A multicentric study of radiomics and artificial intelligence analysis on contrast-enhanced mammography to identify different histotypes of breast cancer.

OBJECTIVE: To evaluate the performance of radiomic analysis on contrast-enhanced mammography images to identify different histotypes of breast cancer mainly in order to predict grading, to identify hormone receptors, to discriminate human epidermal growth factor receptor 2 (HER2) and to identify luminal histotype of the breast cancer. METHODS: From four Italian centers were recruited 180 malignant lesions and 68 benign lesions. However, only the malignant lesions were considered for the analysis. All patients underwent contrast-enhanced mammography in cranium caudal (CC) and medium lateral oblique (MLO) view. Considering histological findings as the ground truth, four outcomes were considered: (1) G1 + G2 vs. G3; (2) HER2 + vs. HER2 - ; (3) HR + vs. HR - ; and (4) non-luminal vs. luminal A or HR + /HER2- and luminal B or HR + /HER2 + . For multivariate analysis feature selection, balancing techniques and patter recognition approaches were considered. RESULTS: The univariate findings showed that the diagnostic performance is low for each outcome, while the results of the multivariate analysis showed that better performances can be obtained. In the HER2 + detection, the best performance (73% of accuracy and AUC = 0.77) was obtained using a linear regression model (LRM) with 12 features extracted by MLO view. In the HR + detection, the best performance (77% of accuracy and AUC = 0.80) was obtained using a LRM with 14 features extracted by MLO view. In grading classification, the best performance was obtained by a decision tree trained with three predictors extracted by MLO view reaching an accuracy of 82% on validation set. In the luminal versus non-luminal histotype classification, the best performance was obtained by a bagged tree trained with 15 predictors extracted by CC view reaching an accuracy of 94% on validation set. CONCLUSIONS: The results suggest that radiomics analysis can be effectively applied to design a tool to support physician decision making in breast cancer classification. In particular, the classification of luminal versus non-luminal histotypes can be performed with high accuracy.

Analysis of a monocentric computed tomography dosimetric database using a radiation dose index monitoring software: dose levels and alerts before and after the implementation of the adaptive statistical iterative reconstruction on CT images.

OBJECTIVE: To analyze dosimetric data of a single center by a radiation dose index monitoring software evaluating quantitatively the dose reduction obtained with the implementation of the adaptive statistical iterative reconstruction (ASIR) on Computed Tomography in terms of both the value of the dose length product (DLP) and the alerts provided by the dose tool. METHODS: Dosimetric quantities were acquired using Qaelum DOSE tool (QAELUM NV, Leuven-Heverlee, Belgium). Dose data pertaining to CT examinations were performed using a General Electric Healthcare CT tomography with 64 detectors. CT dose data were collected over 4 years (January 1, 2017 to December 31, 2020) and included CT dose length product (DLP). Moreover, all CT examinations that triggered a high radiation dose (twice the median for that study description), termed alerts on Dose tool, were retrieved for the analysis. Two radiologists retrospectively assessed CT examinations in consensus for the images quality and for the causes of the alerts issued. A Chi-square test was used to assess whether there were any statistically significant differences among categorical variable while a Kruskal Wallis test was considered to assess differences statistically significant for continuous variables. RESULTS: Differences statistically significant were found for the DLP median values between the dosimetric data recorded on 2017-2018 versus 2019-2020. The differences were linked to the implementation of ASIR technique at the end of 2018 on the CT scanner. The highest percentage of alerts was reported in the CT study group "COMPLETE ABDOMEN + CHEST + HEAD" (range from 1.26% to 2.14%). A reduction year for year was relieved linked to the CT protocol optimization with a difference statistically significant. The highest percentage of alerts was linked to wrong study label/wrong study protocol selection with a range from 29 to 40%. CONCLUSIONS: Automated methods of radiation dose data collection allowed for detailed radiation dose analysis according to protocol and equipment over time. The use of CT ASIR technique could determine considerable reduction in radiation dose.

Validation of the standardized index of shape tool to analyze DCE-MRI data in the assessment of neo-adjuvant therapy in locally advanced rectal cancer.

PURPOSE: Standardized index of shape (SIS) tool validation to examine dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) in preoperative chemo-radiation therapy (pCRT) assessment of locally advanced rectal cancer (LARC) in order to guide the surgeon versus more or less conservative treatment. MATERIALS AND METHODS: A total of 194 patients (January 2008-November 2020), with III-IV locally advanced rectal cancer and subjected to pCRT were included. Three expert radiologists performed DCE-MRI analysis using SIS tool. Degree of absolute agreement among measurements, degree of consistency among measurements, degree of reliability and level of variability were calculated. Patients with a pathological tumour regression grade (TRG) 1 or 2 were classified as major responders (complete responders have TRG 1). RESULTS: Good significant correlation was obtained between SIS measurements (range 0.97-0.99). The degree of absolute agreement ranges from 0.93 to 0.99, the degree of consistency from 0.81 to 0.9 and the reliability from 0.98 to 1.00 (p value < < 0.001). The variability coefficient ranges from 3.5% to 26%. SIS value obtained to discriminate responders by non-responders a sensitivity of 95.9%, a specificity of 84.7% and an accuracy of 91.8% while to detect complete responders, a sensitivity of 99.2%, a specificity of 63.9% and an accuracy of 86.1%. CONCLUSION: SIS tool is suitable to assess pCRT response both to identify major responders and complete responders in order to guide the surgeon versus more or less conservative treatment.

A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873.

Standardized Index of Shape (SIS): a quantitative DCE-MRI parameter to discriminate responders by non-responders after neoadjuvant therapy in LARC.

OBJECTIVES: To investigate the potential of DCE-MRI to discriminate responders from non-responders after neoadjuvant chemo-radiotherapy (CRT) for locally advanced rectal cancer (LARC). We investigated several shape parameters for the time-intensity curve (TIC) in order to identify the best combination of parameters between two linear parameter classifiers. METHODS: Seventy-four consecutive patients with LARC were enrolled in a prospective study approved by our ethics committee. Each patient gave written informed consent. After surgery, pathological TNM and tumour regression grade (TRG) were estimated. DCE-MRI semi-quantitative analysis (sqMRI) was performed to identify the best parameter or parameter combination to discriminate responders from non-responders in response monitoring to CRT. Percentage changes of TIC shape descriptors from the baseline to the presurgical scan were assessed and correlated with TRG. Receiver operating characteristic analysis and linear classifier were applied. RESULTS: Forty-six patients (62.2%) were classified as responders, while 28 subjects (37.8%) were considered as non-responders. sqMRI reached a sensitivity of 93.5% and a specificity of 82.1% combining the percentage change in Maximum Signal Difference (ΔMSD) and Wash-out Slope (ΔWOS), the Standardized Index of Shape (SIS). CONCLUSIONS: SIS obtains the best result in discriminating responders from non-responders after CRT in LARC, with a cut-off value of -3.0%. KEY POINTS: • DCE-MRI shape descriptors are investigated to assess preoperative CRT response in LARC. • Identification of the best TIC shape descriptors combination through a linear classifier. • Identification of a single MRI index to predict neoadjuvant treatment response.

A prognostic model comprising pT stage, N status, and the chemokine receptors CXCR4 and CXCR7 powerfully predicts outcome in neoadjuvant resistant rectal cancer patients.

Despite the optimization of the local treatment of advanced rectal cancer (LARC), combination of preoperative chemoradiotherapy (CRT) and surgery, approximately one third of patients will develop distant metastases. Since the chemokine receptor CXCR4 has been implicated in metastasis development and prognosis in colorectal cancer, the role of the entire axis CXCR4-CXCL12-CXCR7 was evaluated to identify high relapse risk rectal cancer patients. Tumor specimens of 68 LARC patients undergoing surgery after neoadjuvant-CRT were evaluated for CXCR4, CXCR7, and CXCL12 expression through immunohistochemistry. Multivariable prognostic model was developed using classical prognostic factors along with chemokine receptor expression profiles. High CXCR4 correlated with a shorter relapse-free survival (RFS) (p = 0.0006) and cancer specific survival (CSS) (p = 0.0004). Concomitant high CXCR4-negative/low CXCR7 or high CXCR4-negative/low CXCL12 significantly impaired RFS (p = 0.0003 and p = 0.0043) and CSS (p = 0.0485 and p = 0.0026). High CXCR4/N+ identified the worst prognostic category for RFS (p < 0.0001) and CSS (p = 0.0003). The optimal multivariable predictive model for RFS was a five-variable model consisting of gender, pT stage, N status, CXCR4, and CXCR7 (AUC = 0.92, 95% CI = 0.77-0.98). The model is informative and supportive for adjuvant treatment and identifies CXCR4 as a new therapeutic target in rectal cancer.

Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid--short Radiotherapy--rectum 3rd trial).

BACKGROUND: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target. METHODS/DESIGN: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT. DISCUSSION: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.EudraCT Number: 2012-002831-28. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01898104.

An Informative Review of Radiomics Studies on Cancer Imaging: The Main Findings, Challenges and Limitations of the Methodologies.

The aim of this informative review was to investigate the application of radiomics in cancer imaging and to summarize the results of recent studies to support oncological imaging with particular attention to breast cancer, rectal cancer and primitive and secondary liver cancer. This review also aims to provide the main findings, challenges and limitations of the current methodologies. Clinical studies published in the last four years (2019-2022) were included in this review. Among the 19 studies analyzed, none assessed the differences between scanners and vendor-dependent characteristics, collected images of individuals at additional points in time, performed calibration statistics, represented a prospective study performed and registered in a study database, conducted a cost-effectiveness analysis, reported on the cost-effectiveness of the clinical application, or performed multivariable analysis with also non-radiomics features. Seven studies reached a high radiomic quality score (RQS), and seventeen earned additional points by using validation steps considering two datasets from two distinct institutes and open science and data domains (radiomics features calculated on a set of representative ROIs are open source). The potential of radiomics is increasingly establishing itself, even if there are still several aspects to be evaluated before the passage of radiomics into routine clinical practice. There are several challenges, including the need for standardization across all stages of the workflow and the potential for cross-site validation using real-world heterogeneous datasets. Moreover, multiple centers and prospective radiomics studies with more samples that add inter-scanner differences and vendor-dependent characteristics will be needed in the future, as well as the collecting of images of individuals at additional time points, the reporting of calibration statistics and the performing of prospective studies registered in a study database.

Early FDG PET response assessment of preoperative radiochemotherapy in locally advanced rectal cancer: correlation with long-term outcome.

PURPOSE: The aim of the present study is to prospectively evaluate the prognostic value of previously defined [(18)F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) criteria of early metabolic response in patients with locally advanced rectal cancer (LARC) after long-term follow-up. METHODS: Forty-two patients with poor prognosis LARC underwent three biweekly courses of chemotherapy with oxaliplatin, raltitrexed and 5-fluorouracil modulated by levofolinic acid during pelvic radiotherapy. FDG PET studies were performed before and 12 days after the beginning of the chemoradiotherapy (CRT) treatment. Total mesorectal excision (TME) was carried out 8 weeks after completion of CRT. A previously identified cutoff value of ≥52 % reduction of the baseline mean FDG standardized uptake value (SUV(mean)) was applied to differentiate metabolic responders from non-responders and correlated to tumour regression grade (TRG) and survival. RESULTS: Twenty-two metabolic responders showed complete (TRG1) or subtotal tumour regression (TRG2) and demonstrated a statistically significantly higher 5-year relapse-free survival (RFS) compared with the 20 non-responders (86 vs 55 %, p = .014) who showed TRG3 and TRG4 pathologic responses. A multivariate analysis demonstrated that early ∆SUV(mean) was the only pre-surgical parameter correlated to the likelihood of recurrence (p = .05). CONCLUSION: This study is the first prospective long-term evaluation demonstrating that FDG PET is not only an early predictor of pathologic response but is also a valuable prognostic tool. Our results indicate the potential of FDG PET for optimizing multidisciplinary management of patients with LARC.

Artificial Intelligence and COVID-19 Using Chest CT Scan and Chest X-ray Images: Machine Learning and Deep Learning Approaches for Diagnosis and Treatment.

OBJECTIVE: To report an overview and update on Artificial Intelligence (AI) and COVID-19 using chest Computed Tomography (CT) scan and chest X-ray images (CXR). Machine Learning and Deep Learning Approaches for Diagnosis and Treatment were identified. METHODS: Several electronic datasets were analyzed. The search covered the years from January 2019 to June 2021. The inclusion criteria were studied evaluating the use of AI methods in COVID-19 disease reporting performance results in terms of accuracy or precision or area under Receiver Operating Characteristic (ROC) curve (AUC). RESULTS: Twenty-two studies met the inclusion criteria: 13 papers were based on AI in CXR and 10 based on AI in CT. The summarized mean value of the accuracy and precision of CXR in COVID-19 disease were 93.7% ± 10.0% of standard deviation (range 68.4-99.9%) and 95.7% ± 7.1% of standard deviation (range 83.0-100.0%), respectively. The summarized mean value of the accuracy and specificity of CT in COVID-19 disease were 89.1% ± 7.3% of standard deviation (range 78.0-99.9%) and 94.5 ± 6.4% of standard deviation (range 86.0-100.0%), respectively. No statistically significant difference in summarized accuracy mean value between CXR and CT was observed using the Chi square test (p value > 0.05). CONCLUSIONS: Summarized accuracy of the selected papers is high but there was an important variability; however, less in CT studies compared to CXR studies. Nonetheless, AI approaches could be used in the identification of disease clusters, monitoring of cases, prediction of the future outbreaks, mortality risk, COVID-19 diagnosis, and disease management.

Organ Sparing for Locally Advanced Rectal Cancer after Neoadjuvant Treatment Followed by Electrochemotherapy.

BACKGROUND: Currently, 45-55% of rectal cancer patients receive preoperative chemo- radio-therapy for Locally Advanced Rectal Cancer (LARC). The idea of our study is to use Electrochemotherapy (ECT) before surgery, in patients with major clinical response after neoadjuvant therapy, to allow for a more conservative surgical approach. OBJECTIVE: To evaluate the increase of the complete response rate after neoadjuvant treatment in LARC and to spare organ function due to total mesorectal excision (TME). PATIENTS AND METHODS: This is a Phase II randomized controlled trial enrolling 70 patients that will be developed in two stages. In the first step, 28 patients will be enrolled: 14 of these will receive ECT for four weeks after neo-adjuvant treatment and then local excision (treatment group) and 14 patients will receive neo-adjuvant treatment and then local excision (control group). If an increase of response rate is observed in the first stage, and/or feasibility/safety is demonstrated, the second stage of the trial will be performed, enrolling an additional 42 patients. The treatment response. in both the control arm and the treatment arm, will be assessed using the histopathological tumor regression grade on tissue specimens after local excision.

Treatment of splenic flexure colon cancer: a comparison of three different surgical procedures: Experience of a high volume cancer center.

Extended right or left hemicolectomy are the most common surgical treatments for splenic flexure colon cancer. Extended resection (including distal pancreasectomy and/or splenectomy), has been often indicated for the treatment for the splenic flexure cancer, because the lymphatic drainage at this site is poorly defined and assumed as heterogeneous. Between January 2006 and May 2016, 103 patients with splenic flexure colon cancer were enrolled in the study. We evaluated the clinicopathological findings and outcomes of all patients and associated them to the different surgical treatment. Out of 103 selected cases an extended right hemicolectomy was performed in 22 (21.4%) patients, an extended left hemicolectomy in 24 (23.3%) patients, a segmental resection of the splenic flexure in 57 (55.3%) patients; the combined resection of adjacent organs showing tumor adherence was carried out in 11 (10.7%) patients. The tumor infiltrated near organs (T4) in 5 patients. No significant differences in complications were found among the three groups. In all groups no differences were found in the total number of harvested lymphnodes. After a median follow-up of 42 months, 30 recurrences and 19 deaths occurred (12 for tumor progression). There was no difference in overall and progression free survival among the three different surgical treatments. According to our results, the partial resection of splenic flexure was not associated with a worse prognosis and it was leading for a satisfactory oncological outcome. It is our opinion that the extended surgery is seldomly indicated to cure splenic flexure cancer.

Diffusion and perfusion MR parameters to assess preoperative short-course radiotherapy response in locally advanced rectal cancer: a comparative explorative study among Standardized Index of Shape by DCE-MRI, intravoxel incoherent motion- and diffusion kurtosis imaging-derived parameters.

PURPOSE: To assess preoperative short-course radiotherapy (SCR) tumor response in locally advanced rectal cancer (LARC) by means of Standardized Index of Shape (SIS) by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) parameters derived from diffusion-weighted MRI (DW-MRI). MATERIALS AND METHODS: Thirty-four patients with LARC who underwent MRI scans before and after SCR followed by delayed surgery, retrospectively, were enrolled. SIS, ADC, IVIM parameters [tissue diffusion (Dt), pseudo-diffusion (Dp), perfusion fraction (fp)] and DKI parameters [mean diffusivity (MD), mean of diffusional kurtosis (MK)] were calculated for each patient. IVIM parameters were estimated using two methods, namely conventional biexponential fitting (CBFM) and variable projection (VARPRO). After surgery, the pathological TNM and tumor regression grade (TRG) were estimated. For each parameter, percentage changes between before and after SCR were evaluated. Furthermore, an artificial neural network was trained for outcome prediction. Nonparametric sample tests and receiver operating characteristic curve (ROC) analysis were performed. RESULTS: Fifteen patients were classified as responders (TRG ≤ 2) and 19 as not responders (TRG > 3). Seven patients had TRG 1 (pathological complete response, pCR). Mean and standard deviation values of pre-treatment CBFM Dp and mean value of VARPRO Dp pre-treatment showed statistically significant differences to predict pCR. (p value at Mann-Whitney test was 0.05, 0.03 and 0.008, respectively.) Exclusively SIS percentage change showed significant differences between responder and non-responder patients after SCR (p value << 0.001) and to assess pCR after SCR (p value << 0.001). The best results to predict pCR were obtained by VARPRO Fp mean value pre-treatment with area under ROC of 0.84, a sensitivity of 96.4%, a specificity of 71.4%, a positive predictive value (PPV) of 92.9%, a negative predictive value (NPV) of 83.3% and an accuracy of 91.2%. The best results to assess after treatment complete pathological response were obtained by SIS with an area under ROC of 0.89, a sensitivity of 85.7%, a specificity of 92.6%, a PPV of 75.0%, a NPV of 96.1% and an accuracy of 91.2%. Moreover, the best results to differentiate after treatment responders vs. non-responders were obtained by SIS with an area under ROC of 0.94, a sensitivity of 93.3%, a specificity of 84.2%, a PPV of 82.4%, a NPV of 94.1% and an accuracy of 88.2%. Promising initial results were obtained using a decision tree tested with all ADC, IVIM and DKI extracted parameter: we reached high accuracy to assess pathological complete response after SCR in LARC (an accuracy of 85.3% to assess pathological complete response after SCR using VARPRO Dp mean value post-treatment, ADC standard deviation value pre-treatment, MD standard deviation value post-treatment). CONCLUSION: SIS is a hopeful DCE-MRI angiogenic biomarker to assess preoperative treatment response after SCR with delayed surgery. Furthermore, an important prognostic role was obtained by VARPRO Fp mean value pre-treatment and by a decision tree composed by diffusion parameters derived by DWI and DKI to assess pathological complete response.

18F-FDG PET/CT Is an Early Predictor of Pathologic Tumor Response and Survival After Preoperative Radiochemotherapy with Bevacizumab in High-Risk Locally Advanced Rectal Cancer.

There is an unmet need for predictive biomarkers of the clinical benefit of antiangiogenic drugs. The aim of the present study was to prospectively evaluate the value of 18F-FDG PET/CT performed during and after preoperative chemoradiotherapy with bevacizumab for the prediction of complete pathologic tumor regression and survival in patients with MRI-defined high-risk locally advanced rectal cancer. Methods: Sixty-one patients treated in a nonrandomized phase II study (BRANCH) with concomitant or sequential (4 d before chemoradiotherapy) administration of bevacizumab with preoperative chemoradiotherapy were included. 18F-FDG PET/CT was performed at baseline, 11 d after the beginning of chemoradiotherapy (early), and before surgery (late). Metabolic changes were compared with pathologic complete tumor regression (TRG1) versus incomplete tumor regression (TRG2-TRG5), progression-free survival, cancer-specific survival, and overall survival. Receiver-operating-characteristic curves were calculated for those 18F-FDG PET/CT parameters that significantly correlated with TRG1. Results: Early total-lesion glycolysis and its percentage change compared with baseline (ΔTLG-early) could discriminate TRG1 from TRG2-TRG5. Only receiver-operating-characteristic analysis of ΔTLG-early showed an area under the curve greater than 0.7 (0.76), with an optimal cutoff at 59.5% (80% sensitivity, 71.4% specificity), for identifying TRG1. Late metabolic assessment could not discriminate between the 2 groups. After a median follow-up of 98 mo (range, 77-132 mo), metabolic responders (ΔTLG-early ≥ 59.5%) demonstrated a significantly higher 10-y progression-free survival (89.3% vs. 63.6%, P = 0.02) and cancer-specific survival (92.9% vs. 72.6%, P = 0.04) than incomplete metabolic responders. Conclusion: Our results suggest that early metabolic response can act as a surrogate marker of the benefit of antiangiogenic therapy. The findings provide further support for the use of early 18F-FDG PET/CT evaluation to predict pathologic response and survival in the preoperative treatment of patients with locally advanced rectal cancer. ΔTLG-early showed the best accuracy in predicting tumor regression and may be particularly useful in guiding treatment-modifying decisions during preoperative chemoradiotherapy based on expected response.

Assessing response to neo-adjuvant therapy in locally advanced rectal cancer using Intra-voxel Incoherent Motion modelling by DWI data and Standardized Index of Shape from DCE-MRI.

BACKGROUND: Our aim was to investigate preoperative chemoradiation therapy (pCRT) response in locally advanced rectal cancer (LARC) comparing standardized index of shape (SIS) obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with intravoxel-incoherent-motion-modelling-derived parameters by diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Eighty-eight patients with LARC were subjected to MRI before and after pCRT. Apparent diffusion coefficient (ADC), tissue diffusion (Dt), pseudodiffusion (Dp) and perfusion fraction (f) were calculated and percentage changes ∆ADC, ∆Dt, ∆Dp, ∆f were computed. SIS was derived comparing DCE-MRI pre- and post-pCRT. Nonparametric tests and receiver operating characteristic (ROC) curves were performed. RESULTS: A total of 52 patients were classified as responders (tumour regression grade; TRG ⩽ 2) and 36 as not-responders (TRG > 3). Mann-Whitney U test showed statistically significant differences in SIS, ∆ADC and ∆Dt between responders and not-responders and between complete responders (19 patients with TRG = 1) versus incomplete responders. The best parameters to discriminate responders by nonresponders were SIS and ∆ADC, with an accuracy of 91% and 82% (cutoffs of -5.2% and 18.7%, respectively); the best parameters to detect pathological complete responders were SIS, ∆f and ∆Dp with an accuracy of 78% (cutoffs of 38.5%, 60.0% and 83.0%, respectively). No increase of performance was observed by combining linearly each possible couple of parameters or combining all parameters. CONCLUSION: SIS allows assessment of preoperative treatment response with high accuracy guiding the surgeon versus more or less conservative treatment. DWI-derived parameters reached less accuracy compared with SIS and combining linearly DCE- and DWI-derived parameters; no increase of accuracy was obtained.

DCE-MRI time-intensity curve visual inspection to assess pathological response after neoadjuvant therapy in locally advanced rectal cancer.

PURPOSE: To investigate the potential of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to discriminate responder from non-responder patients after preoperative chemoradiotherapy (pCRT) in locally advanced rectal cancer (LARC). MATERIALS AND METHODS: One hundred and fifty-eight consecutive patients were enrolled in this prospective study. We compared morphological MRI (mMRI) using T2-weighted images about tumor presence and invasiveness, and functional DCE-MRI using time-intensity curve (TIC) visual inspection (qMRI), classifying TIC shape into three types: type 1, persistent enhancement; type 2, high enhancement with plateau; type 3, high enhancement with wash-out. Clinical TNM was obtained before and after CRT by radiological consensus of two expert radiologists. Pathological tumor-nodes-metastasis classification and tumor regression grade (TRG) were confirmed as the golden standard. Non-parametric test, sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: Ninety-eight patients (62%) were classified as responders (TRG ≤ 2), while 60 (38%) were classified as non-responders. Sensitivity, specificity, and accuracy were 52, 78, and 62% for mMRI, and 81, 85, and 82% for qMRI, respectively. CONCLUSIONS: TIC visual inspection may be one of the potential biomarkers over morphological analysis using DCE-MRI data to assess pathological response after pCRT in LARC.

MR imaging perfusion and diffusion analysis to assess preoperative Short Course Radiotherapy response in locally advanced rectal cancer: Standardized Index of Shape by DCE-MRI and intravoxel incoherent motion-derived parameters by DW-MRI.

Our aim is to assess preoperative Short Course Radiotherapy (SCR) tumor response in locally advanced rectal cancer (LARC) through Standardized Index of Shape (SIS) by DCE-MRI, apparent diffusion coefficient (ADC) and intravoxel incoherent motion-derived parameters by DW-MRI. 35 patients with LARC underwent MR scan before and after SCR followed by delayed surgery, retrospectively, were enrolled. SIS, ADC, tissue diffusion (D t), pseudodiffusion (D p), and perfusion fraction (f) were extracted by MRI for each patient before and after SCR. Tumor regression grade (TRG) was estimated. Receiver operating characteristic curve and linear classification were performed. Sixteen patients were classified as responders (TRG ≤ 2) and 19 as non-responders. Seven patients had TRG1 [pathological complete response (pCR)]. The best parameter to discriminate responders by non-responders was SIS (sensitivity 94%, specificity 84%, accuracy 89%, cutoff value = - 7.8%). SIS obtained the best diagnostic performance also to discriminate pCR (sensitivity 86%, specificity 89%, accuracy 89%, cutoff value = 68.2%). No accuracy increase was obtained combining linearly each possible parameters couple or all functional MR-derived parameters. SIS is a hopeful DCE-MRI angiogenic biomarker to assess preoperative treatment response after SCR with delayed surgery, and it permits to discriminate pCR allowing to direct surgery for tailored and conservative treatment.

Synergistic antitumor interaction between valproic acid, capecitabine and radiotherapy in colorectal cancer: critical role of p53.

BACKGROUND: Recurrence with distant metastases has become the predominant pattern of failure in locally advanced rectal cancer (LARC), thus the integration of new antineoplastic agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to implement an intensified therapeutic strategy. The present study examined the combination of the histone deacetylase inhibitor (HDACi) valproic acid (VPA) with fluoropyrimidine-based chemo-radiotherapy on colorectal cancer (CRC) cells. METHODS: HCT-116 (p53-wild type), HCT-116 p53-/- (p53-null), SW620 and HT29 (p53-mutant) CRC cell lines were used to assess the antitumor interaction between VPA and capecitabine metabolite 5'-deoxy-5-fluorouridine (5'-DFUR) in combination with radiotherapy and to evaluate the role of p53 in the combination treatment. Effects on proliferation, clonogenicity and apoptosis were evaluated, along with γH2AX foci formation as an indicator for DNA damage. RESULTS: Combined treatment with equipotent doses of VPA and 5'-DFUR resulted in synergistic effects in CRC lines expressing p53 (wild-type or mutant). In HCT-116 p53-/- cells we observed antagonist effects. Radiotherapy further potentiated the antiproliferative, pro-apoptotic and DNA damage effects induced by 5'-DFUR/VPA combination in p53 expressing cells. CONCLUSIONS: These results highlighted the role of VPA as valuable candidate to be added to preoperative chemo-radiotherapy in LARC. On these bases we launched the ongoing phase I/II study of VPA and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer (V-shoRT-R3).

Standardized Index of Shape (DCE-MRI) and Standardized Uptake Value (PET/CT): Two quantitative approaches to discriminate chemo-radiotherapy locally advanced rectal cancer responders under a functional profile.

PURPOSE: To investigate dynamic contrast enhanced-MRI (DCE-MRI) in the preoperative chemo-radiotherapy (CRT) assessment for locally advanced rectal cancer (LARC) compared to18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). METHODS: 75 consecutive patients with LARC were enrolled in a prospective study. DCE-MRI analysis was performed measuring SIS: linear combination of percentage change (Δ) of maximum signal difference (MSD) and wash-out slope (WOS). 18F-FDG PET/CT analysis was performed using SUV maximum (SUVmax). Tumor regression grade (TRG) were estimated after surgery. Non-parametric tests, receiver operating characteristic were evaluated. RESULTS: 55 patients (TRG1-2) were classified as responders while 20 subjects as non responders. ΔSIS reached sensitivity of 93%, specificity of 80% and accuracy of 89% (cut-off 6%) to differentiate responders by non responders, sensitivity of 93%, specificity of 69% and accuracy of 79% (cut-off 30%) to identify pathological complete response (pCR). Therapy assessment via ΔSUVmax reached sensitivity of 67%, specificity of 75% and accuracy of 70% (cut-off 60%) to differentiate responders by non responders and sensitivity of 80%, specificity of 31% and accuracy of 51% (cut-off 44%) to identify pCR. CONCLUSIONS: CRT response assessment by DCE-MRI analysis shows a higher predictive ability than 18F-FDG PET/CT in LARC patients allowing to better discriminate significant and pCR.