05, t-test), including several miRNAs previously reported to be associated with radiotherapy sensitivity. Functional enrichment analysis revealed that epithelial-to-mesenchymal transition (EMT), stem cell, NF-κB signal, immune response, cell death, cell cycle, and DNA damage response and DNA damage repair processes were significantly enriched. The cancer-type-specific miRNA signatures were identified, which consist of 2-13 of miRNAs in each caner type. Receiver operating characteristic (ROC) analyses showed that the most of individual miRNAs were effective in distinguishing responsive and non-responsive patients (the area under the curve (AUC) ranging from 0.606 to 0.889). The patient stratification was further improved by applying the combinatorial model of miRNA expression (AUC ranging from 0.711 to 0.992). Also, five miRNAs that were significantly associated with overall survival were identified as prognostic miRNAs. Conclusion: These mRNA signatures could be used as potential biomarkers selecting patients who will benefit from radiotherapy. Our study identified a series of miRNA that were differentially expressed between RT good responders and poor responders, providing useful clues for further functional assays to demonstrate a possible regulatory role in radioresistance.

Different clinical and genetic features of Alagille patients with progressive disease versus a jaundice-free course.

Alagille syndrome (ALGS) is a multisystem disorder with variable clinical courses. This study investigated the clinical and genetic features of ALGS patients with different outcomes and analyzed the liver pathology at liver transplantation (LT) compared with that in biliary atresia (BA). We report the clinical characteristics, outcomes, and genetic mutations of 25 children with ALGS followed for a median of 7.3 years. Patients were classified into (i) jaundice-free (JF) group (resolving jaundice after 2 years of age); (ii) progressive disease (PD) group (persistent jaundice or progressive cholestasis). In addition, we analyzed the explant liver in 10 ALGS patients compared with 20 age-matched BA patients at the time of LT. Nine patients (36%) in the JF group had a favorable outcome, with longer native liver survival than patients with PD (n=16, P < 0.001). Fourteen of the PD group patients received LT or died. We identified 18 different JAG1 mutations in 22 patients. Three unrelated probands in the JF group had the same de novo mutation in JAG1, c.2122-2125delCAGT. Compared with BA children, ALGS patients had lower METAVIR scores in liver pathology, higher serum albumin levels, and lower weight-for-age z-scores when receiving LT. One-third of ALGS patients had JF and a favorable course. Children with ALGS presenting with persistent jaundice beyond 2 years of age should be cautioned for poor prognosis. ALGS patients tend to have a lesser extent of cirrhosis, and more growth problems than BA patients at the time of LT.

Usefulness of Immunostaining Scoring for Predicting Response to Single-Agent Nivolumab in Patients with Metastatic Renal Cell Carcinoma

Although several biomarkers have been identified to predict prognosis in renal cell carcinoma (RCC), there are no evidence-based biomarkers to predict the response to immune checkpoint inhibitors. In this study, we focused on lymphocytes and tumor cells in the tumor microenvironment and investigated whether immunostaining scoring could predict the best overall response. We evaluated 32 patients with metastatic RCC (mRCC) who were treated with nivolumab monotherapy between August 2016 and July 2020. We performed immunostaining for CD8 T cells, TIA-1, PD-L1, and HLA class 1 in RCC tissues and assigned a score with a maximum of 4 points each, which we defined as histological score. The best overall response of nivolumab was observed in 4 patients (12.5%) with complete response (CR), 10 patients (31.3%) with partial response (PR), 5 patients (15.6%) with stable disease (SD), and 13 patients (40.6%) with progressive disease (PD). There was no significant difference in patient background between the CR＋PR＋SD group (19 patients) and the PD group (13 patients), but CD8 T cells were significantly higher and TIA-1 positive cells tended to be higher in the CR＋PR＋SD group (CD8 T cell : p＝0.03, TIA-1 : p＝0.07, PD-L1 : p＝0.67, HLA class 1 : p＝1.00). In univariate analysis, histological score ≥3 tended to contribute to the best overall response of nivolumab (p＝0.05). There was no significant difference in overall survival or cancer-specific survival after nivolumab administration between the two groups of patients with histological score ≥3 and those with histological score ＜3. In conclusion, immunostaining scoring based on CD8 T cells may be able to predict the efficacy of single-agent nivolumab in patients with mRCC.

Gut microbiota composition in chemotherapy and targeted therapy of patients with metastatic colorectal cancer.

Studies have reported the effects of the gut microbiota on colorectal cancer (CRC) chemotherapy, but few studies have investigated the association between gut microbiota and targeted therapy. This study investigated the role of the gut microbiota in the treatment outcomes of patients with metastatic CRC (mCRC). We enrolled 110 patients with mCRC and treated them with standard cancer therapy. Stool samples were collected before administering a combination of chemotherapy and targeted therapy. Patients who had a progressive disease (PD) or partial response (PR) for at least 12 cycles of therapy were included in the study. We further divided these patients into anti-epidermal growth factor receptor (cetuximab) and anti-vascular endothelial growth factor (bevacizumab) subgroups. The gut microbiota of the PR group and bevacizumab-PR subgroup exhibited significantly higher α-diversity. The β-diversity of bacterial species significantly differed between the bevacizumab-PR and bevacizumab-PD groups (P = 0.029). Klebsiella quasipneumoniae exhibited the greatest fold change in abundance in the PD group than in the PR group. Lactobacillus and Bifidobacterium species exhibited higher abundance in the PD group. The abundance of Fusobacterium nucleatum was approximately 32 times higher in the PD group than in the PR group. A higher gut microbiota diversity was associated with more favorable treatment outcomes in the patients with mCRC. Bacterial species analysis of stool samples yielded heterogenous results. K. quasipneumoniae exhibited the greatest fold change in abundance among all bacterial species in the PD group. This result warrants further investigation especially in a Taiwanese population.

Efficacy of rechallenge transcatheter arterial chemoembolization after lenvatinib treatment for advanced hepatocellular carcinoma.

We evaluated the efficacy of rechallenge transcatheter arterial chemoembolization (TACE) after lenvatinib (LEN) treatment in patients with previous TACE failure/refractoriness. We enrolled 63 consecutive patients with a history of TACE failure/refractoriness prior to LEN treatment as a first-line systemic therapy. We reviewed the clinical backgrounds and courses of the patients. In total, 25 patients underwent rechallenge TACE after LEN due to LEN-refractoriness (17 cases) or intolerance (8 cases). A complete or partial response was obtained for 13 (65.0%) of the 20 patients whose therapeutic effects were determined. The survival rate of patients who underwent rechallenge TACE was significantly higher than that of patients who did not undergo rechallenge TACE (median survival time, not reached vs 403 days, P=0.015). Rechallenge TACE significantly reduced the risk of death in univariate (hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.08-0.69, P=0.008) and multivariate analyses (HR 0.26, 95% CI 0.08-0.80, P=0.019). If complete or partial response was obtained by rechallenge TACE, the median survival time of these patients was significantly longer than those of the progressive disease (PD) group (P=0.05), and the median survival time of the PD group after rechallenge TACE was not different from that of the group who did not undergo rechallenge TACE (P=0.36). We did not observe a decrease in the ALBI score after TACE. Rechallenge TACE after LEN is an effective treatment that may result in a favorable prognosis.

Arterial enhancement fraction in evaluating the therapeutic effect and survival for hepatocellular carcinoma patients treated with DEB-TACE

BackgroundArterial enhancement fraction (AEF), derived from triphasic CT scans, is considered to indirectly reflect the ratio of hepatic arterial perfusion to total perfusion. The purpose of this study was to retrospectively investigate the relationship between AEF and treatment response and survival in hepatocellular carcinoma (HCC) patients treated with drug-eluting bead (DEB) TACE.MethodsAEF of primary lesion (AEFpre) and residual tumor (AEFpost) in 158 HCC patients were obtained from triphasic liver CT examinations pre- and post-treatment. Wilcoxon-signed rank test was used to compare the AEFpre and AEFpost for different response groups. Survival curves for overall survival (OS) in patients with different AEF were created by using Kaplan-Meier method. Cox regression analyses were used to determine the association between AEF and OS.ResultsThere was no correlation between AEFpre and treatment response. After DEB-TACE, AEFpost was significantly lower than AEFpre either in the partial response group (38.9% vs. 52.7%, p < 0.001) or in the stable disease group (49.3% vs. 52.1%, p = 0.029). In the progression disease group, AEFpost was numerically higher than AEFpre (55.5% vs. 53.0%, p = 0.604). Cox regression analyses showed that risk of death increased in patients with AEFpre > 57.95% (HR = 1.66, p = 0.019) or AEFpost > 54.85% (HR = 2.47, p < 0.001), and the risk reduced in patients with any reduction in tumor AEF (decrease ratio ≥ 0) and with increased AEF but not exceeding the ratio of 0.102 (increase ratio < 0.102) (HR = 0.32, p < 0.001).ConclusionsThe change in AEF of viable tumor is correlated with response of HCC to DEB-TACE. In addition, the AEF could be a helpful predictor in future studies on the embolization treatment for HCC.