Publications by authors named "Lorena Incorvaia"

49 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

Current treatment options for HER2-positive breast cancer patients with brain metastases.

Crit Rev Oncol Hematol 2021 Apr 20;161:103329. Epub 2021 Apr 20.

Medical Oncology Unit, Buccheri La Ferla Fatebenefratelli Hospital, Palermo, Italy.

Brain metastases (BMs) are frequently associated with HER2+ breast cancer (BC). Their management is based on a multi-modal strategy including both local treatment and systemic therapy. Despite therapeutic advance, BMs still have an adverse impact on survival and quality of life and the development of effective systemic therapy to prevent and treat BMs from HER2 + BC represents an unmet clinical need. Trastuzumab-based therapy has long been the mainstay of systemic therapy and over the last two decades other HER2-targeted agents including lapatinib, pertuzumab and trastuzumab emtansine, have been introduced in the clinical practice. More recently, novel agents such as neratinib, tucatinib and trastuzumab deruxtecan have been developed, with interesting activity against BMs. Further research is needed to better elucidate the best sequence of these agents and their combination with local treatment.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103329DOI Listing
April 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

Body Mass Index in Patients Treated with Cabozantinib for Advanced Renal Cell Carcinoma: A New Prognostic Factor?

Diagnostics (Basel) 2021 Jan 18;11(1). Epub 2021 Jan 18.

Oncology Unit, Macerata Hospital, Via Santa Lucia 2, 62100 Macerata, Italy.

We analyzed the clinical and pathological features of renal cell carcinoma (RCC) patients treated with cabozantinib stratified by body mass index (BMI). We retrospectively collected data from 16 worldwide centers involved in the treatment of RCC. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses. We collected data from 224 patients with advanced RCC receiving cabozantinib as second- (113, 5%) or third-line (111, 5%) therapy. The median PFS was significantly higher in patients with BMI ≥ 25 (9.9 vs. 7.6 months, < 0.001). The median OS was higher in the BMI ≥ 25 subgroup (30.7 vs. 11.0 months, = 0.003). As third-line therapy, both median PFS (9.2 months vs. 3.9 months, = 0.029) and OS (39.4 months vs. 11.5 months, = 0.039) were longer in patients with BMI ≥ 25. BMI was a significant predictor for both PFS and OS at multivariate analysis. We showed that a BMI ≥ 25 correlates with longer survival in patients receiving cabozantinib. BMI can be easily assessed and should be included in current prognostic criteria for advanced RCC.
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http://dx.doi.org/10.3390/diagnostics11010138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831923PMC
January 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

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

Impact of Chemotherapy in the Adjuvant Setting of Early Stage Uterine Leiomyosarcoma: A Systematic Review and Updated Meta-Analysis.

Cancers (Basel) 2020 Jul 14;12(7). Epub 2020 Jul 14.

Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy.

Background: Although the use of adjuvant chemotherapy (AC) appears to be increasing over the past few years, several clinical trials and previous meta-analyses failed to determine whether AC could improve clinical outcomes in uterine leiomyosarcoma (uLMS). The aim of this systematic review and meta-analysis was to compare AC (with or without radiotherapy) versus observation (obs) after primary surgery in early stage uLMS.

Materials And Methods: Randomized controlled (RCTs) and non-randomized studies (NRSs) were retrieved. Outcomes of interest were as follows: distant recurrence rate, locoregional recurrence rate and overall recurrence rate. Results about distant recurrence rate, locoregional recurrence rate and overall recurrence rate were compared by calculating odds ratios (ORs) with 95% confidence intervals (CIs); ORs were combined with Mantel-Haenszel method.

Results: Nine studies were included in the analysis, involving 545 patients (AC: 252, obs: 293). Compared with obs, AC did not reduce locoregional and distant recurrence rate, with a pooled OR of 1.36 and 0.63, respectively. Similarly, administration of AC did not decrease overall recurrence rate in comparison to obs.

Conclusion: According to our results, AC (with or without radiotherapy) did not decrease recurrence rate in early stage uLMS; thus, the role of AC in this setting remains unclear.
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http://dx.doi.org/10.3390/cancers12071899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409135PMC
July 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

Real-World Data on Cabozantinib in Previously Treated Patients with Metastatic Renal Cell Carcinoma: Focus on Sequences and Prognostic Factors.

Cancers (Basel) 2019 Dec 30;12(1). Epub 2019 Dec 30.

Urologic Oncology, Champalimaud Clinical Center, 1400-038 Lisbon, Portugal.

Cabozantinib is approved for the treatment of renal cell carcinoma (RCC). However, prognostic factors are still lacking in this context. The aim of this study was to evaluate prognostic factors in RCC patients treated with second- or third-line cabozantinib. A multicenter retrospective real-world study was conducted, involving 32 worldwide centers. A total of 237 patients with histologically confirmed clear-cell and non-clear-cell RCC who received cabozantinib as second- or third-line therapy for metastatic disease were included. We analyzed overall survival (OS), progression-free survival (PFS) and time-to-strategy failure (TTSF) using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses.The median PFS and OS of cabozantinib were 7.76 months (95% CI 6.51-10.88) and 11.57 months (95% CI 10.90-not reached (NR)) as second-line and 11.38 months (95% CI 5.79-NR) and NR (95% CI 11.51-NR) as third-line therapy. The median TTSF and OS were 11.57 and 15.52 months with the sequence of cabozantinib-nivolumab and 25.64 months and NR with nivolumab-cabozantinib, respectively. The difference between these two sequences was statistically significant only in good-risk patients. In the second-line setting, hemoglobin (Hb) levels (HR= 2.39; 95% CI 1.24-4.60, = 0.009) and IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) group (HR = 1.72, 95% CI 1.04-2.87, = 0.037) were associated with PFS while ECOG-PS (HR = 2.33; 95%CI, 1.16-4.69, = 0.018) and Hb levels (HR = 3.12; 95%CI 1.18-8.26, = 0.023) correlated with OS at multivariate analysis, while in the third-line setting, only Hb levels (HR = 2.72; 95%CI 1.04-7.09, = 0.042) were associated with OS. Results are limited by the retrospective nature of the study.This real-world study provides evidence on the presence of prognostic factors in RCC patients receiving cabozantinib.
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http://dx.doi.org/10.3390/cancers12010084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016527PMC
December 2019

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

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

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

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

Recommendations for the implementation of BRCA testing in ovarian cancer patients and their relatives.

Crit Rev Oncol Hematol 2019 Aug 25;140:67-72. Epub 2019 May 25.

Department of Surgical, Oncological & Oral Sciences, Section of Medical Oncology, University of Palermo, Italy. Electronic address:

The current availability of new Poly(ADP-ribose) Polymerase (PARP)-inhibitors for the treatment of ovarian cancer patients independently of the presence of a BRCA pathogenic variant, together with the validation of somatic test for the analysis of BRCA1/2 genes, involves the need to optimise the guidelines for BRCA testing. The AIOM-SIGU-SIBIOC-SIAPEC-IAP Italian Scientific Societies, in this position paper, recommend the implementation of BRCA testing with 2 main objectives: the first is the identification of ovarian cancer patients with higher probability of benefit from specific anticancer treatments (test for response to therapy); the second goal, through BRCA testing in the family members of ovarian cancer patients, is the identification of carriers of pathogenic variant, who have inheredited predisposition to cancer development (test for cancer risk). These individuals with increased risk of cancer, should be encouraged to participate in dedicated high-risk surveillance clinics and specific risk-reducing measures (primary and/or secondary prevention programs).
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http://dx.doi.org/10.1016/j.critrevonc.2019.05.012DOI Listing
August 2019

Correction to: One shot NEPA plus dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) in sarcoma patients receiving multiple-day chemotherapy.

Support Care Cancer 2019 Sep;27(9):3599

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

The title of the original paper is incorrect and is now corrected in this aticle.
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http://dx.doi.org/10.1007/s00520-019-04852-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830059PMC
September 2019

Monitoring blood biomarkers to predict nivolumab effectiveness in NSCLC patients.

Ther Adv Med Oncol 2019 16;11:1758835919839928. Epub 2019 Apr 16.

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

Background: We investigated whether early dynamic changes of circulating free (cfDNA) levels as well as the neutrophil to lymphocyte ratio (NLR) could predict nivolumab effectiveness in pretreated patients with advanced non-small cell lung cancer (NSCLC).

Methods: A total of 45 patients receiving nivolumab 3 mg/kg every 2 weeks were enrolled. Patients underwent a computed tomography scan and responses were evaluated by the response evaluation criteria in solid tumors. Peripheral blood samples were obtained from the patients and the cfDNA level as well as the NLR were assessed. Time to progression (TTP) and overall survival (OS) were determined.

Results: Patients with increased cfDNA >20% at the sixth week reported significantly worse survival outcomes (median OS: 5.7 14.2 months, < 0.001; median TTP: 3.3 10.2 months, < 0.001), as well as patients with increased NLR >20% (median OS: 8.7 14.6 months, = 0.035; median TTP: 5.2 10.3 months, = 0.039). The combined increase of cfDNA and NLR >20% was associated with significantly worse survival outcomes as compared with the remained population (median OS: 5.8 15.5 months, = 0.012; median TTP: 3.2 11.9 months, = 0.028). Multivariable analysis identified three significant factors associated with worse OS: combined cfDNA/NLR increase >20% [hazard ratio (HR): 5.16; 95% confidence interval (CI), 1.09-24.29; = 0.038], liver metastasis (HR: 0.44; 95% CI, 0.20-0.96; = 0.038), and extra-thoracic disease (HR: 0.33; 95% CI, 0.12-0.89; = 0.029).

Conclusion: An early combined increase of both cfDNA and NLR over the course of the first 6 weeks of nivolumab therapy predicted worse survival in pretreated patients with advanced NSCLC, suggesting a potential role in the real-time monitoring of immunotherapy resistance.
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http://dx.doi.org/10.1177/1758835919839928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469277PMC
April 2019

Prognostic significance of circulating PD-1, PD-L1, pan-BTN3As, BTN3A1 and BTLA in patients with pancreatic adenocarcinoma.

Oncoimmunology 2019;8(4):e1561120. Epub 2019 Feb 3.

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.

PDAC is one of the most heterogeneous cancers with low chemotherapeutic sensitivity due to a dense stroma, a weak vasculature and significant biological aggressivity. In cancer, suppressive immune checkpoints are often hyper-activated to ensure an effective evasion of tumor cells from immune surveillance. These immune checkpoints include in part, the B7/butyrophilin-like receptors such as butyrophilin sub-family 3A/CD277 receptors (BTN3A), the B and T lymphocyte attenuator (BTLA) belonging to the B7-like receptors and the programmed death protein (PD-1) with its ligand PD-L1. We evaluated the plasma level of these markers in 32 PDAC patients (learning cohort) by developed ELISA's and showed that there are highly correlated. We used ROC curves and univariate analysis to characterize their prognostic relevance in these patients and showed that their plasma level can serve as survival predictor. Plasma level thresholds that correlate with less than six months survival were established for sPD-1 (>8.6 ng/ml), sPD-L1 (>0.36 ng/ml), sBTLA (>1.91 ng/ml), sBTN3A1 (>6.98 ng/ml) and pan-sBTN3A (>6.92 ng/ml). These thresholds were applied in independent validation cohort composed by 27 new samples and could efficiently discriminate short versus long PDAC survivors. Our study reveals that monitoring the concentration of soluble forms of inhibitory immune checkpoints in plasma can help predict survival in PDAC patients and therefore improve their treatments.
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http://dx.doi.org/10.1080/2162402X.2018.1561120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422385PMC
February 2019

One shot NEPA plus dexamethasone to prevent multiple-day chemotherapy in sarcoma patients.

Support Care Cancer 2019 Sep 14;27(9):3593-3597. Epub 2019 Feb 14.

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

Purpose: Chemotherapy-induced nausea and vomiting (CINV) is one of the most feared and disturbing adverse events of cancer treatment associated with decreased adherence to effective chemotherapy regimens. For high-risk soft tissue sarcoma patients, receiving multiple-day chemotherapy (MD-CT), antiemetic guidelines recommend a combination of an NK receptor antagonist (NK-RA), a 5-HT receptor antagonist (5HT-RA), and dexamethasone on each day of the antineoplastic treatment. NEPA is the first oral fixed-dose combination of a highly selective NK-RA, netupitant, and second-generation 5HT-RA, palonosetron. So far, no data has been published in literature about the efficacy of a single dose of NEPA in MD-CT.

Methods: We performed a prospective, non-comparative study to assess the efficacy of one shot of NEPA plus dexamethasone in sarcoma patients receiving MD-CT. The primary efficacy endpoint was a complete response (CR: no emesis, no rescue medication) during the overall phase (0-120 h) in cycle 1. The main secondary endpoints were CR during the overall phase of cycles 2 and 3.

Results: The primary endpoint was reached in 88.9% of patients. Cycles 2 and 3 overall CR rates were 88.9% and 82.4%, respectively. The antiemetic regimen was well tolerated.

Conclusions: This pilot study showed the benefit of one shot of NEPA to prevent CINV in sarcoma patients receiving MD-chemotherapy.
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http://dx.doi.org/10.1007/s00520-019-4645-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660507PMC
September 2019

Monoclonal antibodies for the treatment of non-hematological tumors: a safety review.

Expert Opin Drug Saf 2018 Dec 28;17(12):1197-1209. Epub 2018 Nov 28.

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

: The introduction of monoclonal antibodies (moAbs) into clinical practice revolutionized the treatment strategies in several solid tumors. These agents differ from cytotoxic chemotherapy for their mechanism of action and toxicity. By targeting specific antigens present on healthy cells and modulating immune system activity, these biological drugs are able to generate a wide spectrum of peculiar adverse events that can negatively impact on patients' quality of life. : In this review, the main side effects associated with the use of moAbs have been described to show their incidence and current management strategies, which may drive clinicians in their daily practice. : The majority of these drugs represents an example of successful innovation, since they are able to induce a significant improvement of patients' survival and quality of life without any increase in related side effects as compared to standard cancer treatments. For this reason, they have become new milestones in personalized therapy for different non-hematological malignancies. With the increasing use of moAbs in treatment regimens, it is strongly recommended that clinicians are knowledgeable about the side effects associated with these agents, their management and monitoring, to optimize the clinical treatment of cancer patients.
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http://dx.doi.org/10.1080/14740338.2018.1550068DOI Listing
December 2018

Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors following progression with imatinib, sunitinib and regorafenib.

Ther Adv Med Oncol 2018 29;10:1758835918794623. Epub 2018 Aug 29.

Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna.

Background: Rechallenge with imatinib is an option in advanced gastrointestinal stromal tumor (GIST) patients following progression with standard tyrosine-kinase inhibitors (TKIs), imatinib, sunitinib and regorafenib. We retrospectively collected data from metastatic Italian GIST patients treated with imatinib resumption after progression to conventional TKIs.

Methods: A total of 104 eligible advanced GIST patients, previously treated with imatinib, sunitinib and regorafenib, were collected from six referral Italian institutions. Mutational analysis was recorded and correlated with survival and response according to RECIST 1.1 or CHOI criteria.

Results: Overall, 71 patients treated with imatinib 400 mg as rechallenge were included. Mutational status was available in all patients. The median follow up was 13 months. In patients who received a rechallenge therapy, the median time to progression (TTP) was 5.4 months [95% confidence interval (CI) 1.9-13.5] and overall survival (OS) was 10.6 months (95% CI 2.8-26.9). A correlation between mutational status, response rate, TTP and OS was not found but comparing deleted nondeleted exon 11 patients, a significant difference was identified in terms of TTP and OS ( = 0.04 and  = 0.02, respectively).

Conclusions: Our retrospective data confirm that imatinib rechallenge is a reasonable option in advanced GIST. The prognostic value of the specific mutations was confirmed in our series.
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http://dx.doi.org/10.1177/1758835918794623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116078PMC
August 2018

Molecular profiling of pancreatic neuroendocrine tumors (pNETS) and the clinical potential.

Expert Rev Gastroenterol Hepatol 2018 May 18;12(5):471-478. Epub 2018 Apr 18.

c Phase I-Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital & Center for Oncological Research (CORE) , Antwerp , Belgium.

Introduction: Pancreatic neuroendocrine tumors (pNETs) represent a small part of pancreatic neoplasms, and the knowledge about their indolent clinical course remains a subject of investigation. They occur sporadically or as part of familial cancer syndromes and are classified by WHO in 3 categories. There is ongoing research to understand their molecular profiling and leading mutations. Areas covered: The aim of this review is to clarify the overall aspects of tumorigenesis, to expose the latest developments in understanding the course of the disease and the possible therapeutic implications of these. The review also discusses functional and non-functional pNETs and associated inherited syndromes as well as pNET molecular profiling and its possible guidance in the use of targeted therapy. Expert commentary: In the next decade, a more extensive application of new technologies will help improve quality of life and survival, individualizing treatment protocols and identifying which therapeutic strategy is more suitable for each kind of NET.
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http://dx.doi.org/10.1080/17474124.2018.1463157DOI Listing
May 2018