Publications by authors named "Giuseppe Badalamenti"

69 Publications

Prognostic Role of Plasma PD-1, PD-L1, pan-BTN3As and BTN3A1 in Patients Affected by Metastatic Gastrointestinal Stromal Tumors: Can Immune Checkpoints Act as a Sentinel for Short-Term Survival?

Cancers (Basel) 2021 Apr 27;13(9). Epub 2021 Apr 27.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.

Gastrointestinal stromal tumors (GISTs) represent 1% of all primary gastrointestinal tumors. Immune surveillance is often overcome by cancer cells due to the activation of immunoregulatory molecules such as programmed death protein (PD-1) and its ligand PD-L1, and butyrophilin sub-family 3A/CD277 receptors (BTN3A). Because several studies demonstrated that tumor PD-1 and PD-L1 expression may have a prominent prognostic function, this investigation aimed to discover if soluble forms of these molecules may be useful in predicting survival of metastatic GIST (mGIST) patients. Through specific ad hoc developed ELISA assays not yet available on the market, the circulating PD-1, PD-L1, BTN3A1, and pan-BTN3As levels were examined in 30 exon 11-mutated mGIST patients, prior to imatinib therapy. Using specific thresholds derived by ROC analysis, we found that high baseline levels of sPD-1 (>8.1 ng/mL), sPD-L1 (>0.7 ng/mL), sBTN3A1 (>7.0 ng/mL), and pan-BTN3As (>5.0 ng/mL) were correlated with shorter progression-free survival (PFS) and poor prognosis. Contrariwise, subjects with lower plasma concentrations exhibited a median PFS about 20 months longer than to the earlier. Finally, an additional multivariate analysis revealed that circulating levels of sPD-L1 ≤ 0.7 ng/mL and pan-sBTN3As ≤ 5.0 ng/mL, and the absence of exon 11 deletions or delins at codons 557 and/or 558 were associated with a longer PFS in mGIST patients. Our investigation, for the first time, revealed that evaluating the plasma concentration of some immune checkpoints may help prognosticate survival in mGIST patients, suggesting their potential use as prognostic biomarkers beyond the presence of exon 11 Del or Delins at codons 557/558.
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http://dx.doi.org/10.3390/cancers13092118DOI Listing
April 2021

Assessment of morphological CT imaging features for the prediction of risk stratification, mutations, and prognosis of gastrointestinal stromal tumors.

Eur Radiol 2021 Apr 21. Epub 2021 Apr 21.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, Via del Vespro 129, 90127, Palermo, Italy.

Objectives: To investigate the correlation between CT imaging features and risk stratification of gastrointestinal stromal tumors (GISTs), prediction of mutation status, and prognosis.

Methods: This retrospective dual-institution study included patients with pathologically proven GISTs meeting the following criteria: (i) preoperative contrast-enhanced CT performed between 2008 and 2019; (ii) no treatments before imaging; (iii) available pathological analysis. Tumor risk stratification was determined according to the National Institutes of Health (NIH) 2008 criteria. Two readers evaluated the CT features, including enhancement patterns and tumor characteristics in a blinded fashion. The differences in distribution of CT features were assessed using univariate and multivariate analyses. Survival analyses were performed by using the Cox proportional hazard model, Kaplan-Meier method, and log-rank test.

Results: The final population included 88 patients (59 men and 29 women, mean age 60.5 ± 11.1 years) with 45 high-risk and 43 low-to-intermediate-risk GISTs (median size 6.3 cm). At multivariate analysis, lesion size ≥ 5 cm (OR: 10.52, p = 0.009) and enlarged feeding vessels (OR: 12.08, p = 0.040) were independently associated with the high-risk GISTs. Hyperenhancement was significantly more frequent in PDGFRα-mutated/wild-type GISTs compared to GISTs with KIT mutations (59.3% vs 23.0%, p = 0.004). Ill-defined margins were associated with shorter progression-free survival (HR 9.66) at multivariate analysis, while ill-defined margins and hemorrhage remained independently associated with shorter overall survival (HR 44.41 and HR 30.22). Inter-reader agreement ranged from fair to almost perfect (k: 0.32-0.93).

Conclusions: Morphologic contrast-enhanced CT features are significantly different depending on the risk status or mutations and may help to predict prognosis.

Key Points: • Lesions size ≥ 5 cm (OR: 10.52, p = 0.009) and enlarged feeding vessels (OR: 12.08, p = 0.040) are independent predictors of high-risk GISTs. • PDGFRα-mutated/wild-type GISTs demonstrate more frequently hyperenhancement compared to GISTs with KIT mutations (59.3% vs 23.0%, p = 0.004). • Ill-defined margins (hazard ratio 9.66) were associated with shorter progression-free survival at multivariate analysis, while ill-defined margins (hazard ratio 44.41) and intralesional hemorrhage (hazard ratio 30.22) were independently associated with shorter overall survival.
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http://dx.doi.org/10.1007/s00330-021-07961-3DOI Listing
April 2021

Trabectedin for Patients with Advanced Soft Tissue Sarcoma: A Non-Interventional, Retrospective, Multicenter Study of the Italian Sarcoma Group.

Cancers (Basel) 2021 Mar 2;13(5). Epub 2021 Mar 2.

Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, 1 Via Pupilli, 40136 Bologna, Italy.

The Italian Sarcoma Group performed this retrospective analysis of patients with advanced soft tissue sarcoma, pretreated with ≥1 anthracycline-based treatment, and treated with trabectedin every three weeks. Primary endpoint was to describe real-life use of trabectedin across Italy. Secondary endpoints included objective response rate (ORR) and safety. Overall, 512 patients from 20 Italian centers were evaluated. Leiomyosarcoma (37.7%)/liposarcoma (30.3%) were the most prevalent histological types (abbreviated as L-sarcoma). Patients received a median of four trabectedin cycles (range: 1-40), mostly as a second-line treatment (~60% of patients). The ORR was 13.7% superior ( < 0.0001) in patients with L-sarcoma compared with patients with non-L-sarcoma (16.6% vs. 9.0%). Median progression-free survival (PFS) was 5.1 months, whereas median overall survival (OS) was 21.6 months. Significantly better PFS and OS were observed in patients with L-sarcoma, those with objective responses and/or disease stabilization, treated in an early line and treated with reduced dose. Bone marrow toxicity (61.4%) and transaminase increases (21.9%) were the most common grade 3/4 adverse events. The results of this real-life study suggest that trabectedin is an active treatment, which is mostly given as a second-line treatment to patients with a good performance status and high-grade, metastatic L-sarcoma (clinical trial information: NCT02793050).
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http://dx.doi.org/10.3390/cancers13051053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958606PMC
March 2021

Type and Gene Location of Mutations Predict Progression-Free Survival to First-Line Imatinib in Gastrointestinal Stromal Tumors: A Look into the Exon.

Cancers (Basel) 2021 Feb 27;13(5). Epub 2021 Feb 27.

Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.

In previous studies on localized GISTs, exon 11 deletions and mutations involving codons 557/558 showed an adverse prognostic influence on recurrence-free survival. In the metastatic setting, there are limited data on how mutation type and codon location might contribute to progression-free survival (PFS) variability to first-line imatinib treatment. We analyzed the type and gene location of and mutations for 206 patients from a GIST System database prospectively collected at an Italian reference center between January 2005 and September 2020. By describing the mutational landscape, we focused on clinicopathological characteristics according to the critical mutations and investigated the predictive role of type and gene location of the exon 11 mutations in metastatic patients treated with first-line imatinib. Our data showed a predictive impact of exon 11 pathogenic variant on PFS to imatinib treatment: patients with deletion or insertion/deletion (delins) in 557/558 codons had a shorter PFS (median PFS: 24 months) compared to the patients with a deletion in other codons, or duplication/insertion/SNV (median PFS: 43 and 49 months, respectively) ( < 0.001). These results reached an independent value in the multivariate model, which showed that the absence of exon 11 deletions or delins 557/558, the female gender, primitive tumor diameter (≤5 cm) and polymorphonuclear leucocytosis (>7.5 109/L) were significant prognostic factors for longer PFS. Analysis of the predictive role of PVs showed no significant results. Our results also confirm the aggressive biology of 557/558 deletions/delins in the metastatic setting and allow for prediction at the baseline which GIST patients would develop resistance to first-line imatinib treatment earlier.
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http://dx.doi.org/10.3390/cancers13050993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956844PMC
February 2021

pathogenic variants in triple-negative luminal-like breast cancers: genotype-phenotype correlation in a cohort of 531 patients.

Ther Adv Med Oncol 2020 16;12:1758835920975326. Epub 2020 Dec 16.

Section of Medical Oncology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, Palermo, Italy.

Background: Several available data suggest the association between specific molecular subtypes and mutational status. Previous investigations showed the association between pathogenic variants (PVs) in specific genomic regions and phenotypic variations of cancer relative risk, while the role of PV type and location in determining the breast cancer (BC) phenotypic features remains still unclear. The aim of this research was to describe the germline PVs in triple-negative breast cancer (TNBC) luminal-like BC and their potential leverage on BC phenotype.

Patients & Methods: We retrospectively collected and analyzed all clinical information of 531 patients with BC genetically tested for germline PVs by Next-Generation Sequencing analysis at University Hospital Policlinico "P. Giaccone" of Palermo (Sicily) from January 2016 to February 2020.

Results: Our results corroborate the evidence that -related tumors often have a profile which resembles the TNBC subtype, whereas -associated tumors have a profile that resembles luminal-like BC, especially the Luminal B subtype. Interestingly, our findings suggest that the PVs identified in TNBC were not largely overlapping with those in luminal-like tumors. Differences in the frequency of two PVs potentially associated with different molecular tumor subtypes were observed. -633delC was detected with relatively higher prevalence in patients with TNBC, whereas -1466delT was found mainly in Luminal B tumors, but in no TNBC patient.

Conclusion: Future studies examining the type and location of PVs within different molecular subtypes are required to verify our hypothesis and could provide an interesting insight into the complex topic of genotype-phenotype correlations. Additionally, a more in-depth understanding of the potential correlations between PVs and clinical and phenotypic features of hereditary BC syndrome patients could be the key to develop better strategies of prevention and surveillance in -positive carriers without disease.
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http://dx.doi.org/10.1177/1758835920975326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747114PMC
December 2020

A "Lymphocyte MicroRNA Signature" as Predictive Biomarker of Immunotherapy Response and Plasma PD-1/PD-L1 Expression Levels in Patients with Metastatic Renal Cell Carcinoma: Pointing towards Epigenetic Reprogramming.

Cancers (Basel) 2020 Nov 16;12(11). Epub 2020 Nov 16.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.

Introduction of checkpoint inhibitors resulted in durable responses and improvements in overall survival in advanced RCC patients, but the treatment efficacy is widely variable, and a considerable number of patients are resistant to PD-1/PD-L1 inhibition. This variability of clinical response makes necessary the discovery of predictive biomarkers for patient selection. Previous findings showed that the epigenetic modifications, including an extensive microRNA-mediated regulation of tumor suppressor genes, are key features of RCC. Based on this biological background, we hypothesized that a miRNA expression profile directly identified in the peripheral lymphocytes of the patients before and after the nivolumab administration could represent a step toward a real-time monitoring of the dynamic changes during cancer evolution and treatment. Interestingly, we found a specific subset of miRNAs, called "lymphocyte miRNA signature", specifically induced in long-responder patients (CR, PR, or SD to nivolumab >18 months). Focusing on the clinical translational potential of miRNAs in controlling the expression of immune checkpoints, we identified the association between the plasma levels of soluble PD-1/PD-L1 and expression of some lymphocyte miRNAs. These findings could help the development of novel dynamic predictive biomarkers urgently needed to predict the potential response to immunotherapy and to guide clinical decision-making in RCC patients.
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http://dx.doi.org/10.3390/cancers12113396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697734PMC
November 2020

Baseline plasma levels of soluble PD-1, PD-L1, and BTN3A1 predict response to nivolumab treatment in patients with metastatic renal cell carcinoma: a step toward a biomarker for therapeutic decisions.

Oncoimmunology 2020 10 27;9(1):1832348. Epub 2020 Oct 27.

Team Pancreatic Cancer, Centre De Recherche En Cancérologie De Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique Et Technologique De Luminy, Marseille, France.

Despite a proportion of renal cancer patients can experiment marked and durable responses to immune-checkpoint inhibitors, the treatment efficacy is widely variable and identifying the patient who will benefit from immunotherapy remains an issue. We performed a prospective study to investigate if soluble forms of the immune-checkpoints PD-1 (sPD-1), PD-L1 (sPD-L1), pan-BTN3As, BTN3A1, and BTN2A1, could be candidate to predict the response to immune-checkpoint blockade therapy. We evaluated the plasma levels in a learning cohort of metastatic clear cell renal carcinoma (mccRCC) patients treated with the anti-PD-1 agent nivolumab by developed ELISA's. Using specific cut-offs determined through ROC curves, we showed that high baseline levels of sPD-1 (>2.11 ng/ml), sPD-L1 (>0.66 ng/ml), and sBTN3A1 (>6.84 ng/ml) were associated with a longer progression-free survival (PFS) to nivolumab treatment [median PFS, levels above thresholds: sPD-1, 20.7 months ( < .0001); sPD-L1, 19 months ( < .0001); sBTN3A1, 17.5 months ( = .002)]. High sPD-1 and sBTN3A1 levels were also associated with best overall response by RECIST and objective response of >20%. The results were confirmed in a validation cohort of 20 mccRCC patients. The analysis of plasma dynamic changes after nivolumab showed a statistically significant decrease of sPD-1 after 2 cycles (Day 28) in the long-responder patients. Our study revealed that the plasma levels of sPD-1, sPD-L1, and sBTN3A1 can predict response to nivolumab, discriminating responders from non-responders already at therapy baseline, with the advantages of non-invasive sample collection and real-time monitoring that allow to evaluate the dynamic changes during cancer evolution and treatment.
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http://dx.doi.org/10.1080/2162402X.2020.1832348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595592PMC
October 2020

Fatal Heart Failure Induced by Pazopanib in a Sarcoma Patient Previously Treated with Gemcitabine.

J Saudi Heart Assoc 2020 15;32(2):285-287. Epub 2020 Jul 15.

Cardiology Unit, University Hospital P. Giaccone, Department of Excellence of Sciences for Health Promotion and Maternal-Child Care, Internal Medicine and Specialities (ProMISE) "G. D'Alessandro", Palermo, Italy.

Gemcitabine is commonly used for various solid organ malignancies with rarely reported cardiac side effects such as cardiomyopathy. Pazopanib usually can cause arterial hypertension but cases of heart failure have recently been reported. We describe a case of fatal heart failure after treatment with gemcitabine and pazopanib in a 55-year-old female with sarcoma. Patient developed left ventricular dysfunction after gemcitabine treatment and acute heart failure after 22 days of pazopanib treatment which led to death. Physicians should be aware of the cardiotoxicity risk when managing the use of pazopanib especially in patients previously treated with other cardiotoxic drugs.
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http://dx.doi.org/10.37616/2212-5043.1125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640551PMC
July 2020

Duodenal perforation as presentation of gastric neuroendocrine tumour: A case report.

Int J Surg Case Rep 2020 19;77S:S105-S108. Epub 2020 Sep 19.

Department of Surgical, Oncological and Oral Sciences, Section of General and Urgent Surgery, University of Palermo, Italy. Electronic address:

Introduction: Neuroendocrine tumors (NETs) represent uncommon neoplasms with different characteristics. They can be asymptomatic and benign or they can also proliferate and manifest themselves with neoplastic mass symptoms such as intestinal occlusion or with carcinoid syndrome. Gastric neuroendocrine neoplasms (g-NENs) are the most frequent digestive NENs while duodenal neuroendocrine neoplasms (d-NENs) may be sporadic or associated with multiple endocrine neoplasia type 1 (MEN-1) and present a functional syndrome (e.g. gastrinoma with Zollinger-Ellison syndrome).

Presentation Of Case: We report a case of duodenal perforation due to a unknown gastrinoma responsible of Zollinger-Ellison Syndrome. He underwent an emergency contrast enhanced CT abdominal scan that showed a perforation. We performed a distal gastrectomy. The histopathological examination revealed a g-NET configuring a possible picture of Zollinger-Ellison Syndrome.

Discussion: The management of NETs is diffulcult and controversial because of their rarity. It is useful to know the pathologic assessment of tumor differentiation and/or grade, evaluate surgical resectability and control the carcinoid syndrome symptoms.

Conclusion: This case report shows that gastric NETs can be found in cases of duodenal perforation. Our future goal is to evaluate the possibilities to diagnose the Zollinger Ellison Syndrome as early as possible and to treat it with targeted therapy in order to prevent its related complications.
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http://dx.doi.org/10.1016/j.ijscr.2020.09.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876995PMC
September 2020

Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond .

Cancers (Basel) 2020 Aug 25;12(9). Epub 2020 Aug 25.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.

Patients with unilateral breast cancer (UBC) have an increased risk of developing bilateral breast cancer (BBC). The annual risk of contralateral BC is about 0.5%, but increases by up to 3% in or (PV) carriers. Our study was aimed to evaluate whether all BBC patients should be offered multi-gene panel testing, regardless their cancer family history and age at diagnosis. We retrospectively collected all clinical information of 139 BBC patients genetically tested for germline PVs in different cancer susceptibility genes by NGS-based multi-gene panel testing. Our investigation revealed that 52 (37.4%) out of 139 BBC patients harbored germline PVs in high- and intermediate-penetrance breast cancer (BC) susceptibility genes including , , , , , , . Nineteen out of 53 positively tested patients harbored a PV in a known BC susceptibility gene (no-). Interestingly, in the absence of an analysis performed via multi-gene panel, a significant proportion (14.4%) of PVs would have been lost. Therefore, offering a NGS-based multi-gene panel testing to all BBC patients may significantly increase the detection rates of germline PVs in other cancer susceptibility genes beyond , avoiding underestimation of the number of individuals affected by a hereditary tumor syndrome.
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http://dx.doi.org/10.3390/cancers12092415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564956PMC
August 2020

Recent Advances in Desmoid Tumor Therapy.

Cancers (Basel) 2020 Aug 1;12(8). Epub 2020 Aug 1.

Department of Medical Oncology, Università Campus Bio-Medico, 00128 Rome, Italy.

The desmoid tumor is a locally aggressive proliferative disease within the family of soft-tissue sarcomas. Despite its relatively good prognosis, the clinical management of desmoid tumors requires constant multidisciplinary evaluation due to its highly variable clinical behavior. Recently, active surveillance has being regarded as the appropriate strategy at diagnosis, as indolent persistence or spontaneous regressions are not uncommon. Here, we review the most recent advances in desmoid tumor therapy, including low-dose chemotherapy and treatment with tyrosine kinase inhibitors. We also explore the recent improvements in our knowledge of the molecular biology of this disease, which are leading to clinical trials with targeted agents.
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http://dx.doi.org/10.3390/cancers12082135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463981PMC
August 2020

Hereditary Breast and Ovarian Cancer in Families from Southern Italy (Sicily)-Prevalence and Geographic Distribution of Pathogenic Variants in Genes.

Cancers (Basel) 2020 May 5;12(5). Epub 2020 May 5.

Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.

Recent advances in the detection of germline pathogenic variants (PVs) in genes have allowed a deeper understanding of the -related cancer risk. Several studies showed a significant heterogeneity in the prevalence of PVs across different populations. Because little is known about this in the Sicilian population, our study was aimed at investigating the prevalence and geographic distribution of inherited PVs in families from this specific geographical area of Southern Italy. We retrospectively collected and analyzed all clinical information of 1346 hereditary breast and/or ovarian cancer patients genetically tested for germline PVs at University Hospital Policlinico "P. Giaccone" of Palermo from January 1999 to October 2019. Thirty PVs were more frequently observed in the Sicilian population but only some of these showed a specific territorial prevalence, unlike other Italian and European regions. This difference could be attributed to the genetic heterogeneity of the Sicilian people and its historical background. Therefore hereditary breast and ovarian cancers could be predominantly due to PVs different from those usually detected in other geographical areas of Italy and Europe. Our investigation led us to hypothesize that a higher prevalence of some germline PVs in Sicily could be a population-specific genetic feature of -positive carriers.
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http://dx.doi.org/10.3390/cancers12051158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280980PMC
May 2020

Perioperative Chemotherapy in Poorly Differentiated Neuroendocrine Neoplasia of the Bladder: A Multicenter Analysis.

J Clin Med 2020 May 5;9(5). Epub 2020 May 5.

Department of Medical and Surgical Sciences, S.Orsola-Malpighi University Hospital, 40138 Bologna, Italy.

There is scant evidence about optimal management of poorly differentiated neuroendocrine carcinoma of the bladder (BNEC). We performed a multicenter retrospective study on BNEC patients from 13 Italian neuroendocrine-dedicated centers to analyze strategies associated with better outcomes. Mixed adeno-neuroendocrine carcinomas (MANEC) were included. We analyzed overall survival (OS) in the overall cohort, relapse-free survival (RFS) in radically operated patients and progression-free survival (PFS) in patients who received chemotherapy for metastatic disease. Fifty-one BNEC patients were included (male: 46, median age: 70 years). Overall, median OS was 16.0 months, radical tumor resection was performed in 37 patients (72.5%) and 11 of these (29.7%) also received peri-operative platinum-etoposide chemotherapy. Median OS was longer in patients with better performance status (PS) and in those with stage I-III disease at diagnosis compared to stage IV. Among patients who underwent radical tumor resection ( = 37), RFS was longer in patients with better PS and showed a trend towards a longer RFS in those treated with peri-operative chemotherapy than with surgery alone (11 vs. 6 months; = 0.078). Among 28 patients receiving chemotherapy for metastatic disease, PFS was 5.0 months and there was a trend towards improved PFS in patients receiving carboplatin-etoposide chemotherapy compared to other regimens. A multivariate model unmasked a significant association between carboplatin-etoposide chemotherapy and risk for disease progression or death (HR: 0.39 (95%CI: 0.16-0.96) = 0.040). Performance status might be associated with improved RFS in radically operated patients, while type of chemotherapy might affect PFS in patients receiving chemotherapy for metastatic BNEC.
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http://dx.doi.org/10.3390/jcm9051351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290869PMC
May 2020

Cardiovascular Toxicity in Cancer Patients Treated with Tyrosine Kinase Inhibitors: A Real-World Single-Center Experience.

Oncology 2020 29;98(7):445-451. Epub 2020 Apr 29.

Department of Surgical, Oncological, and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.

Background: Target therapy can cause various cardiovascular complications. The aim of this study was to evaluate the burden of cardiovascular complications related to treatment with anti-BCR-ABL tyrosine kinase inhibitors (TKIs) and to determine if there are differences between the latest- and first-generation TKIs.

Methods: A retrospective observational study was carried out on 55 patients (39 men, 16 women; mean age ± SD: 58 ± 11 years) treated with TKIs targeting Bcr-Abl for a median period of 3.5 years. Patients were divided in two groups according to the type of treatment. Group A included patients treated with latest-generation TKI (nilotinib, dasatinib, and ponatinib), while group B included patients treated with first-generation TKI (imatinib). Cardiological evaluation included electrocardiogram, echocardiogram with global longitudinal strain of left ventricle (GLS), and carotid ultrasound scan with arterial stiffness measurement (pulse wave velocity, PWV). Adverse cardiovascular events were recorded in both groups.

Results: Statistical analysis showed that cardiovascular adverse events (myocardial ischemia, peripheral artery disease, deep vein thrombosis, and pleural effusion) were significantly more frequent in group A than group B (p value = 0.044). Moreover, there was a significant reduction in GLS and PWV in group A when compared to group B (respectively, p = 0.03 and p = 0.004).

Conclusions: Our study confirms that imatinib is a relatively safe drug, while it reveals that the latest-generation TKIs may cause a burden of cardiovascular complications. GLS and PWV allow detection of early signs of cardiac and vascular toxicity in oncohematologic patients treated with TKI, and their use is advisable.
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http://dx.doi.org/10.1159/000505486DOI Listing
July 2020

Mitotane Concentrations Influence Outcome in Patients with Advanced Adrenocortical Carcinoma.

Cancers (Basel) 2020 Mar 20;12(3). Epub 2020 Mar 20.

Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, 10043 Turin, Italy.

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.
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http://dx.doi.org/10.3390/cancers12030740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140087PMC
March 2020

Familial adenomatosis polyposis-related desmoid tumours treated with low-dose chemotherapy: results from an international, multi-institutional, retrospective analysis.

ESMO Open 2020 01;5(1)

Medical Oncology, Universita Campus Bio-Medico di Roma, Roma, Lazio, Italy

Introduction: Desmoid tumour (DT) is a locally aggressive fibroblastic proliferative disease representing the most common extraintestinal manifestation of familial adenomatosis polyposis (FAP). As data on the activity of chemotherapy in these patients are limited, we examined the outcomes of patients treated with low-dose methotrexate (MTX)+vinca alkaloids (vinorelbine or vinblastine).

Patients And Methods: We retrospectively reviewed clinical and outcome data from all patients with confirmed FAP-associated DTs treated with weekly MTX+vinca alkaloids in seven European sarcoma reference centres between January 2000 and December 2018. Radiological responses were assessed using RECIST V.1.0 and V.1.1. The Kaplan-Meier method associated to the log-rank test was used to estimate and compare survival curves.

Results: We identified 37 patients (median age 29 years, range 7-44). According to RECIST, 20/37 (54.1%) patients achieved partial response (PR), 15/37 (40.5%) patients had stable disease and 2/37 (5.4%) had progressive disease as best response. Overall, the median progression-free survival (PFS) was 6.5 years (range, 0.3-12.1 years). In the subset of patients achieving PR as best response, the median PFS was not reached. In a subset of 11 patients with progressive disease offered MTX+vinca alkaloids rechallenge (after chemotherapy withdrawal following prolonged disease control), the disease control rate was 100%, resulting in a median PFS after rechallenge of 5.8 years.

Conclusions: This is the largest series on the activity of low-dose chemotherapy in patients with FAP-related DT. In this population, MTX+vinca alkaloids is an active combination, as already reported in patients with sporadic DT.
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http://dx.doi.org/10.1136/esmoopen-2019-000604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003390PMC
January 2020

Surgical treatment of primary gastrointestinal stromal tumors (GISTs): Management and prognostic role of R1 resections.

Am J Surg 2020 08 10;220(2):359-364. Epub 2019 Dec 10.

University of Palermo, Department of Surgical Oncological and Oral Sciences, Italy. Electronic address:

Background: Surgery represents the best treatment for primary gastrointestinal stromal tumors (GISTs). The aim of this study is to analyse outcomes of surgical management in order to evaluate the influence of microscopically R1 margins on survival and recurrence in patients affected by GISTs.

Methods: The study reviewed retrospective data from 74 patients surgically treated for primary GISTs without metastasis at diagnosis. Clinical and pathological findings, surgical procedures, information about follow up and outcomes were analyzed.

Results: Recurrence rate was low and no patients died in the R1 group during the follow up period. The difference in recurrence free survival for patients undergoing an R0 (n = 54) versus an R1 (n = 20) resections was not statistically significant (76% versus 85% at 3 years, logrank test p-value = 0,14; 63% versus 86% at 5 years, logrank test p-value = 0,48) CONCLUSIONS: Microscopically positive margin has no influence on overall and relapse-free survival in GIST patients. Thus, when R0 surgery implies major functional sequelae, it may be decided to accept possible R1 margins, especially for low risk tumors.
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http://dx.doi.org/10.1016/j.amjsurg.2019.12.006DOI Listing
August 2020

Are Long Noncoding RNAs New Potential Biomarkers in Gastrointestinal Stromal Tumors (GISTs)? The Role of H19 and MALAT1.

J Oncol 2019 15;2019:5458717. Epub 2019 Nov 15.

Department of Surgical, Oncological, and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.

Long noncoding RNAs (lncRNAs) are emerging as key regulators of genetic and epigenetic networks, and their deregulation may underlie complex diseases, such as carcinogenesis. Several studies described lncRNA alterations in patients with solid tumors. In particular, HOTAIR upregulation has been associated with tumor aggressiveness, metastasis, and poor survival in gastrointestinal stromal tumor (GIST) patients. We analyzed expression levels of other lncRNAs, H19 and MALAT1, in FFPE tissue specimens from 40 surgically resected and metastatic GIST patients, using real-time PCR analysis. H19 and MALAT1 were both upregulated in 50% of GIST patients. MALAT1 lncRNA expression levels seem to be correlated with mutation status. The percentage of both H19 and MALAT1 upregulation was significantly higher in patients with time to progression (TTP) < 6 months as compared to patients with TTP > 6 months. The median TTP was significantly lower in patients with both H19 and MALAT1 lncRNA upregulation as compared to those with lncRNA downregulation. These data suggest a potential role for both H19 and MALAT1 lncRNAs as prognostic biomarker for the clinical selection of the best candidate to first-line treatment with imatinib.
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http://dx.doi.org/10.1155/2019/5458717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885275PMC
November 2019

Activity and safety of temozolomide in advanced adrenocortical carcinoma patients.

Eur J Endocrinol 2019 Dec;181(6):681-689

Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Brescia, Italy.

Objective: Temozolomide has shown a significant anti-proliferative activity on adrenocortical cancer (ACC) cells in vitro.

Design: On the basis of these results the drug was prescribed as second/third line in advanced metastatic ACC patients in four referral centers in Italy.

Methods: We retrospectively collected anagraphic, clinical and pathological data of patients with advanced ACC with disease progression to standard chemotherapy plus mitotane who were treated with temozolomide at the dose of 200 mg/m2/die given for 5 consecutive days every 28 days. The primary endpoint was the disease control rate, defined as objective response or disease stabilization after 3 months. Secondary endpoints were overall survival (OS), progression-free survival (PFS) and drug safety.

Results: Twenty-eight patients have been included in the study. Ten patients (35.8%, 95% CI: 17.8-53.8) obtained a disease control from temozolomide treatment. In particular, 1 patient had a complete response, 5 patients a partial response and 4 patients stable disease. Median PFS was 3.5 months and median OS was 7.2 months. Disease response was more frequently observed in patients with methylation of O6-methylguanine-DNA methyltransferase (MGMT) gene. Temozolomide therapy was well tolerated and most toxicities were limited to grade G1-2 according to WHO criteria.

Conclusion: Temozolomide was found active in the management of advanced ACC patients. The disease control rate obtained, however, was short-lived and the prognosis of treated patients was poor.
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http://dx.doi.org/10.1530/EJE-19-0570DOI Listing
December 2019

Lanreotide Therapy vs Active Surveillance in MEN1-Related Pancreatic Neuroendocrine Tumors < 2 Centimeters.

J Clin Endocrinol Metab 2020 01;105(1)

Department of Clinical Medicine and Surgery, Division of Endocrinology, University Federico II of Naples, Naples, Italy.

Purpose: Pancreatic neuroendocrine tumors (pNETs) are frequent in multiple endocrine neoplasia type 1 (MEN1) syndrome. They are usually not surgically treated unless larger than 1 to 2 cm or a growth rate > 0.5 cm per year. Somatostatin analogues represent one of the main therapeutic options in pNETs, but they have never been prospectively investigated in MEN1-related pNETs. The aim of this study was to prospectively evaluate the effectiveness of lanreotide in patients with MEN1-related pNETs < 2 cm.

Methods: MEN1 patients with 1 or more pNETs < 2 cm of maximal diameter were considered. Study design was prospective observational, comparing patients treated with lanreotide autogel 120 mg every 28 days (LAN group) and patients in active surveillance, not receiving any therapy (AS group).

Results: Forty-two patients were enrolled: 23 in LAN and 19 in AS group. Median follow-up was 73 months. Initial imaging identified a total of 91 pNETs. The median progression-free survival was significantly longer in the LAN than in the AS group (median not reached vs 40 months, P < 0.001). In the LAN group, 4 patients had an objective tumor response, 15 patients had stable disease, while 4 had tumor progression. In the AS group, 13 patients had pNET progression, while 6 were stable.

Conclusions: This is the first prospective study evaluating the efficacy of somatostatin analogues in MEN1-related pNETs. These findings highlight that lanreotide autogel is effective as antiproliferative therapy in MEN1-related pNETs < 2cm, suggesting the utility of somatostatin analogues to arrest the development of tumor lesions as well as to delay or avoid pancreatic surgery.
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http://dx.doi.org/10.1210/clinem/dgz007DOI Listing
January 2020

Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor.

J Clin Endocrinol Metab 2020 01;105(1)

NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy.

Purpose: To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment.

Methods: A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or shortened interval between administrations [dose density]). Main endpoints were progression-free survival (PFS) and safety.

Results: Of 198 patients, 140 matched inclusion criteria and were included in the analysis. Overall, median PFS was 31 months. Use of HD-SSA as second-line treatment was associated with reduced risk for progression or death compared with third- or further-line treatment (HR: 2.12; P = 0.004). There was no difference in PFS between HD-SSA by increased dose density (N = 133; 95%) or intensity (N = 7; 5%). Partial response according to RECIST criteria was observed in 12 patients (8.6%), and stable disease was achieved in 106 (75.7%) patients. Adverse events occurred in 21 patients (15.0%), 2 of whom had grade 3 biliary stone disease. No patients discontinued HD-SSA treatment due to adverse events.

Conclusions: HD-SSA is an active and safe treatment option in patients with progressive well-differentiated GEP-NET. The high rate of objective responses observed deserves prospective validation in ad hoc clinical trials.
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http://dx.doi.org/10.1210/clinem/dgz035DOI Listing
January 2020

Detection of RAS mutations in circulating tumor DNA: a new weapon in an old war against colorectal cancer. A systematic review of literature and meta-analysis.

Ther Adv Med Oncol 2019 10;11:1758835919874653. Epub 2019 Sep 10.

Medical Oncology Director, Department of Oncology, A.O.U.P. P. Giaccone University Hospital, 2013 ESMO Designated Centers of Integrated Oncology and Palliative Care, Via del Vespro 129, Palermo, 90127, Italy.

Background: Tissue evaluation for RAS (KRAS or NRAS) gene status in metastatic colorectal cancer (mCRC) patients represent the standard of care to establish the optimal therapeutic strategy. Unfortunately, tissue biopsy is hampered by several critical limitations due to its invasiveness, difficulty to access to disease site, patient's compliance and, more recently, neoplastic tissue spatial and temporal heterogeneity.

Methods: The authors performed a systematic literature review to identify available trials with paired matched tissue and ctDNA RAS gene status evaluation. The authors searched EMBASE, MEDLINE, Cochrane, www.ClinicalTrials.gov, and abstracts from international meetings. In total, 19 trials comparing standard tissue RAS mutational status matched paired ctDNA evaluated through polymerase chain reaction (PCR), next generation sequencing (NGS) or beads, emulsions, amplification and magnetics (BEAMing) were identified.

Results: The pooled sensitivity and specificity of ctDNA were 0.83 (95% CI: 0.80-0.85) and 0.91 (95% CI: 0.89-0.93) respectively. The pooled positive predictive value (PPV) and negative predictive value (NPV) of the ctDNA were 0.87 (95% CI: 0.81-0.92) and 0.87 (95% CI: 0.82-0.92), respectively. Positive likelihood ratio (PLR) was 8.20 (95% CI: 5.16-13.02) and the negative likelihood ratio (NLR) was 0.22 (95% CI: 0.16-0.30). The pooled diagnostic odds ratio (DOR) was 50.86 (95% CI: 26.15-98.76), and the area under the curve (AUC) of the summary receiver operational characteristics (sROC) curve was 0.94.

Conclusion: The authors' meta-analysis produced a complete and updated overview of ctDNA diagnostic accuracy to test RAS mutation in mCRC. Results provide a strong rationale to include the RAS ctDNA test into randomized clinical trials to validate it prospectively.
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http://dx.doi.org/10.1177/1758835919874653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737868PMC
September 2019

How to Deal with Second Line Dilemma in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis.

Cancers (Basel) 2019 Aug 15;11(8). Epub 2019 Aug 15.

Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, 90127 Palermo, Italy.

Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy with chemotherapy (CT) as second line treatment for metastatic colorectal cancer (mCRC). The right sequence of the treatments in all RAS (KRAS/NRAS) wild type (wt) patients has not precisely defined. We evaluated the impact of aforementioned targeted therapies in second line setting, analyzing efficacy and safety data from phase III clinical trials. We performed both direct and indirect comparisons between anti-EGFR and anti-VEGF. Outcomes included disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and G3-G5 toxicities. Our results showed significantly improved OS (HR 0.83, 95% CI 0.72-0.94) and DCR (HR 1.27, 95% CI 1.04-1.54) favouring anti-VEGF combinations in overall population; no statistically significant differences in all RAS wt patients was observed (HR 0.87, 95% CI 0.70-1.09). Anti-EGFR combinations significantly increased ORR in all patients (RR 0.54, 95% CI 0.31-0.96), showing a trend also in all RAS wt patients (RR 0.63, 95% CI 0.48-0.83). No significant difference in PFS and DCR all RAS was registered. Our results provided for the first time a strong rationale to manage both targeted agents in second line setting.
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http://dx.doi.org/10.3390/cancers11081189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721481PMC
August 2019

Denosumab for bone health in prostate and breast cancer patients receiving endocrine therapy? A systematic review and a meta-analysis of randomized trials.

J Bone Oncol 2019 Oct 16;18:100252. Epub 2019 Jul 16.

Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy.

Hormonal therapies for receptor positive-breast and prostate cancer patients have shown clinical efficacy but also several side effects including osteoporosis, loss of bone mass and increased fracture risk. Denosumab represents an anti RANKL (receptor activator of nuclear factor-kB ligand) monoclonal anti-body acting as inhibitor of osteoclasts formation, function, and survival, then increasing bone mass. Herein, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the role of Denosumab in saving bone health in prostate and breast cancer patients receiving respectively androgen deprivation therapy and adjuvant endocrine therapy. Moreover, selected patients have to be treated with Denosumab at the dose of 60 mg every six month or placebo. Outcomes studied included the bone mass density (BMD) increase at 24 and 36 months, BMD loss, reduction of fractures risk (in particular vertebral) at 24 and 36 months and safety (overall, serious adverse events - SAEs and discontinuation rate). Our results showed a reduction of the BMD loss up to 36 months both at the lumbar and femoral level and a BMD increase both at 24 and 36 months. It was also found a reduction in the number of new vertebral and femoral fractures at 24 and 36 months. Finally, our pooled analysis showed that Denosumab did not affect both the SAEs and therapy discontinuation risk. In conclusion, Denosumab administration can be considered effective and safe in the prevention and management of the above mentioned adverse events related to hormonal therapies designed for breast and prostate tumors.
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http://dx.doi.org/10.1016/j.jbo.2019.100252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700425PMC
October 2019

CT and MR imaging of chemotherapy-induced hepatopathy.

Abdom Radiol (NY) 2019 10;44(10):3312-3324

Dipartimento di Biomedicina, Neuroscienze e Diagnostica avanzata (BIND), University of Palermo, Palermo, Italy.

Chemotherapy-induced hepatopathy includes a wide variety of parenchymal and vascular hepatic changes on imaging, including diffuse or focal hepatopathies (i.e. hepatitis, steatosis, fibrosis, pseudocirrhosis, or sinusoidal obstruction). These changes can profoundly alter the hepatic parenchyma on imaging and result in both false negative and false-positive diagnoses of hepatic metastases and lead to errors in patient management strategies. It is therefore important for radiologists to have a comprehensive knowledge of the imaging patterns that may develop following chemotherapy. The purpose of this review is to explore the broad spectrum of hepatic parenchymal and vascular chemotherapy-induced changes on CT and MR imaging.
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http://dx.doi.org/10.1007/s00261-019-02193-yDOI Listing
October 2019

Programmed Death Ligand 1 (PD-L1) as a Predictive Biomarker for Pembrolizumab Therapy in Patients with Advanced Non-Small-Cell Lung Cancer (NSCLC).

Adv Ther 2019 10 20;36(10):2600-2617. Epub 2019 Aug 20.

Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy.

Recently, immunotherapy has been shown to be an effective and helpful therapeutic option for the treatment of advanced non-small-cell lung cancer (NSCLC). The activity of antitumor T cells may be restored through the checkpoint blockade using anti-programmed death 1 or anti-programmed death ligand 1 (PD-L1) antibodies, showing, in several cancer patients, an increased progression-free survival and overall survival compared with classical chemotherapy. As recently shown by several studies, the PD-L1 expression levels in tumors may offer a selection criterion for patients to predict their immunotherapy response. In particular, NSCLC patients with high tumor PD-L1 levels (proportional score ≥ 50% for first-line therapy and ≥ 1% for second-line treatment, respectively) showed better response rates to immunotherapy and longer survival in first-line therapy compared with conventional chemotherapy. PD-L1, whose expression is evaluated by using immunohistochemistry analysis, is currently the only biomarker approved for clinical use in the first- and second-line monotherapy setting and therefore plays a central role in treatment decision-making for patients with advanced NSCLC. In this review we will discuss the key role of PD-L1 as a predictive biomarker of response to pembrolizumab therapy in NSCLC patients by describing the appropriate techniques and methodologies for immunohistochemical evaluation of PD-L1 expression and providing an overview of the clinical studies supporting its predictive significance.
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http://dx.doi.org/10.1007/s12325-019-01057-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822831PMC
October 2019

Use of Cardioprotective Dexrazoxane Is Associated with Increased Myelotoxicity in Anthracycline-Treated Soft-Tissue Sarcoma Patients.

Chemotherapy 2019 7;64(2):105-109. Epub 2019 Aug 7.

Department of Medical Oncology, Università Campus Bio-Medico, Rome, Italy,

Background: Dexrazoxane (DEX) is indicated as a cardioprotective agent for breast cancer patients receiving the anthracycline doxorubicin. Two meta-analyses in metastatic breast cancer reported an apparent increase in the severity of myelosuppression when DEX was used. So far, no data in soft-tissue sarcoma (STS) patients are available.

Methods: We retrospectively analyzed hematological toxicity data from 133 consecutive STS patients who received a chemotherapy regimen containing an anthracycline and ifosfamide (AI) in the perioperative or metastatic settings between January 2006 and December 2017. Of these, 46 received off-label DEX concurrently with the AI treatment. The differences between incidence of any of the explored outcomes were assessed according to the Fisher exact test.

Results: Compared with the non-DEX group, DEX treatment was associated with significantly higher rates of grade 3/4 hematological toxicities: leukopenia (56.5 vs. 28.7%; p = 0.0014), neutropenia (69.6 vs. 24.1%; p = 0.0001), febrile neutropenia (52.2 vs. 20.7%; p = 0.0004), anemia (41.3 vs. 28.7%; p = 0.1758), and thrombocytopenia (54.3 vs. 32.1%; p = 0.0159). Similarly, in the DEX group dose reductions were more frequent compared to the non-DEX group (39.1 vs. 19.5%; p = 0.0221).

Conclusion: Adding DEX to AI in STS patients leads to higher rates of bone marrow suppression in all blood components, as well as to more frequent events of febrile neutropenia and dose reductions.
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http://dx.doi.org/10.1159/000501195DOI Listing
November 2019

How do skeletal morbidity rate and special toxicities affect 12-week versus 4-week schedule zoledronic acid efficacy? A systematic review and a meta-analysis of randomized trials.

Crit Rev Oncol Hematol 2019 Oct 25;142:68-75. Epub 2019 Jul 25.

Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.

Background: Zoledronic Acid is a bisphosphonate used in a 4-week schedule for the treatment of bone metastases. Some randomized trials supported its role also when administered every 12 weeks.

Methods: we performed a systematic review and a meta-analysis in order to evaluate the two different schedules in terms of skeletal morbidity rate (SMR), skeletal related events (SRE) and adverse events (AEs).

Results: our results showed a clinical difference favouring the 12-week schedule in terms of AEs (RR 1.17, 95% CI 1.06-1.29). No signifcant differences were found for SMR (RR 0.97, 95% CI 0.84-1.13) and SRE (RR 1.02, 95% CI 0.89-1.16).

Conclusions: Our findings support in clinical practice the 12-week schedule an alternative to the standard 4-week schedule in advanced breast and prostate cancer, in particular when the clinical comorbidities of the patients suggest a higher risk of renal failure or hypocalcaemia.
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http://dx.doi.org/10.1016/j.critrevonc.2019.07.013DOI Listing
October 2019

Can the plasma PD-1 levels predict the presence and efficiency of tumor-infiltrating lymphocytes in patients with metastatic melanoma?

Ther Adv Med Oncol 2019 13;11:1758835919848872. Epub 2019 May 13.

Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.

Background: The immune response in melanoma patients is locally affected by presence of tumor-infiltrating lymphocytes (TILs), generally divided into brisk, nonbrisk, and absent. Several studies have shown that a greater presence of TILs, especially brisk, in primary melanoma is associated with a better prognosis and higher survival rate.

Patients And Methods: We investigated by enzyme-linked immunosorbent assay (ELISA) the correlation between PD-1 levels in plasma and the presence/absence of TILs in 28 patients with metastatic melanoma.

Results: Low plasma PD-1 levels were correlated with brisk TILs in primary melanoma, whereas intermediate values correlated with the nonbrisk TILs, and high PD-1 levels with absent TILs. Although the low number of samples did not allow us to obtain a statistically significant correlation between the plasma PD-1 levels and the patients' overall survival depending on the absence/presence of TILs, the median survival of patients having brisk type TILs was 5 months higher than that of patients with absent and nonbrisk TILs.

Conclusions: This work highlights the ability of measuring the plasma PD-1 levels in order to predict the prognosis of patients with untreated metastatic melanoma without a mutation at the time of diagnosis.
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http://dx.doi.org/10.1177/1758835919848872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535916PMC
May 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