Publications by authors named "Vito Longo"

45 Publications

Successful treatment of triple EGFR mutation T785A/L861Q/H297_E298 with afatinib.

Thorac Cancer 2021 May 19. Epub 2021 May 19.

Medical Thoracic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.

Patients with non-small cell lung cancer (NSCLC) and uncommon epidermal growth factor receptor (EGFR) mutation are characterized by high heterogeneity, and globally considered to have a worse prognosis than patients with the two common mutations; exon 19 deletion, and exon 21 L858R. Nevertheless, some uncommon mutations do confer sensitivity to tyrosine kinase inhibitors (TKIs) which is comparable with common mutations. In particular, some compound EGFR mutations seem to be characterized by a favorable prognosis. Unfortunately, the rarity of complex EGFR mutations results in difficult clinical decision-making. Herein, to the best of our knowledge, we report the first case of an NSCLC patient with an EGFR triple mutation containing T785A/L861Q/H297_E298 who was successfully treated with afatinib.
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http://dx.doi.org/10.1111/1759-7714.13953DOI Listing
May 2021

[RET rearrangements in advanced lung cancer: a target to always look for.]

Recenti Prog Med 2021 Feb;112(2):33e-36e

SSD Oncologia Medica per la Patologia Toracica, IRCCS Istituto Tumori "Giovanni Paolo II", Bari.

Introduction . RET rearrangements have been recently aroused growing interest, due to the availability of target therapies increasingly active and safe. The search for these oncogenic alterations in patients with advanced lung adenocarcinoma has become an integral part of the biomolecular tumoral assessment, in order to possibly provide a selective therapeutical option also for rare subgroups of patients, but belonging to lung cancer that is considered a "big killer", representing the most frequent cause of cancer-related death worldwide. Following to the introduction of modern biomolecular techniques, such as the comprehensive genome profiling (CGP), that has been added to the immunohistochemistry (IHC) and the "in situ fluorescent ibridation" (FISH), the availability of techniques based on genomic sequencing such as the next generation sequencing (NGS), achievable either on tumoral tissue or on plasma, has made it easier to identify oncogenic alterations that, although rare, are potentially treatable with molecularly targeted drugs. A complete molecular assessment should preferable be obtained at the first diagnosis, in order not to neglect the possibility of using target drugs if indicated, but it is possible and desiderable to complete or to re-determine the biomolecular profile also during the clinical course, due to the possibility of spontaneous or drug-induced resistance mechanisms that can modify the biomolecular tumoral characteristics; this reassessment is achievable both through tissutal rebiopsy and by plasma test, the so-called "liquid biopsy". Clinical case . In this report, we describe the case of a patient with advanced lung adenocarcinoma, pretreated with multiple chemo- and immuno-therapic lines of treatment; at baseline, the biomolecular profile was not complete, as well as during the clinical course through repeated re-biopsies. Conclusions . At the time of further disease progression, a liquid biopsy with NGS revealed the presence of a RET rearrangement. This clinical case underscores the importance of a complete biomolecolar assessment in order to identify target linked to effective and innovative treatment options; it is also highlighted the usefulness of the modern CGP techniques, applicable to tumoral tissue and plasma.
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http://dx.doi.org/10.1701/3559.35382DOI Listing
February 2021

[Efficacy of pralsetinib in a patient with advanced lung adenocarcinoma positive for RET rearrangement: the importance of Comprehensive Genomic Profiling.]

Recenti Prog Med 2021 Jan;112(1):10e-13e

IRCCS Istituto Tumori Giovanni Paolo II, SSD Oncologia Medica per la Patologia Toracica, Bari.

Modern gene profiling techniques have allowed in recent years considerable progresses in the knowledge of molecular alterations in the context of non-small cell lung cancer (NSCLC). In some cases, these alterations have been recognized as having a pathogenic role and targeted therapies capable of inhibiting tumor proliferation by selective and specific blocking of the enzymatic activity of the related abnormal proteins have been developed. This has made it possible to improve the effectiveness of the treatments by minimizing toxicity. Today it is essential to apply Comprehensive Genomic Profiling methods also in clinical practice, in order to allow the best treatment available for each patient, possibly also in the context of clinical trials. Below we report the clinical history of a patient with advanced stage adenocarcinoma of the lung with molecular diagnosis of RET fusion, treated with pralsetinib with excellent clinical and radiological response and good tolerability. This clinical case emphasizes the importance of the broader molecular profiling in patients with advanced NSCLC (especially for non-squamous histology) from the diagnosis before starting first-line treatment.
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http://dx.doi.org/10.1701/3525.35132DOI Listing
January 2021

Impact of tobacco control interventions on smoking initiation, cessation, and prevalence: a systematic review.

J Thorac Dis 2020 Jul;12(7):3844-3856

Thoracic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.

This article investigates the effects of tobacco control policies on smoking initiation, cessation and prevalence by examining the papers published in the last 5 years. Twenty-one articles have been selected by two authors and sorted by four types of tobacco control: tobacco prices, anti-smoking campaigns for young people, mass media intervention and public smoking bans. Price/tax increase has deterrent effect on smoking initiation but does not promote smoking cessation; intervention on young people could reduce the smoking initiation if carried out at an early age and if acted on social skills and with peer-led approach, as opposed to restraining measures which hare generally easily circumvented by young people. The mass media campaigns showed positive effect on attempts to quit among smokers if carried forward over time and by involving multiple communication channels (TV, internet, radio). The bans in public have little effect on smoking cessation but could improve the overall well-being of non-smokers. Heterogeneous results have been described by different studies probably because of different research methodologies, cultural aspects and the really effective implementation of the rules for each country. In conclusion, comprehensive tobacco control interventions to reduce smoking prevalence and modify the smoking behavior are recommended. Moreover, the use of e-cigarettes and heat-not-burn (HnB) products, as possible helping tool for smoke cessation, currently remains controversial.
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http://dx.doi.org/10.21037/jtd.2020.02.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399441PMC
July 2020

Smoking Prevalence, Knowledge and Perceptions on Tobacco Control Among Healthcare Professionals: A Survey in an Italian Cancer Center.

J Community Health 2021 Jun;46(3):597-602

IRCCS Istituto Tumori "Giovanni Paolo II" 65, Viale Orazio Flacco, 70124, Bari, Italy.

Smoking is recognized as the major cause of lung cancer. Healthcare professionals play an important role in lung cancer prevention policies, as they act as a source of guidance for patients and advocates. The following survey evaluated prevalence, knowledge, and attitudes toward tobacco smoking among a sample of workers in "IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, an Italian cancer hospital. An anonymous questionnaire was completed by 104 healthcare professionals to collect personal and occupational data about smoking status, knowledge about the harms of smoking, current legislation in place, Second-Hand Smoke (SHS) awareness, and, for ex-smokers, the reasons for quitting. Among participants, 17.8% were current smokers, 26.2% former smokers, and 56% never smoked. Only 40% acknowledged that the smoking ban is generally respected, and 63.2% reported that they smoke during working hours. Most of the participants perceived tobacco control policy as an efficient way to protect public health. Currently, the implementation of Italian anti-smoking legislation has so far improved neither smoking cessation rates nor the will to quit smoking completely. Our experience highlights that to date the anti-smoking strategies have limited efficacy even in a cancer center; in fact, there is still a large prevalence of smokers among hospital personnel. Therefore, it is strongly suggested that interventions be shared with all healthcare workers, specifically aimed at developing a culture of health promotion.
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http://dx.doi.org/10.1007/s10900-020-00907-8DOI Listing
June 2021

DiM: Prognostic Score for Second- or Further-line Immunotherapy in Advanced Non-Small-Cell Lung Cancer: An External Validation.

Clin Lung Cancer 2020 09 7;21(5):e337-e348. Epub 2020 Mar 7.

Medical Thoracic Oncology Unit, IRCCS Oncologico Giovanni Paolo II of Bari, Bari, Italy.

Background: Other than the programmed cell death ligand 1 (PD-L1) value, oncologists have only the clinical characteristics of patients with advanced non-small-cell lung cancer (aNSCLC) to determine candidates for immunotherapy. A clinical prognostic score composed of the Eastern Cooperative Oncology Group performance status, sex, histologic type, stage, platinum-based first-line therapy, and response to first-line therapy has categorized 3 prognostic groups for patients undergoing second-line chemotherapy. We sought to validate the same score for patients with aNSCLC treated with second- or further-line immunotherapy.

Materials And Methods: We collected data from 2 Italian centers. A score was generated to divide patients into 3 prognostic groups: best, score < 5; intermediate, score 5 to 9; and worst, score > 9. Overall survival (OS) and progression-free survival (PFS) were the endpoints.

Results: A total of 347 patients were included for analysis. Their median age was 66 years (range, 30-88 years), most were aged < 70 years (67.5%), 70.7% were men, 79.5% were smokers, and 74.6% had had adenocarcinoma. The Eastern Cooperative Oncology Group performance status was 0 for 23%, 1 for 54.5%, and 2 for 22.5%. Of the 347 patients, 28% were in the best prognosis, 51% in the intermediate, and 21% in the worst prognosis group, respectively. The median OS was 18.0 months for the best, 8.5 months for the intermediate (hazard ratio [HR] vs. best, 1.83; 95% confidence interval [CI], 1.35-2.47; P < .001) and 2.6 months for worst (HR vs. best, 5.77; 95% CI, 3.99-8.33; P < .001) group. The median PFS was 3.4 months for the best, 3.7 months for the intermediate (HR vs. best, 1.35; 95% CI, 1.03-1.77; P = .032), and 1.9 months for the worst (HR vs. best, 2.51; 95% CI, 1.80-3.50; P < .001) group.

Conclusions: The prognostic score was able to predict the outcomes of patients with aNSCLC who had received immunotherapy. The worst category showed a dismal life expectancy and probably would not benefit from active systemic therapy. Thus, for these patients, best supportive care could be the best choice.
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http://dx.doi.org/10.1016/j.cllc.2020.01.005DOI Listing
September 2020

EPSILoN: A Prognostic Score Using Clinical and Blood Biomarkers in Advanced Non-Small-cell Lung Cancer Treated With Immunotherapy.

Clin Lung Cancer 2020 07 7;21(4):365-377.e5. Epub 2020 Mar 7.

Medical Thoracic Oncology Unit, Clinical Cancer Center "Giovanni Paolo II", Bari, Italy.

Background: Second-line immunotherapy (IO) has shown an overall survival benefit. However, only 18% to 20% of patients with advanced non-small-cell lung cancer (aNSCLC) will respond, with a median progression-free survival (PFS) of 2 to 4 months. Thus, biomarkers to select those patients most likely to benefit from IO are greatly needed.

Patients And Methods: We conducted a retrospective analysis of 154 patients with aNSCLC who had received anti-programmed cell death 1 therapy as second line or further treatment. We assessed the absolute neutrophil, lymphocyte, monocyte, and eosinophil counts at baseline (T0) and the second (T1) and third (T2) cycles. The neutrophil/lymphocyte ratio (NLR), derived-NLR (dNLR), lymphocyte/monocyte ratio (LMR), and their percentage of change at T1 and T2 compared with T0 were evaluated. The clinical characteristics and lactate dehydrogenase (LDH) level were also considered. Univariate and multivariate analyses were performed. Significant biomarkers for PFS on multivariate analysis were combined in a prognostic score.

Results: For overall survival, the negative prognostic biomarkers were Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, NLR at T0, and dNLR at T1; the LMR at T0, T1, and T2 was identified as a positive prognostic biomarker. For PFS, the negative prognostic biomarkers were ECOG PS 2, liver metastases, NLR at T0, dNLR at T1 and T2, and ≥ 30% increase of NLR from T0 to T1; the positive prognostic biomarkers were heavy smoking, LDH, and LMR at T2. The ≥ 30% increase of LMR from T0 to T1 and T0 to T2 correlated with the overall response rate. A prognostic score (EPSILoN score; smoking, ECOG PS, liver metastases, LDH, NLR) identified 3 prognostic groups (median PFS, 10.2, 4.9, and 1.7 months, respectively; P < .001).

Conclusions: The EPSILoN score combines 5 baseline clinical and blood biomarkers and can help to identify patients with aNSCLC who will most likely benefit from second-line IO. Further studies are warranted.
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http://dx.doi.org/10.1016/j.cllc.2019.11.017DOI Listing
July 2020

Immune system and bone microenvironment: rationale for targeted cancer therapies.

Oncotarget 2020 Jan 28;11(4):480-487. Epub 2020 Jan 28.

Medical Oncology Unit, "S. Cuore di Gesù" Hospital, Gallipoli, Italy.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator of NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.
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http://dx.doi.org/10.18632/oncotarget.27439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996902PMC
January 2020

Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies.

Medicina (Kaunas) 2019 Nov 21;55(12). Epub 2019 Nov 21.

Medical Oncology Unit, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.

The few therapeutic strategies for advance hepatocellular carcinoma (HCC) on poor knowledge of its biology. For several years, sorafenib, a tyrosine kinase inhibitors (TKI) inhibitor, has been the approved treatment option, to date, for advanced HCC patients. Its activity is the inhibition of the retrovirus-associated DNA sequences protein (RAS)/Rapidly Accelerated Fibrosarcoma protein (RAF)/mitogen-activated and extracellular-signal regulated kinase (MEK)/extracellular-signal regulated kinases (ERK) signaling pathway. However, the efficacy of sorafenib is limited by the development of drug resistance, and the major neuronal isoform of RAF, BRAF and MEK pathways play a critical and central role in HCC escape from TKIs activity. Advanced HCC patients with a BRAF mutation display a multifocal and/or more aggressive behavior with resistance to TKI. Moreover, also long non-coding RNA (lnc-RNA) have been studied in epigenetic studies for BRAF aggressiveness in HCC. So far, lnc-RNA of BRAF could be another mechanism of cancer proliferation and TKI escape in HCC and the inhibition could become a possible strategy treatment for HCC. Moreover, recent preclinical studies and clinical trials evidence that combined treatments, involving alternative pathways, have an important role of therapy for HCC and they could bypass resistance to the following TKIs: MEK, ERKs/ribosomal protein S6 kinase 2 (RSK2), and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). These initial data must be confirmed in clinical studies, which are currently ongoing. Translational research discoveries could create new strategies of targeted therapy combinations, including BRAF pathway, and they could eventually bring light in new treatment of HCC.
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http://dx.doi.org/10.3390/medicina55120754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956203PMC
November 2019

Predictive and Prognostic Factors in HCC Patients Treated with Sorafenib.

Medicina (Kaunas) 2019 Oct 21;55(10). Epub 2019 Oct 21.

Medical Oncology Unit, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.

Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first.
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http://dx.doi.org/10.3390/medicina55100707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843290PMC
October 2019

Emerging role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.

Medicina (Kaunas) 2019 Oct 17;55(10). Epub 2019 Oct 17.

Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, 70124 Bari, Italy.

Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70-80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib had been the standardcare for almost a decade until 2018 when the Food and Drug Administration approved an alternative first-line agent namely lenvatinib. Cabozantinib, regorafenib, and ramucirumab also displayed promising results in second line settings. FOLFOX4, however, results inan alternative first-line treatment for the Chineseclinical oncology guidelines. Moreover,nivolumab and pembrolizumab,two therapeutics against the Programmed death (PD)-ligand 1 (PD-L1)/PD1 axis have been recently approvedfor subsequent-line therapy. However, similar to other solid tumors, the response rate of single agent targeting PD-L1/PD1 axis is low. Therefore, a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors (ICIs), the addition of ICIs after resection or during loco-regional therapy, ICIs in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with a careful assessmentof new ICIs-based combinatory approaches.
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http://dx.doi.org/10.3390/medicina55100698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843273PMC
October 2019

Molecular Characterization of a Long-Term Survivor Double Metastatic Non-Small Cell Lung Cancer and Pancreatic Ductal Adenocarcinoma Treated with Gefitinib in Combination with Gemcitabine Plus Nab-Paclitaxel and mFOLFOX6 as First and Second Line Therapy.

Cancers (Basel) 2019 May 29;11(6). Epub 2019 May 29.

ScientificDirectorate, IRCCS IstitutoTumori "Giovanni Paolo II", Viale OrazioFlacco, 65, 70124 Bari, Italy.

The management of multiple primary cancers, an event not so infrequent in oncology practice, is a critical issue due to the lack of literature. In this study, we reported the case of a patient with non-small cell metastatic lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) who received gefitinib in combination with gemcitabine plus nab-paclitaxel and with mFOLFOX6 in first and second line, respectively. It achieved a progression-free survival and a28-months overall survival (OS) for NSCLC and PFS-1 and OS of 20 and 13 months, respectively for PDAC. Moreover, the combination of gefitinib and chemotherapy treatmentsshowed a good safety profile. Given the insignificant frequency of this case, we performed a molecular characterization of both neoplasms with the aim to investigate the existence of particular activated pathways and/or similar immunological mutations. It is interesting to note that two neoplasms shared a common mutation ofthe B7-H3 gene, with the consecutive impairment of its expressed protein. In both PDAC and NSCLC, the expression of this protein was associated with a worse survival rate. Since B7-H3 is an anti-apoptotic protein, the reduction of its expression or function should justify a pro-apoptotic activity with a leading justification of the long survival of the patient considered in this report.
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http://dx.doi.org/10.3390/cancers11060749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627355PMC
May 2019

Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other Than Abscopal Effect: A Systematic Review.

Cancers (Basel) 2019 Apr 15;11(4). Epub 2019 Apr 15.

Scientific Guidance, IRCCS Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.

Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitourinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response such as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a higher expression of immune checkpoint molecules, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors in order to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve the response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitory receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.
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http://dx.doi.org/10.3390/cancers11040539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521062PMC
April 2019

Inflammatory cells infiltrate and angiogenesis in locally advanced and metastatic cholangiocarcinoma.

Eur J Clin Invest 2019 May 3;49(5):e13087. Epub 2019 Mar 3.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.

Background: Cholangiocarcinoma (CCA) is the second most common subtype of primary hepatobiliary cancer and one of the most aggressive characterized by an extremely poor prognosis with limited treatment options. Inflammatory cells in tumour microenvironment support tumour growth in term of progression, angiogenesis and metastatic capacity. A link between inflammation and biliary carcinogenesis has been previously observed but the mechanisms involved remain to be determined.

Methods: We investigated the microvascular density (MVD) and inflammatory cells in tissue samples from 40 patients with CCA with locally advanced CCA and metastatic CCA by means of immunohistochemical analysis of macrophages, mast cells, B and T lymphocytes and we correlated inflammatory infiltrate with MVD.

Results: We observed significant decrease in the levels of CD31 positive vessels, and CD8, CD4, CD68 and tryptase-positive cells in metastatic lesions as compared to the localized ones. A negative correlation between CD31 and CD8 and CD31 and CD4 in localized CCA samples was found as assessed by Spearman correlation analysis.

Conclusions: In locally advanced CCA patients, there is a significant increase of immune cell infiltrate constituted by CD8 and CD4 lymphocytes, macrophages and mast cells as compared to the metastatic ones. This alteration in the tumour microenvironment infiltrate is related to a significant increased MVD in localized CCA lesions compared with the metastatic ones. Moreover, we observed a negative correlation between MVD and CD8 , CD4 cells in localized CCA patients.
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http://dx.doi.org/10.1111/eci.13087DOI Listing
May 2019

expression in resected lung adenocarcinoma.

Transl Lung Cancer Res 2018 Dec;7(Suppl 4):S364-S366

Medical Thoracic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.

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http://dx.doi.org/10.21037/tlcr.2018.09.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328692PMC
December 2018

Mast cells and angiogenesis in pancreatic ductal adenocarcinoma.

Clin Exp Med 2018 Aug 28;18(3):319-323. Epub 2018 Feb 28.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.

Mast cells are recognized as critical components of the tumor stromal microenvironment in several solid and hematological malignancies, promoting angiogenesis and tumor growth. A correlation between mast cells infiltration, angiogenesis and tumor progression has been reported for pancreatic ductal adenocarcinoma as well. Mast cells contribute to the aggressiveness of the pancreatic ductal carcinoma enhancing the expression of several pro-angiogenic factors such as vascular endothelial growth factor, fibroblast growth factor-2, platelet-derived growth factor and angiopoietin-1 as well as stimulating the pancreatic cancer cells proliferation by IL-13 and tryptase. The disruption of this pro-angiogenic and proliferative stimulation by inhibiting the mast cells migration and degranulation is under investigation as a potential therapeutic approach in pancreatic ductal adenocarcinoma patients. This review will summarize the literature concerning the mast cells infiltration in the pancreatic ductal adenocarcinoma analyzing its role in angiogenesis and tumor progression.
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http://dx.doi.org/10.1007/s10238-018-0493-6DOI Listing
August 2018

Metastatic HPV-related oropharyngeal carcinoma cured with chemoradiotherapy: importance of pretherapy biomolecular assessment.

Clin Case Rep 2018 01 24;6(1):56-62. Epub 2017 Nov 24.

Institute of Biostructure and Bioimaging National Council of Research Naples Italy.

Pretherapy assessment has a crucial role in the management of advanced oropharyngeal carcinoma. The case report represents an example of how translational research may help to optimize the therapeutic options and to choose a well-shaped therapy adapted to the tumor and the patient.
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http://dx.doi.org/10.1002/ccr3.1107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771910PMC
January 2018

Angiogenesis in adenosquamous cancer of pancreas.

Oncotarget 2017 Nov 27;8(56):95773-95779. Epub 2017 Sep 27.

Molecular Genetics Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", 70124, Bari, Italy.

Adenosquamous carcinoma of the pancreas (ASCP) is an uncommon variant of exocrine pancreatic malignancies, characterized by a histological admixture of adenomatous and squamous cell elements. This cancer is characterized by a poorly differentiated histology and a poorer clinical outcome compared to pancreatic ductal adenocarcinoma (PDAC). Unlike PDAC, that is characterized by a low microvascular density (MVD) and collapsed vasculature, no data are available about angiogenesis in ASPC. Immunohistochemical evaluation of MVD and trypatse-positive mast cells (MCs) were performed on a single case of ASCP compared to PDAC. Moreover, the levels of angiopoietin-1 and -2 (Ang-1, Ang-2), receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2 (Tie-2), vascular endothelial growth factor A (VEGFA), hypoxia-inducible factor 1 alpha (HIF1A), miR-21-5p, miR-181a-5p, miR-122-5p, and miR-27a-3p were evaluated by real-time PCR. Higher number of tryptase-positive MCs and MVD are observed in the ASCP case compared to PDAC one. Lower levels of miR-122-5p and higher expression of VEGFA, HIF1A and Ang-2 genes were observed in ASCP. Furthermore, lower Ang-1 and Tie-2 transcript levels and higher increases of miR-21-5p, miR27a-3p and miR-181a-5p levels were found in the rarest form of pancreatic carcinoma. Our data demonstrate an important angiogenic activity in ASCP with a putative role of miR-21-5p, miR-181a-5p, miR-122-5p and miR-27a-3p in the regulation of this process.
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http://dx.doi.org/10.18632/oncotarget.21319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707059PMC
November 2017

Management of patients with end-stage renal disease undergoing chemotherapy: recommendations of the Associazione Italiana di Oncologia Medica (AIOM) and the Società Italiana di Nefrologia (SIN).

ESMO Open 2017 19;2(3):e000167. Epub 2017 Jul 19.

Department of Medical Oncology and Breast Unit, Sen. Antonio Perrino Hospital, Brindisi, Italy.

Background: The overall risk of some cancers is increased in patients receiving regular dialysis treatment due to chronic oxidative stress, a weakened immune system and enhanced genomic damage. These patients could benefit from the same antineoplastic treatment delivered to patients with normal renal function, but a better risk/benefit ratio could be achieved by establishing specific guidelines. Key considerations are which chemotherapeutic agent to use, adjustment of dosages and timing of dialysis in relation to the administration of chemotherapy.

Methods: We have reviewed available data present in the literature, including recommendations and expert opinions on cancer risk and use of chemotherapeutic agents in patients with end-stage renal disease. Experts selected by the boards of the societies provided additional information which helped greatly in clarifying some issues on which clear-cut information was missing or available data were conflicting.

Results: Data on the optimal use of chemotherapeutic agents or on credible schemes of polychemotherapy in haemodialysed patients are sparse and mainly derive from case reports or small case series. However, recommendations on dosing and timing of dialysis can be proposed for the most prescribed chemotherapeutic agents.

Discussion: The use of chemotherapeutic agents as single agents, or in combination, can be safely given in patients with end-stage renal disease. Appropriate dosage adjustments should be considered based on drug dialysability and pharmacokinetics. Coordinated care between oncologists, nephrologists and pharmacists is of pivotal importance to optimise drug delivery and timing of dialysis.
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http://dx.doi.org/10.1136/esmoopen-2017-000167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703391PMC
July 2017

Immunotherapeutic approaches for hepatocellular carcinoma.

Oncotarget 2017 05;8(20):33897-33910

Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy.

Hepatocellular carcinoma (HCC) is a cancer with a high mortality rate due to the fact that the diagnosis usually occurs at anadvanced stage. Even in case of curative surgical treatment, recurrence is common. Sorafenib and regorafenib are the only therapeutic agents that have been demonstrated to be effective in advanced HCC, thus novel curative approaches are urgently needed. Recent studies focus on the role of immune system in HCC. In fact, the unique immune response in the liver favors tolerance, which can represent a real challenge for conventional immunotherapy in these patients. Spontaneous immune responses against tumor antigens have been detected, and new immune therapies are under investigation: dendritic cell vaccination, immune-modulator strategy, and immune checkpoint inhibition. In recent years different clinical trials examining the use of immunotherapy to treat HCC have been conducted with initial promising results. This review article will summarize the literature data concerning the potential immunotherapeutic approaches in HCC patients.
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http://dx.doi.org/10.18632/oncotarget.15406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464921PMC
May 2017

Targeting Angiogenesis in Biliary Tract Cancers: An Open Option.

Int J Mol Sci 2017 Feb 15;18(2). Epub 2017 Feb 15.

Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.

Biliary tract cancers (BTCs) are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer. Recent studies evaluated the genomic landscape of BTCs and evidenced that aberrations in several genes enrolled in the pro-angiogenic signaling, such as FGF receptor-2 (FGFR-2), are characteristic of BTCs. New drugs targeting the signaling pathways involved in angiogenesis have been tested in preclinical studies both in vitro and in vivo with promising results. Moreover, several clinical studies tested monoclonal antibodies against VEGF and tyrosine kinase inhibitors targeting the VEGF and the MEK/ERK pathways. Herein, we evaluate both the pathogenic mechanisms of BTCs focused on angiogenesis and the preclinical and clinical data available regarding the use of new anti-angiogenic drugs in these malignancies.
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http://dx.doi.org/10.3390/ijms18020418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343952PMC
February 2017

Total and not bevacizumab-bound vascular endothelial growth factor as potential predictive factors to bevacizumab-based chemotherapy in colorectal cancer.

World J Gastroenterol 2016 Jul;22(27):6287-95

Amalia Azzariti, Letizia Porcelli, Michele Signorile, Anna Elisa Quatrale, Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy.

Aim: To identify suitable biomarkers of response to bevacizumab (BV) - it remains an open question. The measurement of serum vascular endothelial growth factor (VEGF) has been proposed as a predictive factor for this drug, even if literature data are contradictory.

Methods: We prospectively evaluated the role of BV, total and not BV-bound VEGF and angiopoietin-2 (Ang-2) serum levels as potential predictive factors of response for BV in combination with an oxaliplatin-based chemotherapy. BV, Ang-2, total and not BV-bound VEGF levels were measured at baseline, before 2(nd) and 5(th) cycle of oxaliplatin-based chemotherapy in 20 consecutive metastatic colorectal cancer patients.

Results: Results were correlated to response to treatment. Variability in BV levels have been found, with decreased level in less responding patients. In particular, the concentration of BV increased of 3.96 ± 0.69 folds in serum of responsive patients after 3 more cycles of therapy compared to those with stable or progressive disease with a 0.72 ± 0.25 and 2.10 ± 0.13 fold increase, respectively. The determination of free and total VEGF demonstrated that the ratio between the two values, evaluated immediately before the 2(nd) and the 5(th) cycle of therapy, decreased from 26.65% ± 1.33% to 15.50% ± 3.47% in responsive patients and from 53.41% ± 4.75 to 34.95% ± 2.88% in those with stable disease. Conversely, in those with progression of disease, the ratio showed the opposite behavior coming up from 25.99% ± 5.23% to 51.71% ± 5.28%. The Ang-2 levels did not show any relationship.

Conclusion: Our data show that the ratio of not BV-bound VEGF to total VEGF serum and BV plasma concentrations for predicting the response to BV plus oxaliplatin-based chemotherapy could be a promising biomarker of response to BV.
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http://dx.doi.org/10.3748/wjg.v22.i27.6287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945987PMC
July 2016

Angiogenesis in pancreatic ductal adenocarcinoma: A controversial issue.

Oncotarget 2016 Sep;7(36):58649-58658

Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy.

Pancreatic ductal adenocarcinoma (PDAC) occurs in the majority of cases with early loco-regional spread and distant metastases at diagnosis, leading to dismal prognosis with a 5-year overall survival rate moderately over than 5%. This malignancy is largely resistant to chemotherapy and radiation, but the reasons of the refractoriness to the therapies is still unknown. Evidence is accumulating to indicate that the PDAC microenvironment and vascularity strongly contribute to the clinical features of this disease. In particular, PDAC is characterized by excessive dense extracellular matrix deposition associated to vasculature collapse and hypoxia with low drug delivery, explaining at least partly the low efficacy of antiangiogenic drugs in this cancer. Strategies aimed to modulate tumor stroma favoring vasculature perfusion and chemotherapeutics delivery are under investigation.
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http://dx.doi.org/10.18632/oncotarget.10765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295459PMC
September 2016

Innovative surgical approaches for hepatocellular carcinoma.

World J Hepatol 2016 May;8(13):591-6

Riccardo Memeo, Vito de Blasi, Zineb Cherkaoui, Jacques Marescaux, Didier Mutter, Patrick Pessaux, Department of Digestive Surgery, University Hospital of Strasbourg, 67091 Stra-sbourg, France.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, with an increasing diffusion in Europe and the United States. The management of such a cancer is continuously progressing and the objective of this paper is to evaluate innovation in the surgical treatment of HCC. In this review, we will analyze the modern concept of preoperative management, the role of laparoscopic and robotic surgery, the intrao-perative use of three dimensional models and augme-nted reality, as well as the potential application of fluore-scence.
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http://dx.doi.org/10.4254/wjh.v8.i13.591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858623PMC
May 2016

Neoadjuvant multimodal treatment of pancreatic ductal adenocarcinoma.

Crit Rev Oncol Hematol 2016 Feb 23;98:309-24. Epub 2015 Nov 23.

Medical Oncology Clinic, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy.

Treatment of pancreatic ductal adenocarcinoma (PDAC) is increasingly multidisciplinary, with neoadjuvant strategies (chemotherapy, radiation, and surgery) administered in patients with resectable, borderline resectable, or locally advanced disease. The rational supporting this management is the achievement of both higher margin-negative resections and conversion rates into potentially resectable disease and in vivo assessment of novel therapeutics. International guidelines suggest an initial staging of the disease followed by a multidisciplinary approach, even considering the lack of a treatment approach to be considered as standard in this setting. This review will focus on both literature data supporting these guidelines and on new opportunities related to current more active chemotherapy regimens. An analysis of the pathological assessment of response to therapy and the potential role of target therapies and translational biomarkers and ongoing clinical trials of significance will be discussed.
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http://dx.doi.org/10.1016/j.critrevonc.2015.11.016DOI Listing
February 2016

Cancer survivorship: long-term side-effects of anticancer treatments of gastrointestinal cancer.

Curr Opin Oncol 2015 Jul;27(4):351-7

aMedical Oncology and Hematology, Ospedale U.Parini, Aosta bMedical Oncology Unit, 'Mons R Dimiccoli' Hospital, Barletta cMedical Oncology Unit, National Cancer Institute 'Giovanni Paolo II', Bari, Italy.

Purpose Of Review: Surveillance of patients with a history of cancer is a frequent practice in oncology. However, it is often aimed at the early diagnosis of relapse and tends to underestimate the evaluation and care of factors impairing quality of life (QoL). Among these, long-term toxicities of anticancer treatments are one of the major threats to a complete physical and psychosocial recovery. We aimed to review the relevant literature on long-term side-effects of treatment in gastrointestinal cancers.

Recent Findings: We focused on esophageal, gastric, pancreatic, liver and colorectal cancers. A significant fraction of patients treated for these cancers suffer with some form of late toxicity from surgery, radiotherapy or chemotherapy. Prompt evaluation and management is of the utmost importance in reducing the impact of these symptoms on QoL.

Summary: The knowledge of the reviewed data should encourage a multidisciplinary approach to surveillance and convince clinicians of the comprehensive role of survivorship care.
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http://dx.doi.org/10.1097/CCO.0000000000000203DOI Listing
July 2015

Bone metastases in hepatocellular carcinoma: an emerging issue.

Cancer Metastasis Rev 2014 Mar;33(1):333-42

Department of Internal Medicine and Clinical Oncology, University of Bari "Aldo Moro", Piazza Giulio Cesare, Bari, 11 70124, Italy.

The nature and the characteristics of bone metastases (BMs) in hepatocellular carcinoma (HCC) have not been fully explored in literature, presumably because HCC skeletal involvement was rarely diagnosed until a few years ago. Recently, the prognosis and the management of HCC clinical progression have been improved thanks to novel imaging techniques and multidisciplinary treatment approaches. As in other osteotropic cancers, both angiogenesis and the epithelial-to-mesenchymal transition play a crucial role in skeletal colonization, with the cooperation of additional factors including vascular endothelial growth factor, transforming growth factor beta, platelet-derived growth factor, insulin-like growth factors I and II, bone morphogenetic proteins, secretory protein clusterin, and others. BMs from HCC are often characterized by soft-tissue expansion with an abundant vascular component and elevated tumor burden. As the majority of metastatic bone lesions from HCC are osteolytic, they are detectable by computerized tomography only at a late stage and not usually visualized by traditional bone scintigraphy. For this reason, new imaging tools are currently being investigated, such as dual tracer positron emission computerized tomography. HCC is frequently complicated by liver failure, resulting in a lower tolerance to opioids used for pain control, but radiotherapy and other local-regional treatments are useful in the treatment of BMs from HCC.
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http://dx.doi.org/10.1007/s10555-013-9454-4DOI Listing
March 2014

[Bone health in the oncologic patient].

Recenti Prog Med 2012 Oct;103(10):373-83

Sezione di Medicina Interna e Oncologia Clinica, Dipartimento di Scienze Biomediche e Oncologia Umana, Università Aldo Moro, 70124 Bari.

Progressive bone loss, resulting in both osteoporosis and osteomalacia, is a frequent long-term complication in cancer patients undergoing common anti-tumor treatment programs. Monitoring of bone health by both imaging techniques and biochemical markers measurement, is useful in preventing the severe skeleton default.
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http://dx.doi.org/10.1701/1171.12980DOI Listing
October 2012