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1.
J Exp Clin Cancer Res ; 38(1): 432, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31661001

RESUMO

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 × 106) or B16-hCXCR4 (5 × 105). 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.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31483883

RESUMO

OBJECTIVE: Fine needle cytology (FNC) is the first-line diagnostic method to determine the benign or malignant nature of thyroid nodules. The gray zone of cytological classifications remains, however, a crucial and challenging area for cytopathologists. DESIGN, PATIENTS AND MEASUREMENTS: In the present study, 141 thyroid cytological samples, with ultrasonographic suspicious features, have been prospectively analysed. Molecular analyses were performed by an innovative technology using two multiplex PCRs for the amplification of BRAF, N-H-K-RAS and RET exon genes. RNA samples were studied for RET/PTC1 and RET/PTC3 rearrangements by PCR amplification, and the conditions were set-up to study, with a single experiment, both wild-type PAX8 and PAX8/PPARÉ£ rearrangements. In total, 111 samples were examined for BRAF, N-H-KRAS and RET genes. An ultrasonographic, cytological and molecular correlation was also carried out in an attempt to suggest a possible way to manage the patients with thyroid nodules. Cyto-histological correlation was available in 115 cases, and it was used to verify the global diagnostic accuracy of this combined approach. RESULTS: According to the histopathological diagnosis, FNC accuracy was 100% for TIR5 and metastases; 89% for TIR4; 84% for TIR3A and 58% for TIR3B. About 11% of the studied samples showed either RET-PTC1 or RET/PTC3 chromosomal rearrangements, and only one sample simultaneously presented RET/PTC1 and RET/PTC3 rearrangements. PAX8/PPARÉ£ rearrangement was found in 6% of the samples. CONCLUSIONS: A multidisciplinary approach to the thyroid is therefore necessary to develop innovative methods suitable for an improved diagnostic and prognostic definition of thyroid cancer.

3.
BMC Cancer ; 19(1): 899, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500586

RESUMO

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 ).

4.
J Transl Med ; 17(1): 315, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533733

RESUMO

Following publication of the original article [1], the authors reported that one of the authors, Corrado Caracò, has been accidentally omitted from the author list. In this Correction the author has been added to the author list.

5.
Int J Cancer ; 145(10): 2827-2839, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31381136

RESUMO

Fibroblasts are among the most abundant stromal cells in the tumor microenvironment (TME), progressively differentiating into activated, motile, myofibroblast-like, protumorigenic cells referred to as Cancer-Associated Fibroblasts (CAFs). To investigate the mechanisms by which epithelial cells direct this transition, the early stages of tumorigenesis were exemplified by indirect cocultures of WI-38 or human primary breast cancer fibroblasts with human mammary epithelial cells expressing an inducible c-Myc oncogene (MCF10A-MycER). After c-Myc activation, the conditioned medium (CM) of MCF10A-MycER cells significantly enhanced fibroblast activation and mobilization. As this was accompanied by decreased insulin-like growth factor binding protein-6 (IGFBP-6) and increased insulin-like growth factor-1 and IGF-II (IGF-I, IGF-II) in the CM, IGFs were investigated as key chemotactic factors. Silencing IGFBP-6 or IGF-I or IGF-II expression in epithelial cells or blocking Insulin-like growth factor 1 receptor (IGF-1R) activity on fibroblasts significantly altered fibroblast mobilization. Exposure of WI-38 fibroblasts to CM from induced MCF10A-MycER cells or to IGF-II upregulated FAK phosphorylation on Tyr397 , as well as the expression of α-smooth muscle actin (α-SMA), features associated with CAF phenotype and increased cell migratory/invasive behavior. In three-dimensional (3D)-organotypic assays, WI-38 or human primary fibroblasts, preactivated with either CM from MCF10A-MycER cells or IGFs, resulted in a permissive TME that enabled nontransformed MCF10A matrix invasion. This effect was abolished by inhibiting IGF-1R activity. Thus, breast epithelial cell oncogenic activation and stromal fibroblast transition to CAFs are linked through the IGFs/IGF-1R axis, which directly promotes TME remodeling and increases tumor invasion.

6.
J Transl Med ; 17(1): 266, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412885

RESUMO

BACKGROUND: Recently the 8th version of the American Joint Committee on Cancer (AJCC) classification has been introduced, and has attempted to define a more accurate and precise definition of prognosis in line with the major progresses in understanding the biology and pathogenesis of melanoma. This new staging system introduces major changes in the stage III staging system. Indeed, surgical practice is changing in stage III patients, since, according to recent evidence, there is no survival benefit in radical lymph node dissection following a positive sentinel lymph node dissection. Therefore, some patients currently staged IIIB-C after dissection could be downgraded to IIIA (as in the case of patients with metastatic non-sentinel lymph nodes) since many completion lymph node dissections will no longer be performed. Moreover, new and effective targeted and immune strategies are being introduced in the pharmacological armamentarium in the adjuvant setting, showing major efficacy. CONCLUSIONS: This article provides the authors' personal view on the above-mentioned topics.

7.
J Transl Med ; 17(1): 289, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31455347

RESUMO

BACKGROUND: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. Limited information is available in the current scientific literature on the concordance of genetic alterations between primary and metastatic CMM. In the present study, we performed next-generation sequencing (NGS) analysis of the main genes participating in melanoma pathogenesis and progression, among paired primary and metastatic lesions of CMM patients, with the aim to evaluate levels of discrepancies in mutational patterns. METHODS: Paraffin-embedded tumor tissues of the paired lesions were retrieved from the archives of the institutions participating in the study. NGS was performed using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup (IMI) to explore the mutational status of selected regions (343 amplicons; amplicon range: 125-175 bp; coverage 100%) within the main 25 genes involved in CMM pathogenesis; sequencing was performed with the Ion Torrent PGM System. RESULTS: A discovery cohort encompassing 30 cases, and a validation cohort including eleven Sardinian patients with tissue availability from both the primary and metachronous metastatic lesions were identified; the global number of analyzed tissue specimens was 90. A total of 829 genetic non-synonymous variants were detected: 101 (12.2%) were pathogenic/likely pathogenic, 131 (15.8%) were benign/likely benign, and the remaining 597 (72%) were uncertain/unknown significance variants. Considering the global cohort, the consistency in pathogenic/pathogenic like mutations was 76%. Consistency for BRAF and NRAS mutations was 95.2% and 85.7% respectively, without statistically significant differences between the discovery and validation cohort. CONCLUSIONS: Our study showed a high level of concordance in mutational patterns between primary and metastatic CMM, especially when pathogenic mutations in driver genes were considered.

8.
Future Oncol ; 15(29): 3327-3336, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432705

RESUMO

Pembrolizumab is a humanized monoclonal antibody against PD-1 capable of enhancing antitumor immune activity. The KEYNOTE-001 study showed that pembrolizumab has activity in advanced non-small-cell lung cancer patients and identified programmed death ligand 1 (PD-L1) as a companion test to select patients most likely to benefit from pembrolizumab. Five randomized clinical trials showed the efficacy of pembrolizumab in non-small-cell lung cancer: in second-line setting PD-L1 ≥1% (KEYNOTE-010), in first-line setting PD-L1 ≥50% (KEYNOTE-024 and KEYNOTE-042) and in first-line setting in combination with platinum doublets, any expression of PD-L1 (KEYNOTE-189 and KEYNOTE-407). Future challenges are the identification of the role of pembrolizumab in adjuvant, neoadjuvant, locally advanced disease or oncogene-addicted patients, in combination with radiotherapy or other biological agents.

9.
Cell Death Dis ; 10(8): 562, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332163

RESUMO

Development of distant metastasis relies on interactions between cancer and stromal cells. CXCL12, also known as stromal-derived factor 1α (SDF-1α), is a major chemokine constitutively secreted in bone marrow, lymph nodes, liver and lung, playing a critical role in the migration and seeding of neoplastic cells. CXCL12 activates the CXCR4 receptor that is overexpressed in several human cancer cells. Recent evidence reveals that tumors induce pre-metastatic niches in target organ producing tumor-derived factors. Pre-metastatic niches represent a tumor growth-favoring microenvironment in absence of cancer cells. A commercially available dermal filler, hyaluronic acid (HA) -based gel, loaded with CXCL12 (CLG) reproduced a "fake" pre-metastatic niche. In vitro, B16-hCXCR4-GFP, human cxcr4 expressing murine melanoma cells efficiently migrated toward CLG. In vivo, CLGs and empty gels (EGs) were subcutaneously injected into C57BL/6 mice and 5 days later B16-hCXCR4-GFP cells were intravenously inoculated. CLGs were able to recruit a significantly higher number of B16-hCXCR4-GFP cells as compared to EGs, with reduced lung metastasis in mice carrying CLG. CLG were infiltrated by higher number of CD45-positive leukocytes, mainly neutrophils CD11b+Ly6G+ cells, myeloid CD11b+Ly6G- and macrophages F4/80. CLG recovered cells recapitulated the features of B16-hCXCR4-GFP (epithelial, melanin rich, MELAN A/ S100/ c-Kit/CXCR4 pos; α-SMA neg). Thus a HA-based dermal filler loaded with CXCL12 can attract and trap CXCR4+tumor cells. The CLG trapped cells can be recovered and biologically characterized. As a corollary, a reduction in CXCR4 dependent lung metastasis was detected.

10.
J Transl Med ; 17(1): 234, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331337

RESUMO

Diagnosis of melanocytic lesions, correct prognostication of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to a given therapy remain very real challenges in melanoma. Recent studies have shown that immune checkpoint blockade that represents a forefront in cancer therapy, provide responses but they are not universal. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers they have yet to be fully characterized and implemented clinically. For example, advancements in sequencing and the understanding of the tumor microenvironment in melanoma have led to the use of genome sequencing and gene expression for development of multi-marker assays that show association with inflammatory state of the tumor and potential to predict response to immunotherapy. As such, melanoma serves as a model system for understanding cancer immunity and patient response to immunotherapy, either alone or in combination with other treatment modalities. Overall, the aim for the translational and clinical studies is to achieve incremental improvements through the development and identification of optimal treatment regimens, which increasingly involve doublet as well as triplet combinations, as well as through development of biomarkers to improve immune response. These and other topics in the management of melanoma were the focus of discussions at the fourth Melanoma Bridge meeting (November 29th-December 1st, 2018, Naples, Italy), which is summarised in this report.

11.
BMC Gastroenterol ; 19(1): 129, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340755

RESUMO

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.

13.
BMC Oral Health ; 19(1): 70, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039762

RESUMO

BACKGROUND: Narrow Band Imaging is a noninvasive optical diagnostic tool. It allows the visualization of sub-mucosal vasculature; four patterns of shapes of submucosal capillaries can be recognized, increasingly associated with neoplastic transformation. With such characteristics, it has showed high effectiveness for detection of Oral Squamous Cell Carcinoma. Still, scientific literature highlights several bias/confounding factors, such as Oral Lichen Planus. We performed a retrospective observational study on patients routinely examined with Narrow Band Imaging, investigating for bias, confounding factors and conditions that may limit its applicability. METHODS: Age, sex, smoking, use of dentures, history of head & neck radiotherapy, history of Oral Squamous Cell Carcinoma, site of the lesion and thickness of the epithelium of origin were statistically evaluated as possible bias/confounding factors. Pearson's Chi-squared test, multivariate logistic regression, Positive Predictive Value, Negative Predictive Value, Sensitivity, Specificity, Positive Likelihood Ratio, Negative Likelihood Ratio and accuracy were calculated, normalizing the cohort with/without patients affected by Oral Lichen Planus, to acknowledge its role as bias/confounding factor. RESULTS: Five hundred fifty-six inspections were performed on 106 oral cavity lesions from 98 patients. Age, sex, smoking, use of dentures and anamnesis of Oral Squamous Cell Carcinoma were not found to influence Narrow Band Imaging. History of head & neck radiotherapy was not assessed due to insufficient sample. Epithelium thickness does not seem to interfere with feasibility. Presence of Oral Lichen Planus patients in the cohort led to false positives but not to false negatives. Among capillary patterns, number IV was the most significantly associated to Oral Squamous Cell Carcinoma (p < 0.001), not impaired by the presence of Oral Lichen Planus patients in the cohort (accuracy: 94.3, 95% confidence interval: 88.1-97.9%; odds ratio: 261.7, 95% confidence interval: 37.7-1815.5). CONCLUSION: Narrow Band Imaging showed high reliability in detection of Oral Squamous Cell Carcinoma in a cohort of patients with oral cavity lesions not normalized for bias/confounding factors. Still, Oral Lichen Planus may lead to false positives. Narrow Band Imaging could help in the follow-up of patients with multiple lesions through detection of capillary pattern IV, which seems to be the most significantly associated to neoplastic epithelium.

14.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072041

RESUMO

lncRNAs participate in many cellular processes, including regulation of gene expression at the transcriptional and post-transcriptional levels. In addition, many lncRNAs can contribute to the development of different human diseases including cancer. The tumor microenvironment (TME) plays an important role during tumor growth and metastatic progression, and most of these lncRNAs have a key function in TME intracellular signaling. Among the numerous identified lncRNAs, several experimental evidences have shown the fundamental role of the lncRNA HOTAIR in carcinogenesis, also highlighting its use as a circulating biomarker. In this review we described the contribution of HOTAIR in the TME modulation, highlighting its relation with cellular and non-cellular components during tumor evolution and progression.


Assuntos
Carcinogênese/genética , Neoplasias/genética , RNA Longo não Codificante/genética , Microambiente Tumoral/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos
15.
Sci Rep ; 9(1): 7449, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092853

RESUMO

In the context of precision medicine with immunotherapies there is an increasing need for companion diagnostic tests to identify potential therapy responders and avoid treatment coming along with severe adverse events for non-responders. Here, we present a retrospective case study to discover image-based signatures for developing a potential companion diagnostic test for ipilimumab (IPI) in malignant melanoma. Signature discovery is based on digital pathology and fully automatic quantitative image analysis using virtual multiplexing as well as machine learning and deep learning on whole-slide images. We systematically correlated the patient outcome data with potentially relevant local image features using a Tissue Phenomics approach with a sound cross validation procedure for reliable performance evaluation. Besides uni-variate models we also studied combinations of signatures in several multi-variate models. The most robust and best performing model was a decision tree model based on relative densities of CD8+ tumor infiltrating lymphocytes in the intra-tumoral infiltration region. Our results are well in agreement with observations described in previously published studies regarding the predictive value of the immune contexture, and thus, provide predictive potential for future development of a companion diagnostic test.

17.
J Cell Physiol ; 234(11): 19249-19255, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31032924

RESUMO

Noncoding RNAs (ncRNAs) identify a large family of RNAs that do not encode proteins and represent an important group of tumor biomarkers, directly involved in the process of tumor pathogenesis and progression. Many of them have also been identified in biological fluids of patients with cancer, especially blood, suggesting their role as an emerging class of circulating biomarkers. Many ncRNAs, both miRNAs and lncRNAs, are deregulated in sarcoma tissues, with the most consistent data in osteosarcomas. In patients with osteosarcoma, the role of ncRNAs as circulating biomarkers is taking enormous value, above all for their ability to vary expression levels during disease progression and in response to therapy. In this mini-review, we summarize the main studies supporting the role of circulating ncRNAs in monitoring disease status in patients with osteosarcoma.

18.
J Clin Lab Anal ; 33(5): e22876, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30843304

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is a global health problem especially for its increasing level of mortality. Detailed knowledge of HCV genotypes prevalence has clinical relevance since the efficacy of therapies is impacted by genotypes and subtypes distribution. Moreover, HCV exhibits a great genetic variability regionally. To date, there are no published studies assessing HCV genotypes distribution in specific countries of the Mediterranean basin. The aim of this study was to review data published from 2000 to 2017 with the purpose to estimate genotypes distribution of HCV infection in nine European countries all located in the Mediterranean basin. METHODS: A systematic research of peer-reviewed journals indexed in PubMed, Scopus, and EMBASE databases selected if containing data regarding distribution of HCV genotypes in nine selected European countries (Albania, Bosnia, Croatia, France, Greece, Italy, Montenegro, Slovenia, and Spain) was performed. RESULTS: Genotype 1 is the most common (61.0%), ranging from 80.0% in Croatia to 46.0% in Greece, followed by genotype 3 (20.0%), varying from 38.0% in Slovenia to 7.0% and 8.0%, respectively, in Italy and in Albania and by genotype 4 (10.0%) that shows an increase of 1.1% with respect to data obtained till 2014 probably due to the increasing migrants arrivals to Southern Europe. G2, the fourth most frequent genotype (8.5%), particularly common in Italy (27.0%) and Albania (18.0%) might be probably introduced in Southern Italy as a result of Albanian campaign during Second World War and more and more increased by the migration flows from Albania to Italy in the 90s. CONCLUSION: Epidemiology of HCV infection shows a high variability across the European countries that border the Mediterranean Sea. HCV genotyping is a relevant tool to monitor the dynamic process influenced by both evolving transmission trends and new migration flows on HCV scenario.

20.
J Nucl Med ; 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30877175

RESUMO

There is an unmet need for predictive biomarkers of the clinical benefit of anti-angiogenic drugs.The aim of the present study was to prospectively evaluate the value of FDG-PET/CT performed during and after preoperative radiochemotherapy (CRT) with bevacizumab for the prediction of complete pathologic tumor regression and survival in magnetic resonance imaging (MRI)-defined high-risk locally advanced rectal cancer (LARC) patients Methods: Sixty-one patients treated in a non-randomized phase II study (BRANCH) with concomitant or sequential (4 days before CRT) administration of bevacizumab with preoperative CRT were included. 18F-FDG PET/CT was performed at baseline, 11 days after the beginning of the CRT (early) and before surgery (late). Metabolic changes were compared with pathological complete (TRG1) vs incomplete (TRG2-5) tumor regression, progression-free survival (PFS), cancer specific survival (CSS) and overall survival (OS). Receiver operating characteristic (ROC) curves were calculated for those FDG-PET/CT parameters that significantly correlated with TRG1. Results: Early total lesion glycolysis (TLG-early) and its percent change compared to baseline (ΔTLG-early %) could discriminate TRG1 from TRG2-5. Only ROC analysis of ΔTLG-early % showed an AUC > 0.7 (0.76), with an optimal cutoff at 59.5% (80% sensitivity, 71.4 specificity) for identifying TRG1. Late metabolic assessment could not discriminate between the two groups. After a median follow-up of 98 months (range 77-132) metabolic responders (ΔTLG-early % ≥ 59.5 %) demonstrated a significantly higher 10-year PFS (89.3 vs 63.6 %, P = 0.02) and CSS (92.9 vs 72.6 %, P = 0.04) compared to incomplete metabolic responders . Conclusion: Our results suggest that early metabolic response can act as a surrogate marker of the benefit of antiangiogenic therapy and provide further support for the use of early -FDG-PET/CT evaluation to predict pathological response and survival in the preoperative treatment of patients with LARC. ΔTLG-early% showed the best accuracy in predicting TRG and may be particularly useful in guiding treatment modifying decisions during preoperative CRT based on expected response.

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