Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia:randomized trials and multiomics analysis

Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).

Increased CD4/CD8 Lymphocyte ratio predicts favourable neoadjuvant treatment response in gastric cancer:A prospective pilot study

BACKGROUND Despite optimal neoadjuvant chemotherapy only 40%of gastric cancer tumours achieve complete or partial treatment response.In the absence of treatment response,neoadjuvant chemotherapy in gastric cancer contributes to adverse events without additional survival benefit compared to adjuvant treatment or surgery alone.Additional strategies and methods are required to optimize the allocation of existing treatment regimens such as FLOT chemotherapy(5-Fluorouracil,Leucovorin,Oxaliplatin and Docetaxel).Predictive biomarkers detected using immunohistochemistry(IHC)methods may provide useful data regarding treatment response.AIM To investigate the utility of CD4,CD8,Galectin-3 and E-cadherin in predicting neoadjuvant FLOT chemotherapy tumour response in gastric adenocarcinoma.METHODS Forty-three adult patients with gastric adenocarcinoma,of which 18 underwent neoadjuvant chemotherapy,were included in a prospective clinical cohort.Endoscopic biopsies were obtained from gastric cancer and normal adjacent gastric mucosa.Differences in expression of Galectin-3,Ecadherin,CD4^(+)and CD8^(+)molecules between tumours with and without treatment response to neoadjuvant chemotherapy were assessed with IHC.Treatment response was graded by clinical pathologists using the Tumour Regression Score according to the College of American Pathologists criteria.Treatment response was defined as complete or near complete tumour response,whereas partial or poor/no response was defined as incomplete.Digital IHC images were annotated and quantitatively assessed using QuPath 0.3.1.Biomarker expression between responsive and incomplete response tumours was assessed using a two-sided Wilcoxon test.Biomarker expression was also compared between normal and cancer tissue and between 15 paired tumour samples before and after chemotherapy.We performed a preliminary multivariate analysis and power analysis to guide future study.Statistical analyses were completed using R 4.1.2.RESULTS The ratio between CD4^(+)and CD8^(+)lymphocytes was significantly greater in treatment responsive tumours(Wilcoxon,P=0.03).In univariate models,CD4^(+)/CD8^(+)ratio was the only biomarker that significantly predicted favourable treatment response(Accuracy 86%,P<0.001).Using a glmnet multivariate model,high CD4^(+)/CD8^(+)ratio and low Galectin-3 expression were the most influential variables in predicting a favourable treatment response.Analyses of paired samples found that FLOT chemotherapy also results in increased expression of CD4^(+)and CD8^(+)tumour infiltrating lymphocytes(Paired Wilcoxon,P=0.002 and P=0.008,respectively).Our power analysis suggests future study requires at least 35 patients in each treatment response group for CD8 and Galectin-3 molecules,whereas 80 patients in each treatment response group are required to assess CD4 and E-cadherin biomarkers.CONCLUSION We demonstrate that an elevated CD4^(+)/CD8^(+)Ratio is a promising IHC-based biomarker to predict favourable treatment response to FLOT neoadjuvant chemotherapy in locally advanced gastric cancer.

Computed tomography radiomic features and clinical factors predicting the response to first transarterial chemoembolization in intermediate-stage hepatocellular carcinoma

Background:According to clinical practice guidelines,transarterial chemoembolization(TACE)is the standard treatment modality for patients with intermediate-stage hepatocellular carcinoma(HCC).Early prediction of treatment response can help patients choose a reasonable treatment plan.This study aimed to investigate the value of the radiomic-clinical model in predicting the efficacy of the first TACE treatment for HCC to prolong patient survival.Methods:A total of 164 patients with HCC who underwent the first TACE from January 2017 to September 2021 were analyzed.The tumor response was assessed by modified response evaluation criteria in solid tumors(mRECIST),and the response of the first TACE to each session and its correlation with overall survival were evaluated.The radiomic signatures associated with the treatment response were identified by the least absolute shrinkage and selection operator(LASSO),and four machine learning models were built with different types of regions of interest(ROIs)(tumor and corresponding tissues)and the model with the best performance was selected.The predictive performance was assessed with receiver operating characteristic(ROC)curves and calibration curves.Results:Of all the models,the random forest(RF)model with peritumor(+10 mm)radiomic signatures had the best performance[area under ROC curve(AUC)=0.964 in the training cohort,AUC=0.949 in the validation cohort].The RF model was used to calculate the radiomic score(Rad-score),and the optimal cutoff value(0.34)was calculated according to the Youden’s index.Patients were then divided into a high-risk group(Rad-score>0.34)and a low-risk group(Rad-score≤0.34),and a nomogram model was successfully established to predict treatment response.The predicted treatment response also allowed for significant discrimination of Kaplan-Meier curves.Multivariate Cox regression identified six independent prognostic factors for overall survival,including male[hazard ratio(HR)=0.500,95%confidence interval(CI):0.260–0.962,P=0.038],alpha-fetoprotein(HR=1.003,95%CI:1.002–1.004,P<0.001),alanine aminotransferase(HR=1.003,95%CI:1.001–1.005,P=0.025),performance status(HR=2.400,95%CI:1.200–4.800,P=0.013),the number of TACE sessions(HR=0.870,95%CI:0.780–0.970,P=0.012)and Rad-score(HR=3.480,95%CI:1.416–8.552,P=0.007).Conclusions:The radiomic signatures and clinical factors can be well-used to predict the response of HCC patients to the first TACE and may help identify the patients most likely to benefit from TACE.

Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis

BACKGROUND The association between tumor-infiltrating lymphocyte(TIL)levels and the res-ponse to neoadjuvant therapy(NAT)in patients with triple-negative breast cancer(TNBC)remains unclear.AIM To investigate the predictive potential of TIL levels for the response to NAT in TNBC patients.METHODS A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31,2023.The correlation between TIL levels and the NAT pathologic com-plete response(pCR)in TNBC patients was assessed using a systematic review and meta-analysis.Subgroup analysis,sensitivity analysis,and publication bias analysis were also conducted.RESULTS A total of 32 studies were included in this meta-analysis.The overall meta-ana-lysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup(48.0%vs 27.7%)(risk ratio 2.01;95%confidence interval 1.77-2.29;P<0.001,I2=56%).Subgroup analysis revealed that the between-study hetero-geneity originated from differences in study design,TIL level cutoffs,and study populations.Publication bias could have existed in the included studies.The meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols(all P≤0.01),and there was no significant between-protocol difference in the statistics among the different NAT protocols(P=0.29).Additionally,sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually excluded.CONCLUSION TILs can serve as a predictor of the response to NAT treatment in TNBC patients.TNBC patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs,and this predictive capability is con-sistent across different NAT regimens.

Hepatocellular carcinoma Liver Imaging Reporting and Data Systems treatment response assessment: Lessons learned and future directions

Hepatocellular carcinoma(HCC)is a leading cause of morbidity and mortality worldwide,with rising clinical and economic burden as incidence increases.There are a multitude of evolving treatment options,including locoregional therapies which can be used alone,in combination with each other,or in combination with systemic therapy.These treatment options have shown to be effective in achieving remission,controlling tumor progression,improving disease free and overall survival in patients who cannot undergo resection and providing a bridge to transplant by debulking tumor burden to downstage patients.Following locoregional therapy(LRT),it is crucial to provide treatment response assessment to guide management and liver transplant candidacy.Therefore,Liver Imaging Reporting and Data Systems(LI-RADS)Treatment Response Algorithm(TRA)was created to provide a standardized assessment of HCC following LRT.LIRADS TRA provides a step by step approach to evaluate each lesion independently for accurate tumor assessment.In this review,we provide an overview of different locoregional therapies for HCC,describe the expected post treatment imaging appearance following treatment,and review the LI-RADS TRA with guidance for its application in clinical practice.Unique to other publications,we will also review emerging literature supporting the use of LI-RADS for assessment of HCC treatment response after LRT.

Utility of positron emission tomography-computed tomography scan in detecting residual hepatocellular carcinoma post treatment:Series of case reports

BACKGROUND Multi-phase computed tomography(CT)or magnetic resonance imaging(MRI)has been the standard of care for hepatocellular carcinoma(HCC)diagnosis for years.CASE SUMMARY We report a case series of four patients in whom positron emission tomographycomputed tomography(PET-CT)scan complemented the conventional CT/MRI scans in evaluating treatment response.In these four cases the conventional multi-phase CT and MRI failed to identify residual HCC disease post-treatment,while PET-CT complemented and aided in treatment response evaluation.In each case,the addition of PET-CT identified and located residual HCC disease,allowed retreatment,and altered medical management.CONCLUSION This case series suggests that PET-CT should perhaps play a role in the HCC management algorithm,in addition to the conventional contrast-enhanced multiphase scans.

Pre-treatment platelet counts as a prognostic and predictive factor in stage Ⅱ and Ⅲ rectal adenocarcinoma

AIM To investigate if pre-treatment platelet counts could provide prognostic information in patients with rectal adenocarcinoma that received neo-adjuvant treatment. METHODS Platelet number on diagnosis of stage II and III rectal cancer was evaluated in 51 patients receiving neoadjuvant treatment and for whom there were complete follow-up data on progression and survival, as well as pathologic outcome at the time of surgery. Pathologic responses on the surgical specimen of patients with lower platelet counts(150-300 × 10~9/L) were compared with these of patients with higher platelet counts(> 300 × 10~9/L) by the χ~2 test. Overall and progression free survival Kaplan-Meier curves of the two groups were constructed and compared with the Log-Rank test.RESULTS A significant difference was present between the two groups in regards to pathologic response with patients with lower platelet counts being more likely to exhibit a good or complete response to neo-adjuvant treatment than patients with higher platelet counts(P = 0.015). Among other factors evaluated, there was also a significant difference between the carcinoembryonic antigen(CEA) at presentation of patients that exhibited a good or complete response and those that had no response or a minimal to moderate response. Patients with a good or complete response were more likely to present with a CEA of less than 5 μg/L(P = 0.00066). There was no significant difference in overall and progression free survival between the two platelet count groups(Log-Rank tests P = 0.42 and P = 0.35, respectively).CONCLUSION In this retrospective analysis of stage II and III rectal cancer patients, platelet counts at the time of diagnosis had prognostic value for neo-adjuvant treatment pathologic response. Pre-treatment CEA also held prognostic value in regards to treatment effect.

Recent advances and future directions for the pharmacogenetic basis of anti-VEGF treatment response in neovascular age-related macular degeneration

Age related macular degeneration （AMD） is a complex progres- sive neurodegenerative disease causing blindness in 30-35 million people worldwide. It affects the macula region of the retina leading to severe vision loss and legal blindness in individuals 〉 50 years of age （Wong et al., 2014）. The precise aetiology of AMD is unknown but smoking, age and genetic factors are major risk factors for AMD predisposition （Ding et al., 2009）. The genetic basis of AMD is well described with a recent study from the International AMD gene consortium （IAMDGC） reporting 52 genetic variants across 34 loci associated with the risk of AMD pathogenesis and explaining more than 50% of the genetic heritabilitv of the disease （Fritsche et al., 2016）.

Single-cell trajectories of melanoma cell resistance to targeted treatment

Objective:Cellular heterogeneity is regarded as a major factor affecting treatment response and resistance in malignant melanoma.Recent developments in single-cell sequencing technology have provided deeper insights into these mechanisms.Methods:Here,we analyzed a BRAFV600 E-mutant melanoma cell line by single-cell RNA-seq under various conditions:cells sensitive to BRAF inhibition with BRAF inhibitor vemurafenib and cells resistant to BRAF inhibition with vemurafenib alone or vemurafenib in combination with the MEK1/2 inhibitors cobimetinib or trametinib.Dimensionality reduction by t-distributed stochastic neighbor embedding and self-organizing maps identified distinct trajectories of resistance development clearly separating the 4 treatment conditions in cell and gene state space.Results:Trajectories associated with resistance to single-agent treatment involved cell cycle,extracellular matrix,and de-differentiation programs.In contrast,shifts detected in double-resistant cells primarily affected translation and mitogen-activated protein kinase pathway reactivation,with a small subpopulation showing markers of pluripotency.These findings were validated in pseudotime analyses and RNA velocity measurements.Conclusions:The single-cell transcriptomic analyses reported here employed a spectrum of bioinformatics methods to identify mechanisms of melanoma resistance to single-and double-agent treatments.This study deepens our understanding of treatmentinduced cellular reprogramming and plasticity in melanoma cells and identifies targets of potential relevance to the management of treatment resistance.

Upper esophageal sphincter abnormalities on high-resolution esophageal manometry and treatment response of type Ⅱ achalasia

BACKGROUND Little is known about the clinical significance of upper esophageal sphincter(UES)motility disorders and their association with the treatment response of typeⅡachalasia.None of the three versions of the Chicago Classification of Esophageal Motility Disorders has defined UES abnormality metrics or their function.UES abnormalities exist in some patients and indicate a clinically significant problem in patients with achalasia.AIM To demonstrate the manometric differentiation on high-resolution esophageal manometry between subjects with abnormal UES and normal UES,and the association between UES type and the treatment response of typeⅡachalasia.METHODS In total,498 consecutive patients referred for high-resolution esophageal manometry were analyzed retrospectively.The patients were divided into two groups,those with normal and abnormal UES function.UES parameters were analyzed after determining lower esophageal sphincter(LES)function.Patients with typeⅡachalasia underwent pneumatic dilation for treatment.Using mixed model analyses,correlations between abnormal UES and treatment response were calculated among subjects with typeⅡachalasia.RESULTS Of the 498 consecutive patients,246(49.40%)were found to have UES abnormalities.Impaired relaxation alone was the most common UES abnormality(52.85%,n=130).The incidence rate of typeⅡachalasia was significantly higher in subjects with abnormal UES than those with normal UES(9.77%vs 2.58%,P=0.01).After pneumatic dilation,LES resting pressure,LES integrated relaxation pressure,and UES residual pressure were significantly decreased(41.91±9.20 vs 26.18±13.08,38.94±10.28 vs 16.71±5.65,and 11.18±7.93 vs 5.35±4.77,respectively,P<0.05).According to the Eckardt score,subjects with typeⅡachalasia and abnormal UES presented a significantly poorer treatment response than those with normal UES(83.33%vs 0.00%,P<0.05).CONCLUSION Impaired relaxation alone is the most common UES abnormality.The incidence of typeⅡachalasia is associated with abnormal UES.TypeⅡachalasia with abnormal UES has a poorer treatment response,which is a potentially prognostic indicator of treatment for this disease.

THERAPEUTIC EFFECT OF NON-SURGICAL TREATMENT OF CHRONIC PERIODONTITIS IN DIABETIC CHINESE

Objective To observe the therapeutic effect of non-surgical treatment on diabetic Chinese withchronic periodontitis. Methods Moderate to advanced chronic periodontitis ( CP) was studied in 36 diabetes mellitus (DM) patients classified as 20 with high and fluctuating blood glucose level (DM-H) and 16 with relatively low and stable blood glucose level (DM-L). 28 non-DM CP patients acted as controls (Non-DM). Plaque index (PlI) , gingival index (GI) , bleeding on probing (BOP) , probing depth (PD) and clinical attachment loss (AL) of all patients were recorded at 6 sites on each tooth at the baseline and 1, 3 and 6 months after oral hygiene instruction (OHI), scaling and root planing. Results It was found that the short-term effect of non-surgical periodon-tal procedure had resulted in significant resolution of gingival inflammation and pronounced reduction in pocket depth and gain of attachment loss in both DM and Non-DM CP patients. Conclusion The pilot study suggested that non-surgical periodontal treatment allowed for favorable treatment responses in a group of Chinese diabetic subjects with chronic periodontitis and that their various profiles of blood glucose did not influence the short-term healing response to OHI, scaling and root planning.

Molecular mechanisms of insulin resistance in chronic hepatitis C

It is now widely recognized that chronic hepatitis C (CHC)is associated with insulin resistance(IR)and type 2 diabetes,so can be considered a metabolic disease.IR is most strongly associated with hepatitis C virus(HCV)genotype 1,in contrast to hepatic steatosis, which is associated with genotype 3 infection.Apart from the well-described complications of diabetes,IR in CHC predicts faster progression to fibrosis and cirrhosis that may culminate in liver failure and hepatocellular carcinoma.More recently,it has been recognized that IR in CHC predicts a poor response to antiviral therapy. The molecular mechanisms for the association between IR and HCV infection are not well defined.This review will elaborate on the clinical associations between CHC and IR and summarize current knowledge regarding the molecular mechanisms that potentially mediate HCV-associated IR.

Effect of b value on monitoring therapeutic response by diffusion-weighted imaging

AIM： To explore the diffusion gradient b-factor that optimizes both apparent diffusion coefficient （ADC） measurement and contrast-to-noise （CNR） for assessing tumor response to transarterial chemoembolization （TACE） in a rabbit model. METHODS： Twelve New Zealand white rabbits bearing VX2 tumors in the liver were treated with TACE. Diffusion-weighted imaging （DWI） with various b values was performed using the same protocol before and 3 d after treatment with TACE. ADC values and CNR of each tumor pre- and post-treatment with different b factors were analyzed. Correlation between ADC values and extent of necrosis in histological specimens was analyzed by a Pearson＇s correlation test.RESULTS： The quality of diffusion-weighted images diminished as the b value increased. A substantial decrease in the mean lesion-to-liver CNR was observed on both pre- and post-treatment DW images, the largest difference in CNR pre- and post-treatment was manifested at a b value of 1000 s/mm^2 （P = 0.036 ）. The effect of therapy on diffusion early after treatment was shown by a significant increase in ADCs （P = 0.007）, especially with large b factors （≥ 600 s/mm^2）. The mean percentage of necrotic cells present within the tumor was 76.3%-97.5%. A significant positive correlation was found between ADC values and the extent of necrosis with all b values except for b200, a higher relative coefficient between ADC values and percentage of necrosis was found on DWI with bl000 and b2000 （P = 0.002 and 0.006, respectively）. CONCLUSION： An increasing b value of up to 600 s/mm^2 would increase ADC contrast pre- and post-treatment, but decrease image quality. Taking into account both CNR and ADC measurement, diffusion-weighted imaging obtained with a b value of 1000 s/mm^2 is recommended for monitoring early hepatic tumor response to TACE.

Predictive value of ^(18)F-fluorodeoxyglucose PET/CT for transarterial chemolipiodolization of hepatocellular carcinoma

AIM： To investigate the correlation of 18F-fluorodeoxy- glucose （18F-FDG） positron emission tomography （PET） with clinical features and the prediction of treatment response. METHODS： A total of 83 hepatocellular carcinoma （HCC） patients undergoing 18F-FDG PET before transar- terial chemolipiodolization with systemic chemo-infusion between October, 2006 and May, 2009 were retrospec-tively enrolled. The patients included 68 men and 15 women （mean age, 60 ~ 10.7 years）. The effect of 18F- FDG-monitored PET uptake on clinical features and on the evaluated treatment response was ascertained with modified Response Evaluation Criteria in Solid Tumors. The PET parameters of maximal standardized uptake value of the tumor （Tsuvmax）, the ratio of the tumor maximal standardized uptake value （SUV） to the liver maximal SUV （Tsuvmax/Lsuwax） and the ratio of tumor maximal SUV to the liver mean SUV （msuvmax/LSUVrnean） were tested as predictive factors. RESULTS： Among the 3 SUV parameters, the TSUV- =maxdLsuvmean ratio （cutoff value of 1.90） was significantly associated with tumor burden including tumor size, tu- mor number, α-fetoprotein levels and tumor stage （P 〈 0.001, P = 0.008, P = 0.011, P 〈 0.001, respectively）. The objective response rates in patients with a high SUV ratio （≥ 1.90） were significantly better than those with a low SUV ratio （〈 1.90） （P = 0.020）. The overall survival rates of patients exhibiting a low Tsuvmax/Lsu- Vmean ratio （〈 1.90） and those with a high SUV ratio （≥1.90） was 38.2 and 10.3 mo, respectively （P 〈 0.01）. However, the time to progression showed no significant difference between the groups （P = 0.15）. CONCLUSION： 18F-FDG PET can be an important predictor of HCC treatment. In particular, the Tsuvmax/ Lsuwean ratio （cutoff value of 1.90） can provide useful information in treatment prognosis for HCC patients treated with Iocoregional therapy.

Transarterial chemoembolization with drug-eluting beads in hepatocellular carcinoma

Transarterial chemoembolization(TACE) is a widely used standard treatment for patients with hepatocellular carcinoma(HCC) who are not suitable candidates for curative treatments. The rationale for TACE is that intra-arterial chemotherapy using lipiodol and chemotherapeutic agents, followed by selective vascular embolization, results in a strong cytotoxic effect as well as ischemia(conventional TACE). Recently, drugeluting beads(DC Beads?) have been developed for transcatheter treatment of HCC to deliver higher doses of the chemotherapeutic agent and to prolong contact time with the tumor. DC Beads? can actively sequester doxorubicin hydrochloride from solution and release it in a controlled sustained fashion. Treatment with DC Beads? substantially reduced the amount of chemotherapeutic agent that reached the systemic circulation compared with conventional, lipiodol-based regimens, significantly reducing drug-related adverse events. In this article, we describe the treatment response, survival, and safety of TACE used with drugeluting beads for the treatment of HCC and discuss future therapeutic possibilities.

Radiotherapy for 65 patients with advanced unresectable hepatocellular carcinoma

AIM: To evaluate the efficacy of radiotherapy (RT) in patients with advanced unresectable hepatocellular carcinoma (HCC). METHODS: A total of 65 patients were treated with RT in the Korea University Medical Center. The median age of the patients was 60 years, and 86.2% were men. 18.5% and 81.5% of the patients were diagnosed as TNM stage Ⅲ and Ⅳ-A, respectively. Treatment response was assessed 4 mo after initiation of RT. Tumor regression rate 1 mo after initiation of RT (TRR1m) was also assessed. Duration of survival was calculated from the initiation of RT. RESULTS: The objective treatment response was 56.9%. The 12 mo survival rate was 34.7%. Predictive factors for survival were Child-Pugh grade, α-fetoprotein level and treatment response. An objective response was achieved more frequently in patients with TRR1m ≥ 20% than in those with TRR1m < 20% (P < 0.001). CONCLUSION: RT is effective in treating advanced HCC with a tumor response rate of 56.9%.

Application of intravoxel incoherent motion diffusion-weighted imaging in hepatocellular carcinoma

The morbidity and mortality of hepatocellular carcinoma(HCC)rank 6th and 4th,respectively,among malignant tumors worldwide.Traditional diffusion-weighted imaging(DWI)uses the apparent diffusion coefficient(ADC)obtained by applying the monoexponential model to reflect water molecule diffusion in active tissue;however,the value of ADC is affected by microcirculation perfusion.Using a biexponential model,intravoxel incoherent motion(IVIM)-DWI quantitatively measures information related to pure water molecule diffusion and microcirculation perfusion,thus compensating for the shortcomings of DWI.The number of studies examining the application of IVIM-DWI in patients with HCC has gradually increased over the last few years,and many results show that IVIMDWI has vital value for HCC differentiation,pathological grading,and predicting and evaluating the treatment response.The present study principally reviews the principle of IVIM-DWI and its research progress in HCC differentiation,pathological grading,predicting and evaluating the treatment response,predicting postoperative recurrence and predicting gene expression prediction.

Role of dynamic perfusion magnetic resonance imaging in patients with local advanced rectal cancer

BACKGROUND The management of rectal cancer patients is mainly based on the use of the magnetic resonance imaging(MRI)technique as a diagnostic tool for both staging and restaging.After treatment,to date,the evaluation of complete response is based on the histopathology assessment by using different tumor regression grade(TRG)features(e.g.,Dworak or Mandard classifications).While from the radiological point of view,the main attention for the prediction of a complete response after chemotherapy treatment focuses on MRI and the potential role of diffusion-weighted images and perfusion imaging represented by dynamiccontrast enhanced MRI.The main aim is to find a reliable tool to predict tumor response in comparison to histopathologic findings.AIM To investigate the value of dynamic contrast-enhanced perfusion-MRI parameters in the evaluation of the healthy rectal wall and tumor response to chemo-radiation therapy in patients with local advanced rectal cancer with histopathologic correlation.METHODS Twenty-eight patients with biopsy-proven rectal adenocarcinoma who underwent a dynamic contrast-enhanced MR study performed on a 1.5 T MRI system(Achieva,Philips),before(MR1)and after chemoradiation therapy(MR2),were enrolled in this study.The protocol included T1 gadolinium enhanced THRIVE sequences acquired on axial planes.A dedicated workstation was used to generate color permeability maps.Region of interest was manually drawn on tumor tissue and normal rectal wall,hence the following parameters were calculated and statistically analyzed:Relative arterial enhancement(RAE),relative venous enhancement(RVE),relative late enhancement(RLE),maximum enhancement(ME),time to peak and area under the curve(AUC).Perfusion parameters were related to pathologic TRG(Mandard’s criteria;TRG1=complete regression,TRG5=no regression).RESULTS Ten tumors(36%)showed complete or subtotal regression(TRG1-2)at histology and classified as responders;18 tumors(64%)were classified as non-responders(TRG3-5).Perfusion MRI parameters were significantly higher in the tumor tissue than in the healthy tissue in MR1(P<0.05).At baseline(MR1),no significant difference in perfusion parameters was found between responders and nonresponders.After chemo-radiation therapy,at MR2,responders showed significantly(P<0.05)lower perfusion values[RAE(%)54±20;RVE(%)73±24;RLE(%):82±29;ME(%):904±429]compared to non-responders[RAE(%):129±45;RVE(%):154±39;RLE(%):164±35;ME(%):1714±427].Moreover,in responders group perfusion values decreased significantly at MR2[RAE(%):54±20;RVE(%):73±24;RLE(%):82±29;ME(%):904±429]compared to the corresponding perfusion values at MR1[RAE(%):115±21;RVE(%):119±21;RLE(%):111±74;ME(%):1060±325];(P<0.05).Concerning the time-intensity curves,the AUC at MR2 showed significant difference(P=0.03)between responders and non-responders[AUC(mm2×10-3)121±50 vs 258±86],with lower AUC values of the tumor tissue in responders compared to nonresponders.In non-responders,there were no significant differences between perfusion values at MR1 and MR2.CONCLUSION Dynamic contrast perfusion-MRI analysis represents a complementary diagnostic tool for identifying vascularity characteristics of tumor tissue in local advanced rectal cancer,useful in the assessment of treatment response.

Chemotherapy response evaluation in a mouse model of gastric cancer using intravoxel incoherent motion diffusionweighted MRI and histopathology

AIM To determine the role of intravoxel incoherent motion(IVIM) diffusion-weighted(DW) magnetic resonance imaging(MRI) using a bi-exponential model in chemotherapy response evaluation in a gastric cancer mouse model.METHODS Mice bearing MKN-45 human gastric adenocarcinoma xenografts were divided into four treated groups(TG1, 2, 3 and 4, n = 5 in each group) which received Fluorouracil and Calcium Folinate and a control group(CG, n = 7). DW-MRI scans with 14 b-values(0-1500 s/mm2) were performed before and after treatment on days 3, 7, 14 and 21. Fast diffusion component(presumably pseudo-perfusion) parameters including the fast diffusion coefficient(D*) and fraction volume(f p), slow diffusion coefficient(D) and the conventional apparent diffusion coefficients(ADC) were calculated by fitting the IVIM model to the measured DW signals. The median changes from the baseline to each posttreatment time point for each measurement(ΔADC, ΔD* and Δf p) were calculated. The differences in the median changes between the two groups were compared using the mixed linear regression model by the restricted maximum likelihood method shown as z values. Histopathological analyses including Ki-67, CD31, TUNEL and H&E were conducted in conjunction with the MRI scans. The median percentage changes were compared with the histopathological analyses between the pre-and post-treatment for each measurement.RESULTS Compared with the control group, D* in the treated group decreased significantly(ΔD*treated% =-30%,-34% and-20%, with z =-5.40,-4.18 and-1.95. P = 0.0001, 0.0001 and 0.0244) and f p increased significantly(Δfptreated% = 93%, 113% and 181%, with z = 4.63, 5.52, and 2.12, P = 0.001, 0.0001 and 0.0336) on day 3, 7 and 14, respectively. Increases in ADC in the treated group were higher than those in the control group on days 3 and 14(z = 2.44 and 2.40, P = 0.0147 and P = 0.0164). CONCLUSION Fast diffusion measurements derived from the biexponential IVIM model may be more sensitive imaging biomarkers than ADC to assess chemotherapy response in gastric adenocarcinoma.

Nomogram for prediction of pathologic complete remission using biomarker expression and endoscopic finding after preoperative chemoradiotherapy in rectal cancer

Objective:The aim of this study is to develop a nomogram for prediction of pathologic complete remission(p CR)after preoperative chemoradiotherapy(CRT)for rectal cancer.Methods:m RNA expression levels of seven molecular markers[p53,p21,Ki-67,vascular endothelial growth factor(VEGF),CD133,CD24,CD44]were measured by reverse transcriptase polymerase chain reaction(RTPCR)in 120 rectal cancers.Endoscopic findings of clinical complete remission(c CR)and biologic variables were used to construct nomogram in the training group(n=80),which was validated in the validation group(n=40).Results:m RNA expression levels of four markers(p53,p21,Ki67,CD133)correlated with p CR(24/80,30.0%)in the training group.Low expression of p53 and/or high expression of p21,Ki67 and CD133 showed greater p CR rate.p CR was shown in 18(69.2%)of 26 cases showing endoscopic c CR in the training group.Higher p CR rate was demonstrated in lower tumor location than middle tumor(19/49,38.8%vs.5/31,16.1%).A nomogram for prediction of p CR was developed from the multivariate prediction model using these six variables,which showed good discrimination ability in the training group[area under the curve(AUC)=0.945]and validation group(AUC=0.922).The calibration plot showed good agreement between actual and predicted p CR in both patient groups.Conclusions:Nomogram for assessment of p CR can be useful for making treatment decisions after CRT according to predicted responses.