Predictive significance of FGFR4 p.G388R polymorphism in metastatic colorectal cancer patients receiving trifluridine/tipiracil (TAS-102) treatment.

BACKGROUND: TAS-102 (Lonsurf®) is an oral fluoropyrimidine consisting of a combination of trifluridine (a thymidine analog) and tipiracil (a thymidine phosphorylation inhibitor). The drug is effective in metastatic colorectal cancer (mCRC) patients refractory to fluorouracil, irinotecan and oxaliplatin. This study is a real-world analysis, investigating the interplay of genotype/phenotype in relation to TAS-102 sensitivity. METHODS: Forty-seven consecutive mCRC patients were treated with TAS-102 at the National Cancer Institute of Naples from March 2019 to March 2021, at a dosage of 35 mg/m2, twice a day, in cycles of 28 days (from day 1 to 5 and from day 8 to 12). Clinical-pathological parameters were described. Activity was evaluated with RECIST criteria (v1.1) and toxicity with NCI-CTC (v5.0). Survival was depicted through the Kaplan-Meyer curves. Genetic features of patients were evaluated with Next Generation Sequencing (NGS) through the Illumina NovaSeq 6000 platform and TruSigt™Oncology 500 kit. RESULTS: Median age of patients was 65 years (range: 46-77). Forty-one patients had 2 or more metastatic sites and 38 patients underwent to more than 2 previous lines of therapies. ECOG (Eastern Cooperative Oncology Group) Performance Status (PS) was 2 in 19 patients. The median number of TAS-102 cycles was 4 (range: 2-12). The most frequent toxic event was neutropenia (G3/G4 in 16 patients). There were no severe (> 3) non-haematological toxicities or treatment-related deaths. Twenty-six patients experienced progressive disease (PD), 21 stable disease (SD). Three patients with long-lasting disease control (DC: complete, partial responses or stable disease) shared an FGFR4 (p.Gly388Arg) mutation. Patients experiencing DC had more frequently a low tumour growth rate (P = 0.0306) and an FGFR4 p.G388R variant (P < 0.0001). The FGFR4 Arg388 genotype was associated with better survival (median: 6.4 months) compared to the Gly388 genotype (median: 4 months); the HR was 0.25 (95% CI 0.12- 0.51; P = 0.0001 at Log-Rank test). CONCLUSIONS: This phenotype/genotype investigation suggests that the FGFR4 p.G388R variant may serve as a new marker for identifying patients who are responsive to TAS-102. A mechanistic hypothesis is proposed to interpret these findings.

Circulating vitamin D level before initiating chemotherapy impacts on the time-to-outcome in metastatic colorectal cancer patients: systematic review and meta-analysis.

BACKGROUND: Vitamin D (VD) is implicated in various health conditions, including colorectal cancer (CRC). To investigate potential relationships between pre-chemotherapy VD levels and the time-to-outcome in metastatic CRC patients, we conducted a systematic review and meta-analysis. METHODS: Following the PRISMA 2020 guidelines, we performed thorough searches in PubMed/MEDLINE and Scopus/ELSEVIER databases (covering the years 2002 to 2022). Inclusion criteria mandated studies to report on individuals aged 18 years and above with histologically confirmed stage IV CRC. Additionally, studies needed to provide data on VD levels before chemotherapy, along with hazard ratios (HR) and 95% confidence intervals (CIs) for overall survival (OS) and/or progression-free survival (PFS). Five articles were identified with the aim of establishing a combined risk estimate for death and progression based on pre-chemotherapy VD levels. Heterogeneity among studies and publication bias were evaluated using Tau2, I2 statistics, and a Funnel plot. RESULTS: Although no significant heterogeneity was observed in time-to-outcome among the selected studies, variations in technical assessments and serum VD concentration measurements were noted. The pooled analysis, involving 1712 patients for OS and 1264 patients for PFS, revealed a 47% increased risk of death (HR: 1.47, 95% CI: 1.21-1.79) and a 38% increased risk of progression (HR: 1.38, 95% CI: 1.13-1.70) for patients with lower VD levels, as indicated by fixed-effects models. CONCLUSIONS: Our results emphasize the adverse effects of low VD concentration on the time-to-outcome in metastatic CRC patients. This underscores the importance of investigating VD supplementation as an innovative approach in this clinical setting to enhance patient outcomes.

Intrahepatic cholangiocarcinoma biomarkers: Towards early detection and personalized pharmacological treatments.

Cholangiocarcinoma (CCA) is a rare malignancy originating from the biliary tree and is anatomically categorized as intrahepatic (iCCA), perihilar, and extrahepatic or distal. iCCA, the second most prevalent hepatobiliary cancer following hepatocellular carcinoma (HCC), constitutes 5-20 % of all liver malignancies, with an increasing incidence. The challenging nature of iCCA, combined with nonspecific symptoms, often leads to late diagnoses, resulting in unfavorable outcomes. The advanced phase of this neoplasm is difficult to treat with dismal results. Early diagnosis could significantly reduce mortality attributed to iCCA but remains an elusive goal. The identification of biomarkers specific to iCCA and their translation into clinical practice could facilitate diagnosis, monitor therapy response, and potentially reveal novel interventions and personalized medicine. In this review, we present the current landscape of biomarkers in each of these contexts. In addition to CA19.9, a widely recognized biomarker for iCCA, others such as A1BG, CYFRA 21-1, FAM19A5, MMP-7, RBAK, SSP411, TuM2-PK, WFA, etc., as well as circulating tumor DNA, RNA, cells, and exosomes, are under investigation. Advancing our knowledge and monitoring of biomarkers may enable us to improve diagnosis, prognostication, and apply treatments dynamically and in a more personalized manner.

Oligo-metastatic neoPlasms from the gastro-intestinal tract: iDentIfiCaTIon of cliNical and molecular drivers: the PREDICTION study.

BACKGROUND: Metastatic disease in tumors originating from the gastrointestinal tract can exhibit varying degrees of tumor burden at presentation. Some patients follow a less aggressive disease course, characterized by a limited number of metastatic sites, referred to as "oligo-metastatic disease" (OMD). The precise biological characteristics that define the oligometastatic behavior remain uncertain. In this study, we present a protocol designed to prospectively identify OMD, with the aim of proposing novel therapeutic approaches and monitoring strategies. METHODS: The PREDICTION study is a monocentric, prospective, observational investigation. Enrolled patients will receive standard treatment, while translational activities will involve analysis of the tumor microenvironment and genomic profiling using immunohistochemistry and next-generation sequencing, respectively. The first primary objective (descriptive) is to determine the prevalence of biological characteristics in OMD derived from gastrointestinal tract neoplasms, including high genetic concordance between primary tumors and metastases, a significant infiltration of T lymphocytes, and the absence of clonal evolution favoring specific driver genes (KRAS and PIK3CA). The second co-primary objective (analytic) is to identify a prognostic score for true OMD, with a primary focus on metastatic colorectal cancer. The score will comprise genetic concordance (> 80%), high T-lymphocyte infiltration, and the absence of clonal evolution favoring driver genes. It is hypothesized that patients with true OMD (score 3+) will have a lower rate of progression/recurrence within one year (20%) compared to those with false OMD (80%). The endpoint of the co-primary objective is the rate of recurrence/progression at one year. Considering a reasonable probability (60%) of the three factors occurring simultaneously in true OMD (score 3+), using a significance level of α = 0.05 and a test power of 90%, the study requires a minimum enrollment of 32 patients. DISCUSSION: Few studies have explored the precise genetic and biological features of OMD thus far. In clinical settings, the diagnosis of OMD is typically made retrospectively, as some patients who undergo intensive treatment for oligometastases develop polymetastatic diseases within a year, while others do not experience disease progression (true OMD). In the coming years, the identification of true OMD will allow us to employ more personalized and comprehensive strategies in cancer treatment. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05806151.

Radiomics textural features by MR imaging to assess clinical outcomes following liver resection in colorectal liver metastases.

PURPOSE: To assess the efficacy of radiomics features obtained by T2-weighted sequences to predict clinical outcomes following liver resection in colorectal liver metastases patients. METHODS: This retrospective analysis was approved by the local Ethical Committee board and radiological databases were interrogated, from January 2018 to May 2021, to select patients with liver metastases with pathological proof and MRI study in pre-surgical setting. The cohort of patients included a training set and an external validation set. The internal training set included 51 patients with 61 years of median age and 121 liver metastases. The validation cohort consisted a total of 30 patients with single lesion with 60 years of median age. For each volume of interest, 851 radiomics features were extracted as median values using PyRadiomics. Nonparametric test, intraclass correlation, receiver operating characteristic (ROC) analysis, linear regression modelling and pattern recognition methods (support vector machine (SVM), k-nearest neighbours (KNN), artificial neural network (NNET) and decision tree (DT)) were considered. RESULTS: The best predictor to discriminate expansive versus infiltrative front of tumour growth was obtained by wavelet_LHL_gldm_DependenceNonUniformityNormalized with an accuracy of 82%; to discriminate high grade versus low grade or absent was the wavelet_LLH_glcm_Imc1 with accuracy of 88%; to differentiate the mucinous type of tumour was the wavelet_LLH_glcm_JointEntropy with accuracy of 92% while to identify tumour recurrence was the wavelet_LLL_glcm_Correlation with accuracy of 85%. Linear regression model increased the performance obtained with respect to the univariate analysis exclusively in the discrimination of expansive versus infiltrative front of tumour growth reaching an accuracy of 90%, a sensitivity of 95% and a specificity of 80%. Considering significant texture metrics tested with pattern recognition approaches, the best performance was reached by the KNN in the discrimination of the tumour budding considering the four textural predictors obtaining an accuracy of 93%, a sensitivity of 81% and a specificity of 97%. CONCLUSIONS: Ours results confirmed the capacity of radiomics to identify as biomarkers, several prognostic features that could affect the treatment choice in patients with liver metastases, in order to obtain a more personalized approach.

Radiomics and machine learning analysis based on magnetic resonance imaging in the assessment of liver mucinous colorectal metastases.

PURPOSE: The purpose of this study is to evaluate the Radiomics and Machine Learning Analysis based on MRI in the assessment of Liver Mucinous Colorectal Metastases.Query METHODS: The cohort of patients included a training set (121 cases) and an external validation set (30 cases) with colorectal liver metastases with pathological proof and MRI study enrolled in this approved study retrospectively. About 851 radiomics features were extracted as median values by means of the PyRadiomics tool on volume on interest segmented manually by two expert radiologists. Univariate analysis, linear regression modelling and pattern recognition methods were used as statistical and classification procedures. RESULTS: The best results at univariate analysis were reached by the wavelet_LLH_glcm_JointEntropy extracted by T2W SPACE sequence with accuracy of 92%. Linear regression model increased the performance obtained respect to the univariate analysis. The best results were obtained by a linear regression model of 15 significant features extracted by the T2W SPACE sequence with accuracy of 94%, a sensitivity of 92% and a specificity of 95%. The best classifier among the tested pattern recognition approaches was k-nearest neighbours (KNN); however, KNN achieved lower precision than the best linear regression model. CONCLUSIONS: Radiomics metrics allow the mucinous subtype lesion characterization, in order to obtain a more personalized approach. We demonstrated that the best performance was obtained by T2-W extracted textural metrics.

Evolution of Treatment in Advanced Cholangiocarcinoma: Old and New towards Precision Oncology.

Cholangiocarcinoma (CCA) is a malignant neoplasm arising in the epithelium of the biliary tract. It represents the second most common primary liver cancer in the world, after hepatocellular carcinoma, and it constitutes 10-15% of hepatobiliary neoplasms and 3% of all gastrointestinal tumors. As in other types of cancers, recent studies have revealed genetic alterations underlying the establishment and progression of CCA. The most frequently involved genes are APC, ARID1A, AXIN1, BAP1, EGFR, FGFRs, IDH1/2, RAS, SMAD4, and TP53. Actionable targets include alterations of FGFRs, IDH1/2, BRAF, NTRK, and HER2. "Precision oncology" is emerging as a promising approach for CCA, and it is possible to inhibit the altered function of these genes with molecularly oriented drugs (pemigatinib, ivosidenib, vemurafenib, larotrectinib, and trastuzumab). In this review, we provide an overview of new biologic drugs (their structures, mechanisms of action, and toxicities) to treat metastatic CCA, providing readers with panoramic information on the trajectory from "old" chemotherapies to "new" target-oriented drugs.

Intrahepatic cholangiocarcinoma and its differential diagnosis at MRI: how radiologist should assess MR features.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary hepatic malignancy. Aim of this work is to analyse the features of ICC and its differential diagnosis at MRI, assessing two categories intraparenchymal and peribiliary lesions. METHODS: The study population included 88 patients with histological diagnosis of ICCs: 61 with mass-forming type, 23 with periductal-infiltrating tumours and 4 with intraductal-growing type. As a control study groups, we identified: 86 consecutive patients with liver colorectal intrahepatic metastases (mCRC) (groups A); 35 consecutive patients with peribiliary metastases (groups B); 62 consecutive patients (groups C) with hepatocellular carcinoma (HCC); 18 consecutive patients (groups D) with combined hepatocellular cholangiocarcinoma (cHCC-CCA); and 26 consecutive patients (groups E) with hepatic hemangioma. For all lesions, magnetic resonance (MR) features were assessed according to Liver Imaging Reporting and Data System (LI-RADS) version 2018. The liver-specific gadolinium ethoxybenzyl dimeglumine-EOB (Primovist, Bayer Schering Pharma, Germany), was employed. Chi-square test was employed to analyse differences in percentage values of categorical variable, while the nonparametric Kruskal-Wallis test was used to test for statistically significant differences between the median values of the continuous variables. However, false discovery rate adjustment according to Benjamin and Hochberg for multiple testing was considered. RESULTS: T1- and T2-weighted signal intensity (SI), restricted diffusion, transitional phase (TP) and hepatobiliary phase (HP) aspects allowed the differentiation between study group (mass-forming ICCs) and each other control group (A, C, D, E) with statistical significance, while arterial phase (AP) appearance allowed the differentiation between study group and the control groups C and D with statistical significance and PP appearance allowed the differentiation between study group and the control groups A, C and D with statistical significance. Instead, no MR feature allowed the differentiation between study group (periductal-infiltrating type) and control group B. CONCLUSION: T1 and T2 W SI, restricted diffusion, TP and HP appearance allowed the differentiation between mass-forming ICCs and mimickers with statistical significance, while AP appearance allowed the differentiation between study group and the control groups C and D with statistical significance and PP appearance allowed the differentiation between study group and the control groups A, C and D.

Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated - NIVACOR trial (GOIRC-03-2018).

BACKGROUND: FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab has shown to be one of the therapeutic regimens in first line with the highest activity in patients (pts.) with metastatic colorectal cancer (mCRC) unselected for biomolecular alterations. Generally, tumors co-opt the programmed death-1/ligand 1 (PD-1/PD-L1) signaling pathway as one key mechanism to evade immune surveillance. As today, anti-PD-1 monoclonal antibodies are FDA approved only for DNA mismatch repair deficient/microsatellite instability-high (MMRd/MSI-H), which represent only about 5% among all mCRC. Nowadays, there are no data demonstrating anti PD-1 activity in proficient and stable disease (MMRp/MSS). A different target in mCRC is also the Vascular Endothelial Growth Factor A (VEGF-A), which acts on endothelial cells to stimulate angiogenesis. VEGF-A inhibition with bevacizumab has shown to increase the immune cell infiltration, providing a solid rationale for combining VEGF targeted agents with immune checkpoint inhibitors. Based on these evidences, we explore the combination of triplet chemotherapy (FOLFOXIRI) with bevacizumab and nivolumab in pts. with mCRC RAS/BRAF mutant regardless of microsatellite status. METHODS/DESIGN: This is a prospective, open-label, multicentric phase II trial where pts. with mCRC RAS/BRAF mutated, in first line will receive nivolumab in combination with FOLFOXIRI/bevacizumab every 2 weeks for 8 cycles followed by maintenance with bevacizumab plus nivolumab every 2 weeks. Bevacizumab will be administered intravenously at dose of 5 mg/kg every 2 weeks and nivolumab intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint is the overall response rate (ORR). This study hypothesis is that the treatment is able to improve the ORR from 66 to 80%. Secondary endpoints include OS, safety, time to progression, duration of response. Collateral translational studies evaluate the i) tumor mutational burden, and ii) genetic alterations by circulating free DNA (cfDNA) obtained from plasma samples. The trial is open to enrollment, 9 of planned 70 pts. have been enrolled. TRIAL REGISTRATION: NIVACOR is registered at ClinicalTrials.gov: NCT04072198 , August 28, 2019.

FGFR Fusions in Cancer: From Diagnostic Approaches to Therapeutic Intervention.

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors involved in many biological processes. Deregulated FGFR signaling plays an important role in tumor development and progression in different cancer types. FGFR genomic alterations, including FGFR gene fusions that originate by chromosomal rearrangements, represent a promising therapeutic target. Next-generation-sequencing (NGS) approaches have significantly improved the discovery of FGFR gene fusions and their detection in clinical samples. A variety of FGFR inhibitors have been developed, and several studies are trying to evaluate the efficacy of these agents in molecularly selected patients carrying FGFR genomic alterations. In this review, we describe the most frequent FGFR aberrations in human cancer. We also discuss the different approaches employed for the detection of FGFR fusions and the potential role of these genomic alterations as prognostic/predictive biomarkers.

Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol.

BACKGROUND: Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients' selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity. METHODS/DESIGN: CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses' duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients' cetuximab-mediated ADCC and characterize the tumor microenvironment. DISCUSSION: The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results' interpretation as well as provide new insights in host-tumor interactions and cetuximab activity. TRIAL REGISTRATION: The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number ( NCT03874062 ).

A radiologist's point of view in the presurgical and intraoperative setting of colorectal liver metastases.

Multidisciplinary management of patients with metastatic colorectal cancer requires in each phase an adequate choice of the most appropriate imaging modality. The first challenging step is liver lesions detection and characterization, using several imaging modality ultrasound, computed tomography, magnetic resonance and positron emission tomography. The criteria to establish the metastases resectability have been modified. Not only the lesions number and site but also the functional volume remnant after surgery and the quality of the nontumoral liver must be taken into account. Radiologists should identify the liver functional volume remnant and during liver surgical procedures should collaborate with the surgeon to identify all lesions, including those that disappeared after the therapy, using intraoperative ultrasound with or without contrast medium.

Hyaluronic Acid Nanohydrogel Loaded With Quercetin Alone or in Combination to a Macrolide Derivative of Rapamycin RAD001 (Everolimus) as a New Treatment for Hormone-Responsive Human Breast Cancer.

The aim of this study is based on the evaluation of anticancer, anti-inflammatory activities, and cellular uptake of hyaluronic acid nanohydrogel of quercetin tested alone and in combination to a macrolide derivative of rapamycin RAD001 (everolimus) on hormone-responsive breast cancer cell line MCF-7. Biological investigations were focused on the receptor mediated cellular internalization of the nanohydrogel and its abilities to reduce secretion of several cytokines (IL-8, IL-6, IL-19), VEGF, and metalloproteases (MMP-2, MMP-9) under pro-inflammatory conditions. Nanohydrogel show a CD44 dependent endocytosis with evident time dependent cytoplasmatic accumulation with abilities to reduce secretion of all cytokines of ∼60% compared to untreated cells. Combination of formulated quercetin and everolimus leads to a synergistic cytotoxic effects with a Combination Index of 0.38. These results highlights the importance of synergistic effect of the hyaluronic acid nanohydrogel of quercetin with everolimus in the regulation of human breast cancer cell proliferation and emphasize the antitumor and anti-inflammatory properties of the nanocarrier. J. Cell. Physiol. 232: 2063-2074, 2017. © 2016 Wiley Periodicals, Inc.

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti-BIL study).

BACKGROUND: Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression. METHODS: This open-label, randomized phase 2 trial recruited chemotherapy-naive patients with advanced BTC displaying a wild-type (WT) KRAS status. Patients were randomized to gemcitabine (1000 mg/m(2) ) and oxaliplatin (100 mg/m(2) ) with (arm A) or without (arm B) panitumumab (6 mg/kg) for up to 12 cycles. The primary endpoint was progression-free survival (PFS) analyzed in an intention-to-treat fashion. RESULTS: Eighty-nine patients (45 in arm A and 44 in arm B) were enrolled between June 2010 and September 2013. After a median follow-up of 10.1 months, the median PFS was 5.3 months (95% confidence interval, 3.3-7.2 months) in arm A and 4.4 months (95% confidence interval, 2.6-6.2 months) in arm B (P = .27). No survival differences were observed: the median overall survival was 9.9 months in arm A and 10.2 months in arm B (P = .42). In a subgroup analysis, no differences in PFS according to the site of the primary tumor were observed; patients with intrahepatic cholangiocarcinoma treated with panitumumab may have had a survival benefit in comparison with the control group (15.1 vs 11.8 months, P = .13). As for safety, skin toxicity was the main adverse event in arm A (80% of the patients). A higher incidence of diarrhea (55.5% vs 31.8%), mucositis (22.2% vs 13.6%), and constipation (24.4% vs 15.9%) was seen in arm A. CONCLUSIONS: These results confirm the marginal role of anti-EGFR therapy even for WT KRAS-selected BTC.

Diabetes and Body Mass Index Are Associated with Neuropathy and Prognosis in Colon Cancer Patients Treated with Capecitabine and Oxaliplatin Adjuvant Chemotherapy.

BACKGROUND: There are few background data on the impact of clinical factors on neurotoxicity and prognosis in patients treated with adjuvant capecitabine and oxaliplatin (CAPOX) chemotherapy. METHODS: 102 stage II high-risk and stage III colorectal cancer patients were treated for 6 months with adjuvant CAPOX, then they were followed up. Associations between clinical variables, metabolic syndrome components, smoking and neurotoxicity were evaluated by the x03C7;2 test. The Kaplan-Meier product limit method was applied to graph disease-free survival (DFS). Univariate analysis was done with the log-rank test. Cox's proportional hazards regression was used to analyze the effect of several risk factors on DFS. RESULTS: Significant associations were found between diabetes (p < 0.001), BMI (p = 0.01) and the occurrence of chronic neurotoxicity. After a median follow-up of 46 months, 14 patients (13.7%) had suffered recurrence. An analysis of the prognostic factors for DFS showed that prognosis is unfavorable for patients with high lymph-nodal involvement (HR: 5.23, p = 0.0007), diabetes (HR: 4.86; p = 0.03) and a BMI ≥25 (HR: 3.69, p = 0.002). DISCUSSION: Common mediators in diabetes and obesity could be involved in peripheral neuropathy and in stimulating micro-metastases. Further studies are necessary to explain this interesting connection between diabetes, obesity and colon cancer.

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.

The target sign in colorectal liver metastases: an atypical Gd-EOB-DTPA "uptake" on the hepatobiliary phase of MR imaging.

PURPOSE: To describe the MRI findings in colorectal cancer liver metastases using gadoxetic acid (Gd-EOB-DTPA), with special emphasis on the target feature seen on the hepatobiliary phase. MATERIAL AND METHODS: The medical records of 45 colorectal cancer patients with an overall number of 150 liver metastases were reviewed. All patients underwent Gd-EOB-DTPA-enhanced MRI before any kind of treatment. We retrospectively evaluated, for each lesion, the signal intensity on the T1-weighted, T2-weighted, and diffusion-weighted images. Additionally, the enhancement pattern during the arterial-, portal-, equilibrium-, and hepatobiliary-phase was assessed. Fourteen lesions had a pathological correlation. RESULTS: Lesions size was 5-40 mm (mean 15 mm). All metastases were hypointense on T1-w imaging. Ninety-nine lesions (66%) had a central area of very high signal intensity on T2-w imaging. Fifty-one metastases (34%) were hyperintense on the T2-w images. In DWI, all lesions had a restricted diffusion. The mean ADC value was 1.31 × 10(-3) mm(2)/s (range 1.10-1.45 × 10(-3) mm(2)/s). During the arterial-phase imaging, 61 lesions (41%) showed a rim enhancement, while 89 lesions (59%) appeared as hypointense. All lesions had low signal intensity in the portal and equilibrium phase. Thirty-nine percent of the lesions also showed an enhancing rim on the portal-phase images. During the hepatobiliary phase, 80 lesions (53.3%) were hypointense, while 70 lesions (46.7%) had a target appearance. CONCLUSION: A number of metastases show an atypical contrast medium uptake during the hepatobiliary phase of gadoxetic acid-enhanced MRI, consisting in a target appearance.

Exploring the Spectrum of VEGF Inhibitors' Toxicities from Systemic to Intra-Vitreal Usage in Medical Practice.

The use of Vascular Endothelial Growth Factor inhibitors (VEGFi) has become prevalent in the field of medicine, given the high incidence of various pathological conditions necessitating VEGF inhibition within the general population. These conditions encompass a range of advanced neoplasms, such as colorectal cancer, non-small cell lung cancer, renal cancer, ovarian cancer, and others, along with ocular diseases. The utilization of VEGFi is not without potential risks and adverse effects, requiring healthcare providers to be well-prepared for identification and management. VEGFi can be broadly categorized into two groups: antibodies or chimeric proteins that specifically target VEGF (bevacizumab, ramucirumab, aflibercept, ranibizumab, and brolucizumab) and non-selective and selective small molecules (sunitinib, sorafenib, cabozantinib, lenvatinib, regorafenib, etc.) designed to impede intracellular signaling of the VEGF receptor (RTKi, receptor tyrosine kinase inhibitors). The presentation and mechanisms of adverse effects resulting from VEGFi depend primarily on this distinction and the route of drug administration (systemic or intra-vitreal). This review provides a thorough examination of the causes, recognition, management, and preventive strategies for VEGFi toxicities with the goal of offering support to oncologists in both clinical practice and the design of clinical trials.