Ability of Delta Radiomics to Predict a Complete Pathological Response in Patients with Loco-Regional Rectal Cancer Addressed to Neoadjuvant Chemo-Radiation and Surgery.

We performed a pilot study to evaluate the use of MRI delta texture analysis (D-TA) as a methodological item able to predict the frequency of complete pathological responses and, consequently, the outcome of patients with locally advanced rectal cancer addressed to neoadjuvant chemoradiotherapy (C-RT) and subsequently, to radical surgery. In particular, we carried out a retrospective analysis including 100 patients with locally advanced rectal adenocarcinoma who received C-RT and then radical surgery in three different oncological institutions between January 2013 and December 2019. Our experimental design was focused on the evaluation of the gross tumor volume (GTV) at baseline and after C-RT by means of MRI, which was contoured on T2, DWI, and ADC sequences. Multiple texture parameters were extracted by using a LifeX Software, while D-TA was calculated as percentage of variations in the two time points. Both univariate and multivariate analysis (logistic regression) were, therefore, carried out in order to correlate the above-mentioned TA parameters with the frequency of pathological responses in the examined patients' population focusing on the detection of complete pathological response (pCR, with no viable cancer cells: TRG 1) as main statistical endpoint. ROC curves were performed on three different datasets considering that on the 21 patients, only 21% achieved an actual pCR. In our training dataset series, pCR frequency significantly correlated with ADC GLCM-Entropy only, when univariate and binary logistic analysis were performed (AUC for pCR was 0.87). A confirmative binary logistic regression analysis was then repeated in the two remaining validation datasets (AUC for pCR was 0.92 and 0.88, respectively). Overall, these results support the hypothesis that D-TA may have a significant predictive value in detecting the occurrence of pCR in our patient series. If confirmed in prospective and multicenter trials, these results may have a critical role in the selection of patients with locally advanced rectal cancer who may benefit form radical surgery after neoadjuvant chemoradiotherapy.

A singular case of primary aorto-duodenal fistula without pre-existing abdominal aortic aneurism: why and when you should suspect it.

Although gastrointestinal hemorrhage from aorto-enteric fistulae (AEF) secondary to previous aortic grafts are well known, a primary aorto-enteric fistula (PAEF) without aortic aneurysm is an extremely rare event resulting in poor prognosis and outcome. PAEF is a rare cause of gastro-intestinal (GI) bleeding that radiologists should consider because often its presence is not easily guessed by clinical features. It is difficult to detect at CT examination therefore PAEF might be not diagnosed until a laparotomy. We report a case of a 74-year-old Italian male who presented to our Emergency Department (ED) with brightly red rectal bleeding that occurred from some hours and a pre-syncopal episode. There was no history of analgesic abuse, peptic ulceration, alcohol excess, and weight loss. Standard resuscitation was commenced with the hope that common sources of bleeding such as peptic ulcers or varices would eventually be discovered by endoscopy and treated definitely. An upper GI endoscopy showed brightly red blood in the stomach and in the first portions of duodenum, but no source of active bleeding was found. Diagnosis of PAEF was made by CT and after confirmed during surgical intervention. Both the duodenum and the aorta were successfully repaired by direct suture and synthetic graft replacement, respectively. Diagnosis of primary aortic duodenal fistula (ADF) has been very difficult in this case especially because our patient did not have abdominal aortic aneurism (AAA) history confirmed by CT examination. Radiologist should remember that upper GI bleeding could however be determined by primary ADF also if atherosclerotic damage is severe as in this case. A technically good and complete exam is mandatory to achieve this rare and complex diagnosis. Particularly, an ultra-tardive acquisition phase (5 min after contrast administration) could be helpful to suspect the presence of PADF: the appearance of contrast into the duodenal lumen is an evocative sign useful to increase clinical and radiological suspicious of ADF. Gl bleeding should be assumed to be caused from a PAEF unless another source can be identified without delay. A timely and accurate diagnosis of primary AEF may be challenging due to insidious episodes of GI bleeding, which are frequently under diagnosed until the occurrence of massive hemorrhage.

Chemotherapy-induced bowel ischemia: diagnostic imaging overview.

Cancer patients need multimodal therapies to treat their disease increasingly. In particular, drug treatment, as chemotherapy, immunotherapy, or various associations between them are commonly used to increase efficacy. However, the use of drugs predisposes a percentage of patients to develop toxicity in multiple organs and systems. Principle chemotherapy drugs mechanism of action is cell replication inhibition, rapidly proliferating cells especially. Immunotherapy is another tumor therapy strategy based on antitumor immunity activation trough agents as CTLA4 inhibitors (ipilimumab) or PD-1/PD-L1 inhibitors as nivolumab. If, on the one hand, all these agents inhibit tumor growth, on the other, they can cause various degrees toxicity in several organs, due to their specific mechanism of action. Particularly interesting are bowel toxicity, which can be clinically heterogeneous (pain, nausea, diarrhea, enterocolitis, pneumocolitis), up to severe consequences, such as ischemia, a rare occurrence. However, this event can occur both in vessels that supply intestine and in submucosa microvessels. We report drug-related intestinal vascular damage main characteristics, showing the radiological aspect of these alterations. Interpretation of imaging in oncologic patients has become progressively more complicated in the context of "target therapy" and thanks to the increasing number and types of therapies provided. Radiologists should know this variety of antiangiogenic treatments and immunotherapy regimens first because they can determine atypical features of tumor response and then also because of their eventual bowel toxicity.

Delta radiomics: a systematic review.

BACKGROUND: Radiomics can provide quantitative features from medical imaging that can be correlated with various biological features and clinical endpoints. Delta radiomics, on the other hand, consists in the analysis of feature variation at different acquisition time points, usually before and after therapy. The aim of this study was to provide a systematic review of the different delta radiomics approaches. METHODS: Eligible articles were searched in Embase, PubMed, and ScienceDirect using a search string that included free text and/or Medical Subject Headings (MeSH) with three key search terms: "radiomics", "texture", and "delta". Studies were analysed using QUADAS-2 and the RQS tool. RESULTS: Forty-eight studies were finally included. The studies were divided into preclinical/methodological (five studies, 10.4%); rectal cancer (six studies, 12.5%); lung cancer (twelve studies, 25%); sarcoma (five studies, 10.4%); prostate cancer (three studies, 6.3%), head and neck cancer (six studies, 12.5%); gastrointestinal malignancies excluding rectum (seven studies, 14.6%), and other disease sites (four studies, 8.3%). The median RQS of all studies was 25% (mean 21% ± 12%), with 13 studies (30.2%) achieving a quality score < 10% and 22 studies (51.2%) < 25%. CONCLUSIONS: Delta radiomics shows potential benefit for several clinical endpoints in oncology (differential diagnosis, prognosis and prediction of treatment response, and evaluation of side effects). Nevertheless, the studies included in this systematic review suffer from the bias of overall low quality, so that the conclusions are currently heterogeneous, not robust, and not replicable. Further research with prospective and multicentre studies is needed for the clinical validation of delta radiomics approaches.

Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer.

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2-driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from ß-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of ß-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/ß-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2-centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.

Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis.

Trop-2 is a transmembrane signal transducer that can induce cancer growth. Using antibody targeting and N-terminal Edman degradation, we show here that Trop-2 undergoes cleavage in the first thyroglobulin domain loop of its extracellular region, between residues R87 and T88. Molecular modeling indicated that this cleavage induces a profound rearrangement of the Trop-2 structure, which suggested a deep impact on its biological function. No Trop-2 cleavage was detected in normal human tissues, whereas most tumors showed Trop-2 cleavage, including skin, ovary, colon, and breast cancers. Coimmunoprecipitation and mass spectrometry analysis revealed that ADAM10 physically interacts with Trop-2. Immunofluorescence/confocal time-lapse microscopy revealed that the two molecules broadly colocalize at the cell membrane. We show that ADAM10 inhibitors, siRNAs and shRNAs abolish the processing of Trop-2, which indicates that ADAM10 is an effector protease. Proteolysis of Trop-2 at R87-T88 triggered cancer cell growth both in vitro and in vivo. A corresponding role was shown for metastatic spreading of colon cancer, as the R87A-T88A Trop-2 mutant abolished xenotransplant metastatic dissemination. Activatory proteolysis of Trop-2 was recapitulated in primary human breast cancers. Together with the prognostic impact of Trop-2 and ADAM10 on cancers of the skin, ovary, colon, lung, and pancreas, these data indicate a driving role of this activatory cleavage of Trop-2 on malignant progression of tumors.

Congenital Solitary Kidney from Birth to Adulthood.

PURPOSE: To evaluate the course of prenatally diagnosed and early-enrolled congenital solitary functioning kidney patients followed until adulthood and to identify risk factors for kidney injury. MATERIALS AND METHODS: Among all congenital solitary functioning kidney patients followed (1993-2018), we recalled 56 patients with prenatal diagnosis and congenital solitary functioning kidney confirmation at 1-3 months of life reaching at least 18 years of age. Serum uric acid, heavy smoking (≥25 cigarettes/day) and overweight/obesity were clustered as modifiable risk factors. Kidney injury was defined by estimated glomerular filtration rate <90 ml/minute/1.73 m2 and/or 24-hour ambulatory blood pressure monitoring confirmed hypertension and/or proteinuria. Modifiable risk factors and congenital anomalies of the kidney and urinary tract (CAKUT) of congenital solitary functioning kidney were evaluated as risk factors for kidney injury. RESULTS: The mean followup period was 21.1 years (range 18-33 years). Mild kidney injury was found in 15 out of 56 patients (26.8%). The mean age at proteinuria, reduced estimated glomerular filtration rate and hypertension onset was 19.7 years (1.2 SDS), 20.7 years (2.7 SDS), and 22 years (5.6 SDS), respectively. Patients with CAKUT of congenital solitary functioning kidney and with both CAKUT of congenital solitary functioning kidney and modifiable risk factors presented survival free from kidney injury of 0% at 22.2 and 24.2 years of age, respectively. Patients with modifiable risk factors presented 42.4% of survival at 30 years. Patients without CAKUT of congenital solitary functioning kidney nor modifiable risk factors presented 100% of survival at 30 years of age (p=0.002). The presence of CAKUT of congenital solitary functioning kidney was the only significant risk factor (HR 4.9; 95% CI 1.8-14.2; p=0.003). CONCLUSIONS: The outcomes of congenital solitary functioning kidney in early adulthood appear better than previously reported. Prompt diagnosis of congenital solitary functioning kidney, healthy lifestyle promotion and monitoring of serum uric acid may improve the prognosis of congenital solitary functioning kidney patients.

Langerhans Cell Histiocytosis with Uncommon Liver Involvement: A Case Report.

BACKGROUND Langerhans cell histiocytosis (LCH), also called histiocytosis X, belongs to a group of rare neoplasms and is a clonal pathology characterized by infiltration of Langerhans cells. The pathology can occur with the involvement of only 1 organ, more frequently the bone or with multi-visceral involvement, and patients frequently receive a delayed diagnosis and empirical treatments. CASE REPORT We report a case of LCH in a 60-year-old woman who presented atypical symptoms, imaging findings of lung and liver involvement. Imaging showed increased liver volume and subverted structure by multiple nodular formations. For the differential diagnosis with other neoplastic liver diseases, the patient underwent liver biopsy, with microscopic typical findings of the disease and positive immunohistochemical markers. CONCLUSIONS Liver involvement in LCH is rare and the differential diagnosis with neoplastic pathology may pose a challenge for the clinician and radiologist, also due to the possible association between LCH and malignant tumors.

MRI of perianal fistulas in Crohn's disease.

Perianal fistulas represent one of the most critical complications of Crohn's disease (CD). Management and treatment need a multidisciplinary approach with an accurate description of imaging findings. AIM: This study aspires to assess the significative role of Magnetic Resonance Imaging (MRI) in the study of perianal fistulas, secondary extensions, and abscess in patients with CD. Therefore it is essential to standardize an appropriate protocol of sequences that allow the correct evaluation of disease activity and complications. METHODS: We selected and reviewed ten recent studies among the most recent ones present in literature exclusively about pelvic MRI imaging and features in CD. We excluded studies that weren't in the English language. CONCLUSIONS: MRI has a crucial role in the evaluation and detection of CD perianal fistulas because, thanks to its panoramic and multiplanar view, it gives excellent anatomic detail of the anal sphincters. Today MRI is the gold standard imaging technique for the evaluation of perianal fistulas, mainly because this technique shows higher concordance with surgical findings than does any other imaging evaluation. Surgical treatment is often required in the management of perianal fistula in patients with CD, which often have complex perineal findings.

Magnetic resonance severity index assessed by T1-weighted imaging for acute pancreatitis: correlation with clinical outcomes and grading of the revised Atlanta classification-a narrative review.

Acute pancreatitis (AP) is a common disease that may involve pancreas and peripancreatic tissues with a prevalence of up to 50 per 100,000 individuals for year. The Atlanta classification was assessed for the first time in 1992 and modified in 2012 in order to describe morphological features of AP and its complications. AP can be morphologically distinguished in two main types: interstitial edematous pancreatitis (IEP) and necrotizing pancreatitis (NEP). This classification is very important because the presence of necrosis is directly linked to local or systemic complications, hospital stays and death. Magnetic resonance (MR) is very useful to characterize morphological features in AP and its abdominal complications. Particularly we would like to underline the diagnostic, staging and prognostic role of T1-weighted images with fat suppression that could be significant to assess many features of the AP inflammatory process and its complications (detection of the pancreatic contour, pancreatic necrosis, presence of haemorrhage). Signs of inflammatory and edema are instead observed by T1-weighted images. MR cholangiopancreatography (MRCP) is necessary to study the main pancreatic duct and the extrahepatic biliary tract and contrast-enhancement magnetic resonance imaging (MRI) allows to assess the extent of necrosis and vascular injuries.

Pitfalls and differential diagnosis on adrenal lesions: current concepts in CT/MR imaging: a narrative review.

The purpose of this pictorial essay is to review the imaging findings of adrenal lesions. Adrenal lesions could be divided into functioning or non-functioning masses, primary or metastatic, and benign or malignant. Imaging techniques have undergone significant advances in recent years. The most significant objective of adrenal imaging is represented by the detection and, when possible, characterization of adrenal lesions in order to direct patient management correctly. The detection and management of adrenal lesions is based on cross-sectional imaging obtained with non-contrast CT (tumour density), contrast-enhanced CT including delayed washout (either absolute percentage washout or relative percentage one) and finally with MR chemical shift analysis (loss of signal intensity between in-phase and out-of-phase images including both qualitative and quantitative estimates of signal loss). The small incidental adrenal nodules are benign, in most of cases; some tumors such as lipid-rich adenoma and myelolipoma have characteristic features that can be diagnosed accurately in CT. On contrary, if the presenting contrast-enhanced CT shows an adrenal mass with uncertain or malignant morphologic features, particularly in patients with a known history of malignancy, further evaluations should be considered. The most significative implications for radiologists are represented by how to assess risk of malignancy on imaging and what follow-up to indicate if an adrenal incidentaloma is not surgically removed.

Diagnostic value/performance of radiological liver imaging during chemoterapy for gastrointestinal malignancy: a critical review.

This article reviews the main toxic effect, complications and relative imaging findings of the liver that may appear during the oncologic follow up among patients affected by gastrointestinal malignancy. Awareness of the causative chemotherapeutic agent and regimens, pathophysiology and relative characteristic imaging findings of hepatic injuries is critical in order to obtain an accurate diagnosis especially when these parenchymal lesions are focal. An accurate synergic radiological diagnosis with Computed Tomography (CT) and Magnetic Resonance (MR) techniques may induce a potential termination of ineffective/toxic chemotherapy during early phases of treatment, changing the therapeutic plan in order to avoid first unnecessary liver biopsy and then invasive treatment as hepatic resection if not required.

Can microvascular invasion in hepatocellular carcinoma be predicted by diagnostic imaging? A critical review.

Imaging still has a limited capacity to detect microvascular invasion (mVI). The objective of this critical review is the evaluation of the most significant predictors of mVI in hepatocellular carcinoma (HCC) detectable by computed tomography, PET/computed tomography and MRI using a mathematical model. We systematically reviewed 15 observational studies from 2008 to 2018 to analyze factors with most impact on mVI detection. The most significant predictors of mVI correlating with imaging techniques were considered. From 1902 patients considered, we individuated 30 total predictors of mVI in a multivariate analysis. The most frequent predictors related to the highest presence with mVI in HCC were: α-fetoprotein (p < 0.0001), tumor size (p < 0.0001) and number of HCC nodules (p = 0.0020).

p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading.

BACKGROUND: Traditional prognostic indicators of breast cancer, i.e. lymph node diffusion, tumor size, grading and estrogen receptor expression, are inadequate predictors of metastatic relapse. Thus, additional prognostic parameters appear urgently needed. Individual oncogenic determinants have largely failed in this endeavour. Only a few individual tumor growth drivers, e.g. mutated p53, Her-2, E-cadherin, Trops, did reach some prognostic/predictive power in clinical settings. As multiple factors are required to drive solid tumor progression, clusters of such determinants were expected to become stronger indicators of tumor aggressiveness and malignant progression than individual parameters. To identify such prognostic clusters, we went on to coordinately analyse molecular and histopathological determinants of tumor progression of post-menopausal breast cancers in the framework of a multi-institutional case series/case-control study. METHODS: A multi-institutional series of 217 breast cancer cases was analyzed. Twenty six cases (12 %) showed disease relapse during follow-up. Relapsed cases were matched with a set of control patients by tumor diameter, pathological stage, tumor histotype, age, hormone receptors and grading. Histopathological and molecular determinants of tumor development and aggressiveness were then analyzed in relapsed versus non-relapsed cases. Stepwise analyses and model structure fitness assessments were carried out to identify clusters of molecular alterations with differential impact on metastatic relapse. RESULTS: p53, Bcl-2 and cathepsin D were shown to be coordinately associated with unique levels of relative risk for disease relapse. As many Ras downstream targets, among them matrix metalloproteases, are synergistically upregulated by mutated p53, whole-exon sequence analyses were performed for TP53, Ki-RAS and Ha-RAS, and findings were correlated with clinical phenotypes. Notably, TP53 insertion/deletion mutations were only detected in relapsed cases. Correspondingly, Ha-RAS missense oncogenic mutations were only found in a subgroup of relapsing tumors. CONCLUSIONS: We have identified clusters of specific molecular alterations that greatly improve prognostic assessment with respect to singularly-analysed indicators. The combined analysis of these multiple tumor-relapse risk factors promises to become a powerful approach to identify patients subgroups with unfavourable disease outcome.

A bicistronic CYCLIN D1-TROP2 mRNA chimera demonstrates a novel oncogenic mechanism in human cancer.

A chimeric CYCLIN D1-TROP2 mRNA was isolated from human ovarian and mammary cancer cells. The CYCLIN D1-TROP2 mRNA was shown to be a potent oncogene as it transforms naïve, primary cells in vitro and induces aggressive tumor growth in vivo in cooperation with activated RAS. Silencing of the chimeric mRNA inhibits the growth of breast cancer cells. The CYCLIN D1-TROP2 mRNA was expressed by a large fraction of the human gastrointestinal, ovarian, and endometrial tumors analyzed. It is most frequently detected in intestinal cell aneuploid cancers and it is coexpressed with activated RAS oncogenes, consistent with a cooperative transforming activity in human cancers. The chimeric mRNA is a bicistronic transcript of post transcriptional origin that independently translates the Cyclin D1 and Trop-2 proteins. This is a novel mechanism of CYCLIN D1 activation that achieves the truncation of the CYCLIN D1 mRNA in the absence of chromosomal rearrangements. This leads to a higher CYCLIN D1 mRNA stability, with inappropriate expression during the cell cycle. The stabilized CYCLIN D1 mRNA cooperates with TROP2 in stimulating the growth of the expressing cells. These findings show a novel epigenetic, oncogenic mechanism, which seems to be widespread in human cancers.

Trop-1 are conserved growth stimulatory molecules that mark early stages of tumor progression.

BACKGROUND: Trop-1 is a cell-cell adhesion regulatory molecule that is overexpressed by a large fraction of tumors in man. METHODS: To identify fundamental, conserved functional features of Trop-1 in transformed cells, a search was performed for evolutionarily conserved structure, expression patterns, and function by gene cloning, DNA array and serial analysis of gene expression (SAGE), Northern and Western blotting, flow cytometry, and immunohistochemistry of sequential stages of tumor progression in experimental systems and in man. RESULTS: TROP1 genes demonstrate conserved structure and promoter regions with parallel expression patterns (high expression in the small intestine and colon; lower expression in prostate, thyroid, salivary glands, breast, kidney, lung, liver, and spleen; very low levels in skin and stomach; no expression in heart, muscle, and brain). Progenitor cells of different tissues were shown to express Trop-1. Hence, the expression and functional role of Trop-1 were analyzed at successive stages of tumor progression in vitro and in vivo. The findings show that Trop-1 is expressed at early stages of tumor development, eg, in dysplastic lesions and immortalized cells, is sufficient to stimulate cell growth of expressing transformed cells, and is required for tumor growth in vivo. CONCLUSIONS: The findings identify Trop-1 as a novel determinant of cell growth at early stages of tumor development and as a marker of early stages of development in normal tissues and in cancer, making this molecule a candidate for novel diagnostic and therapeutic procedures.