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By monitoring ctDNA, the authors reveal the dynamic adaption of clonal populations in colorectal cancer patients treated with anti-EGFR therapy, suggesting that therapeutic re-challenge may have some benefit. Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and clonal evolution. The molecular profile of CRC is routinely assessed in surgical or bioptic samples 1 . Genotyping of CRC tissue has inherent limitations; a tissue sample represents a single snapshot in time, and it is subjected to spatial selection bias owing to tumor heterogeneity. Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy. We exploited circulating tumor DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor (EGFR)-specific antibodies cetuximab or panitumumab. We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes: KRAS , NRAS , MET , ERBB2 , FLT3 , EGFR and MAP2K1. Mutated KRAS clones, which emerge in blood during EGFR blockade, decline upon withdrawal of EGFR-specific antibodies, indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay, whereas the population regains drug sensitivity. ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS . These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade.

Background: Despite great technical advances in imaging, such as multidetector computed tomography and magnetic resonance imaging (MRI), diagnosing pancreatic solid lesions correctly remains challenging, due to overlapping imaging features with benign lesions. We wanted to evaluate functional MRI to differentiate pancreatic tumors, peritumoral inflammatory tissue, and normal pancreatic parenchyma by means of dynamic contrast-enhanced MRI (DCE-MRI)-, diffusion kurtosis imaging (DKI)-, and intravoxel incoherent motion model (IVIM) diffusion-weighted imaging (DWI)-derived parameters. Methods: We retrospectively analyzed 24 patients, each with histopathological diagnosis of pancreatic tumor, and 24 patients without pancreatic lesions. Functional MRI was acquired using a 1.5 MR scanner. Peritumoral inflammatory tissue was assessed by drawing regions of interest on the tumor contours. DCE-MRI, IVIM and DKI parameters were extracted. Nonparametric tests and receiver operating characteristic (ROC) curves were calculated. Results: There were statistically significant differences in median values among the three groups observed by Kruskal–Wallis test for the DKI mean diffusivity (MD), IVIM perfusion fraction (fp) and IVIM tissue pure diffusivity (Dt). MD had the best results to discriminate normal pancreas plus peritumoral inflammatory tissue versus pancreatic tumor, to separate normal pancreatic parenchyma versus pancreatic tumor and to differentiate peritumoral inflammatory tissue versus pancreatic tumor, respectively, with an accuracy of 84%, 78%, 83% and area under ROC curve (AUC) of 0.85, 0.82, 0.89. The findings were statistically significant compared with those of other parameters (p value < 0.05 using McNemar’s test). Instead, to discriminate normal pancreas versus peritumoral inflammatory tissue or pancreatic tumor and to differentiate normal pancreatic parenchyma versus peritumoral inflammatory tissue, there were no statistically significant differences between parameters’ accuracy (p > 0.05 at McNemar’s test). Conclusions: Diffusion parameters, mainly MD by DKI, could be helpful for the differentiation of normal pancreatic parenchyma, perilesional inflammation, and pancreatic tumor.

Lenvatinib is an emerging multi-kinase inhibitor with a preferential anti-angiogenic activity, which has shown efficacy in the treatment of renal cell carcinoma, differentiated thyroid cancer and hepatocellular carcinoma. It inhibits vascular endothelial growth factor receptor family (VEGFR1-3), fibroblast growth factor receptor family (FGFR1-4), platelet-derived growth factor receptor-alpha (PDGFRα), tyrosine-kinase receptor (KIT) and rearranged during transfection receptor (RET). In this review we have evaluated the development from bench to bedside of lenvatinib. PubMed, MEDLINE and clinicaltrials.gov are the sources of data. Furthermore, the preclinical in vitro and in vivo data, as well as efficacy and toxicity results of lenvatinib in the clinic, are presented and discussed. Treatment with lenvatinib causes side effects (hypertension, proteinuria, fatigue and diarrhea), which are predominantly related to the inhibition of angiogenesis. For these reasons, the identification of biomarkers of efficacy and resistance to lenvatinib is a key challenge in order to select responsive patients. This review provides an overview on lenvatinib's clinical use, perspectives and indications for future development.

MRI is the most reliable imaging modality that allows to assess liver metastases. Our purpose is to compare the per-lesion and per-patient detection rate of gadoxetic acid-(Gd-EOB) enhanced liver MRI and fast MR protocol including Diffusion Weighted Imaging (DWI) and T2-W Fat Suppression sequence in the detection of liver metastasis in pre surgical setting. One hundred and eight patients with pathologically proven liver metastases (756 liver metastases) underwent Gd-EOBMRI were enrolled in this study. Three radiologist independently graded the presence of liver lesions on a five-point confidence scale assessed only abbreviated protocol (DWI and sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) fat suppressed sequence) and after an interval of more than 2 weeks the conventional study (all acquired sequences). Per-lesion and per-patient detection rate of metastases were calculated. Weighted к values were used to evaluate inter-reader agreement of the confidence scale regarding the presence of the lesion. MRI detected 732 liver metastases. All lesions were identified both by conventional study as by abbreviated protocol. In terms of per-lesion detection rate of liver metastasis, all three readers had higher detection rate both with abbreviated protocol and with standard protocol with Gd-EOB (96.8% [732 of 756] vs. 96.5% [730 of 756] for reader 1; 95.8% [725 of 756] vs. 95.2% [720 of 756] for reader 2; 96.5% [730 of 756] vs. 96.5% [730 of 756] for reader 3). Inter-reader agreement of lesions detection rate between the three radiologists was excellent (k range, 0.86-0.98) both for Gd-EOB MRI and for Fast protocol (k range, 0.89-0.99). Abbreviated protocol showed the same detection rate than conventional study in detection of liver metastases.

Nat. Med.; doi:10.1038/nm.3870; corrected online 26 June 2015 In the version of this article initially published online, Alberto Bardelli's e-mail address was incorrect. The correct address is alberto.bardelli@unito.it. The error has been corrected in the print, PDF and HTML versions of this article.

Background Imaging is an essential tool in the management of patients with Colorectal cancer (CRC) by helping evaluate number and sites of metastases, determine resectability, assess response to treatment, detect drug toxicities and recurrences. Although multidetector computed tomography (MDCT) is the first tool used for staging and patient’s surveillance, magnetic resonance imaging (MRI) is the most reliable imaging modality that allows to assess liver metastases. Our purpose is to compare the diagnostic performance of gadoxetic acid-(Gd-EOB) enhanced liver MRI and contrast-enhanced MDCT in the detection of liver metastasis from colorectal cancer (mCRC) . Methods One hundred and twenty-eight patients with pathologically proven mCRC (512 liver metastases) underwent Gd-EOB MRI and MDCT imaging. An additional 46 patients without mCRC were included as control subjects. Three radiologists independently graded the presence of liver nodules on a five-point confidence scale. Sensitivity and specificity for the detection of metastases were calculated. Weighted к values were used to evaluate inter-reader agreement of the confidence scale regarding the presence of the lesion. Results MRI detected 489 liver metastases and MDCT 384. In terms of per-lesion sensitivity in the detection of liver metastasis, all three readers had higher diagnostic sensitivity with Gd-EOB MRI than with MDCT (95.5% vs. 72% reader 1; 90% vs. 72% reader 2; 96% vs. 75% reader 3). Each reader showed a statistical significant difference ( p  < <.001 at Chi square test). MR imaging showed a higher performance than MDCT in per-patient detection sensitivity (100% vs. 74.2% [ p  < <.001] reader 1, 98% vs. 73% [ p  < <.001] reader 2, and 100% vs. 78% [ p  < <.001] reader 3). In the control group, MRI and MDCT showed similar per-patient specificity (100% vs. 98% [ p  = 0.31] reader 1, 100% vs. 100% [ p  = 0.92] reader 2, and 100% vs. 96% [ p  = 0.047] reader 3). Inter-reader agreement of lesion detection between the three radiologists was moderate to excellent (k range, 0.56–0.86) for Gd-EOB MRI and substantial to excellent for MDCT (k range, 0.75–0.8). Conclusion Gadoxetic acid-enhanced MRI performs significantly better in the detection of mCRC, than MDCT, particularly in patients treated with chemotherapy, in subcapsular lesions, and in peribiliary metastases .

Background Inefficient T-cell access to the tumor microenvironment (TME) is among the causes of tumor immune-resistance. Previous evidence demonstrated that targeting CXCR4 improves anti-PD-1/PD-L1 efficacy reshaping TME. To evaluate the role of newly developed CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/US2013/0079292A1) in potentiating anti-PD-1 efficacy two syngeneic murine models, the MC38 colon cancer and the B16 melanoma-human CXCR4-transduced, were employed. Methods Mice were subcutaneously injected with MC38 (1 × 10 6 ) or B16-hCXCR4 (5 × 10 5 ). After two weeks, tumors bearing mice were intraperitoneally (ip) treated with murine anti-PD-1 [RMP1–14] (5 mg/kg, twice week for 2 weeks), Pep R (2 mg/kg, 5 days per week for 2 weeks), or both agents. The TME was evaluated through immunohistochemistry and flow-cytometry. In addition, the effects of the human-anti-PD-1 nivolumab and/or Peptide-R54 (Pep R54), were evaluated on human melanoma PES43 cells and xenografts treated. Results The combined treatment, Pep R plus anti-PD-1, reduced the MC38 Relative Tumor Volume (RTV) by 2.67 fold ( p  = 0.038) while nor anti-PD-1, neither Pep R significantly impacted on tumor growth. Significant higher number of Granzyme B (GZMB) positive cells was detected in MC38 tumors from mice treated with the combined treatment ( p  = 0.016) while anti-PD-1 determined a modest but significant increase of tumor-infiltrating GZMB positive cells ( p  = 0.035). Also, a lower number of FoxP3 positive cells was detected ( p  = 0.022). In the B16-hCXCR4 tumors, two weeks of combined treatment reduced tumor volume by 2.27 fold while nor anti-PD-1 neither Pep R significantly impacted on tumor growth. A significant higher number of GRZB positive cells was observed in B16-hCXCR4 tumors treated with combined treatment (p = 0,0015) as compared to anti-PD-1 ( p  = 0.028). The combined treatment reduced CXCR4, CXCL12 and PD-L1 expression in MC38 tumors. In addition, flow cytometry on fresh B16-hCXCR4 tumors showed significantly higher Tregs number following anti-PD-1 partially reversed by the combined treatment Pep R and anti-PD-1. Combined treatment determined an increase of CD8/Tregs and CD8/MDSC ratio. To dissect the effect of anti-PD-1 and CXCR4 targeting on PD-1 expressed by human cancer cells, PES43 human melanoma xenograft model was employed. In vitro human anti-PD-1 nivolumab or pembrolizumab (10 μM) reduced PES43 cells growth while nivolumab (10 μM) inhibited pERK1/2, P38 MAPK, pAKT and p4EBP. PES43 xenograft mice were treated with Pep R54, a newly developed Pep R derivative (AcHN-Arg-Ala-[DCys-Arg- Nal(2′)-His-Pen]- COOH), plus nivolumab. After 3 weeks of combined treatment a significant reduction in tumor growth was shown ( p  = 0.038). PES43 lung disseminated tumor cells (DTC) were detected in fresh lung tissues as melanoma positive MCSP-APC + cells. Although not statistically significant, DTC-PES43 cells were reduced in mice lungs treated with combined treatment while nivolumab or Pep R54 did not affect DTC number. Conclusion Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.

PurposeTo 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 methodsThirty-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.ResultsFifteen 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).ConclusionSIS 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.

Background Increasing evidences showed that the location of the primary tumor on the right (proximal) or left (distal) side of the colon have a prognostic/predictive value for colon cancer patients. However, the understanding of the molecular mechanisms that contribute to the pathogenesis in different location of colon is still unclear. Probably an important role could be played by genes that control the spatial–temporal development of bodily structures, such as HOX genes. Methods The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes and of the HOX regulating lncRNA HOTAIR in distal and proximal CRC cases. We have carried out a Tissue Micro Array with left and right CRC samples associated with all clinical-pathological parameters of patients. The expression of HOX genes was evaluated by immunohistochemistry and the staining of HOTAIR was performed by in situ hybridization using a specifically designed LNA probe. Results All paralogous 13 HOX genes and HOTAIR are silent in normal tissue and expressed in CRC samples. HOXB13, HOXC13 and HOTAIR showed a statistical association with lymph nodes metastasis (p value = 0.003, p value = 0.05, p value = 0.04). HOXB13 , HOXC13 and lncRNA HOTAIR are overexpressed in right CRCs samples (p value < 0 and p value = 0.021). HOTAIR is also strongly correlated with HOXB13 (p value = 0.02) and HOXC13 (p value = 0.042) expression. Conclusions Our data highlighted an important role of posterior HOX genes in colorectal cancer carcinogenesis. Specifically, the aberrant expression of the HOXB13 , HOXC13 and HOTAIR in proximal colon cancers could add an important dowel in understanding molecular mechanisms related to tumor pathogenesis in this location.

We compared diagnostic performance of Magnetic Resonance (MR), Computed Tomography (CT) and Ultrasound (US) with (CEUS) and without contrast medium to identify peribiliary metastasis. We identified 35 subjects with histological proven peribiliary metastases who underwent CEUS, CT and MR study. Four radiologists evaluated the presence of peribiliary lesions, using a 4-point confidence scale. Echogenicity, density and T1-Weigthed (T1-W), T2-W and Diffusion Weighted Imaging (DWI) signal intensity as well as the enhancement pattern during contrast studies on CEUS, CT and MR so as hepatobiliary-phase on MRI was assessed. All lesions were detected by MR. CT detected 8 lesions, while US/CEUS detected one lesion. According to the site of the lesion, respect to the bile duct and hepatic parenchyma: 19 (54.3%) were periductal, 15 (42.8%) were intra-periductal and 1 (2.8%) was periductal-intrahepatic. According to the confidence scale MRI had the best diagnostic performance to assess the lesion. CT obtained lower diagnostic performance. There was no significant difference in MR signal intensity and contrast enhancement among all metastases (p>0.05). There was no significant difference in CT density and contrast enhancement among all metastases (p>0.05). MRI is the method of choice for biliary tract tumors but it does not allow a correct differential diagnosis among different histological types of metastasis. The presence of biliary tree dilatation without hepatic lesions on CT and US/CEUS study may be an indirect sign of peribiliary metastases and for this reason the patient should be evaluated by MRI.