Interrogating colorectal cancer metastasis to liver: a search for clinically viable compounds and mechanistic insights in colorectal cancer Patient Derived Organoids

Approximately 20-50% of patients presenting with localized colorectal cancer progress to stage IV metastatic disease (mCRC) following initial treatment and this is a major prognostic determinant. Here, we have interrogated a heterogeneous set of primary colorectal cancer (CRC), liver CRC metastases and adjacent liver tissue to identify molecular determinants of the colon to liver spreading. Screening Food and Drug Administration (FDA) approved drugs for their ability to interfere with an identified colon to liver metastasis signature may help filling an unmet therapeutic need

A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer.

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C>T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs

La diagnosi elettrocardiografica di infarto miocardico acuto nell'era dell'angioplastica primaria e delle reti hub and spoke

A più di 100 anni dalla sua invenzione, l’ECG standard sta vivendo un vero e proprio “rinascimento”. Per quanto riguarda la cardiopatia ischemica acuta, il fenomeno è dovuto, soprattutto, alla disponibilità di grandi database in cui le caratteristiche elettrocardiografiche di migliaia di pazienti sono raccolte in maniera ordinata e predefinita e sono affiancate, e quindi correlabili, alle caratteristiche cliniche e coronarografiche e ai dati di outcome. La presente rassegna analizza criticamente il ruolo diagnostico dell’ECG standard nelle sindromi coronariche acute con (STEMI) e senza (NSTEMI) sopraslivellamento del tratto ST, con particolare attenzione ai possibili trabocchetti interpretativi e a quelle caratteristiche del tracciato in grado di contribuire a orientare le decisioni terapeutiche. Di fronte al paziente con presentazione clinica suggestiva per infarto miocardico acuto, l’ECG può aiutare a dare una risposta a molte domande. In caso di sospetto STEMI: siamo sicuri di poter escludere che sia in atto un infarto? (il problema dei falsi negativi); siamo sicuri che sia un vero infarto e non un falso positivo? Qual è la coronaria ostruita e a quale livello? Si è verificata riperfusione miocardica? In caso di sospetto NSTEMI: siamo sicuri che sia un vero infarto miocardico acuto (piuttosto che un’embolia polmonare o una dissezione aortica)? Siamo sicuri che sia in atto un NSTEMI piuttosto che uno STEMI dorsale “mascherato”? Quale substrato coronarico e quale grado di estensione dell’ischemia sono ipotizzabili in questo paziente? In particolare è presente un substrato a rischio molto alto, tale da suggerire un approccio invasivo in emergenza

Fatty Acid Synthase (FAS) is a Marker of Increased Risk of Recurrence in Lung Carcinoma

.Background: We explored the expression of Fatty Acid Synthase (FAS) in lung carcinomas and its association with clinico-pathological features and prognosis. FAS is a recently discovered molecule involved in the energy supply of normal cells. FAS is also overexpressed in neoplastic tissues because of their increased necessity for energy. Patients and Methods: One hundred and six patients with non-small cell lung carcinoma were followed-up for an average period of 5 years. FAS expression was detected immunohistochemically. Results: FAS staining was observed in 61 out of 106 cases (57.54%). Statistical analysis revealed that FAS had an overall low prognostic value (p=0.14), while FAS-negative expression in stage I patients showed a trend for better survival (p=0.10). PTNM stage (p0.0001) was the only significant prognostic marker for overall survival. Conclusion: FAS is a reliable marker of low-stage clinically aggressive lung carcinomas. The determination of FAS expression in lung carcinomas may stratify patients and determine therapeutic approaches for their care. Note

TARGETING G-QUADRUPLEX DNA STRUCTURES BY EMICORON HAS A STRONG ANTITUMOR EFFICACY AGAINST ADVANCED MODELS OF HUMAN COLON CANCER

We previously identified EMICORON as a novel G-quadruplex (G4) ligand showing high selectivity for G4 structures over the duplex DNA, causing telomere damage and inhibition of cell proliferation in transformed and tumor cells. Here, we evaluated the antitumoral effect of EMICORON on advanced models of human colon cancer (CRC) that could adequately predict human clinical outcomes. Our results showed that EMICORON was well tolerated in mice, as no adverse effects were reported, and a low ratio of sensitivity across human and mouse bone marrow cells was observed, indicating a good potential for reaching similar blood levels in humans. Moreover, EMICORON showed a marked therapeutic efficacy, as it inhibited the growth of patient-derived xenografts (PDXs)and orthotopic CRC, and strongly reduced the dissemination of tumor cells to lymphnodes, intestine, stomach and liver. Finally, activation of DNA damage, impairment of proliferation and angiogenesis are proved to be key determinants of EMICORON antitumoral activity. Altogether, our results, performed on advanced experimental models of human CRC that bridge the translational gap between preclinical and clinical studies, demonstrated that EMICORON had an unprecedented antitumor activity warranting further studies of EMICORON-based combination treatments

Period 2 (PER-2) biologic profile in advanced colorectal cancer (ACC) patients (pts)

Circadian rhythms modulated by clock genes expression as the Period genes (PER-1, PER-2, PER-3) are involved in cancer growth. PER-2 loss in colorectal cancer cell lines and in animal models increases tumorigenesis by β-catenin and cyclin D activation (Wood P, Cancer Res 2008). PER-2 loss in ACC pts was linked to a worse prognosis (Iacobelli S, ASCO 2008). The aim of our study was to identify a PER-2 biological profile related to proliferative indexes and treatment activity. Moreover miRNA related to clock genes were studied as miR-219, target of CLOCK and B-MAL1, miR-206 which affect mammalian circadian clock, miR-132 acting at the SCN level. Methods: We retrospectively evaluated 59 ACC pts, treated with first line chronomodulated triplet combination (Irinotecan+Oxaliplatin+Folinic Acid+5-Fluorouracil) ± Cetuximab. Immunostaining for PER-2, EGFR, ERβ1, ERβ2, Cyclin D1, β-catenin, K-RAS and B-RAF mutations, miRNAs -206, -132, -192, -194, and -219 evaluated on FFPE tumor tissues and their expression levels by quantitative PCR were examined. Results: Clinical data: M/F 32/27; median age 57 y; liver involvment 53%; Cetuximab use: 38%; liver resection: 42%; response to first line chemotherapy: PR 61%, SD 25.4%, PD 10.2%; pts 2.4% not evaluable. Biological data: PER-2 negative (-) /positive (+) 44/56%; EGFR (+)/(-) 54/46%; KRAS wt/mut 75/25%; ERβ1 (-)/(+) 36/65%; ERβ2 (-)/(+) 39/61%; Cyclin D1 (-)/(+) 51/49%; β-catenin(-)/(+) 31/69%. PER-2(-) patients expressed more frequently EGFR (73%) (p>0.0001), ERβ1 (77%) (p=0.07), ERβ2 (88.5%) (p>0.0001), Cyclin D1 (69.2%) (p=0.06) and β-catenin (84.6%) (p=0.02). PER-2(-) was also associated to high miR-206, miR-192 and miR-219 expression. Explorative multiple correspondence analysis showed response to chemotherapy related to a profile including PER-2 (+), EGFR (-), ERβ1 (-), ERβ2 (-), β-catenin (-) and low expression of miR-206. Conclusions: Our data confirmed that: 1) PER-2 loss was associated to activation of cell proliferation confirming in vitro data; 2) PER-2 expression was linked to negative activation of cell proliferation, low miR-206 expression and response to chemotherapy

Nuclear and cytoplasmic cellular distribution of survivin as survival predictor in resected non-small-cell lung cancer.

AIM: Survivin is a member of the inhibitors of apoptosis (IAP) gene family that acts through pathways different from those involving the bcl-2 family. Largely undetectable in normal adult tissues, survivin is deregulated in most human cancers including non-small-cell lung cancer (NSCLC) and may represent a tumor marker with prognostic and therapeutic implications. Aim of our study was to determine the prognostic role of survivin as an apoptosis-related biomarker in a series of resected NSCLC patients. METHODS: A retrospective series of resected NSCLC patients were retrieved from the files of the Regina Elena National Cancer Institute. Survivin was detected by immunohistochemistry (IHC) using a polyclonal antibody. Survivin displayed two kinds of immunoreactivity: (i) a diffuse cytoplasmic staining and (ii) a distinct nuclear staining. A score-scale to distinguish positive (score 1-2) vs. negative (score 0) pattern was applied. Clinical and biological (nuclear and cytoplasmic survivin staining) covariables were screened for a prognostic relationship with overall survival (OS) and disease-free survival (DFS) into the univariate and multivariate analyses. RESULTS: Data referring to 116 NSCLC patients who underwent surgery for stage I-IIIA NSCLC were collected. Multivariate analyses identified tumor size, nodal status and nuclear, but not cytoplasmic, expression of survivin as significant independent predictors of OS, with a hazard ratio of 2.40 (95% CI 1.44, 3.99, p=0.001), 2.03 (95% CI 1.26, 3.26, p=0.003) and 1.83 (95% CI 1.01, 3.30, p=0.044), respectively. Median OS for nuclear survivin positive (score 1-2) and negative (score 0) patients were 23 months (95% CI 15, 31) and 36 months (95% CI 1, 76), respectively (p=0.01); five-year survival for score 1-2 and score 0 patients were 20% and 44.5%, respectively. Conversely, no significant impact on survival is found when patients are stratified according to cytoplasmic survivin expression. CONCLUSIONS: Data presented herein open the issue that prognosis of stage I-IIIA NSCLC can be linked to the cellular pattern of distribution of survivin