Publications by authors named "Andrea Napolitano"

49 Publications

S-Adenosylmethionine Supplementation May Reduce Cancer-Related Fatigue: A Prospective Evaluation Using the FACIT-F Questionnaire in Colon Cancer Patients Undergoing Oxaliplatin-Based Chemotherapy Regimens.

Chemotherapy 2021 Oct 13:1-8. Epub 2021 Oct 13.

Medical Oncology Unit, Università Campus Bio-Medico di Roma, Rome, Italy.

Background: Fatigue is a common distressing symptom for patients living with chronic or acute diseases, including liver disorders and cancer (Cancer-Related Fatigue, CRF). Its etiology is multifactorial, and some hypotheses regarding the pathogenesis are summarized, with possible shared mechanisms both in cancer and in chronic liver diseases. A deal of work has investigated the role of a multifunctional molecule in improving symptoms and outcomes in different liver dysfunctions and associated symptoms, including chronic fatigue: S-adenosylmethionine (SAM; AdoMet). The aim of this work is actually to consider its role also in oncologic settings.

Patients And Methods: Between January 2006 and December 2009, at the University Campus Bio-Medico of Rome, 145 patients affected by colorectal cancer in adjuvant (n = 91) or metastatic (n = 54; n = 40 with liver metastases) setting and treated with oxaliplatin-based regimen (FOLFOX for adjuvant and bevacizumab + XELOX for metastatic ones), 76 of which with the supplementation of S-adenosylmethionine (AdoMet; 400 mg b.i.d.) (57% of adjuvant patients and 44% of metastatic ones) and 69 without AdoMet supplementation, were evaluated for fatigue prevalence using the Functional Assessment of Chronic Illnesses Therapy-Fatigue (FACIT-F) questionnaire, at 3 and 6 months after the beginning of oncologic treatment. Notably, the number of patients with liver metastases was well balanced between the group of patients treated with AdoMet and those who were not.

Results: Among patients receiving oxaliplatin-based chemotherapy, both in adjuvant and in metastatic settings, after just 3 months from the beginning of chemotherapy, mean scores from questionnaire domains like FACIT-F subscale (7.9 vs. 3.1, p = 0.006), FACIT physical (6.25 vs. 3.32, p = 0.020), FACIT emotional (4.65 vs. 2.19, p = 0.045), and FACIT-F total score (16.5 vs. 8.27, p = 0.021) were higher in those receiving supplementation of AdoMet, resulting in reduced fatigue; a significant difference was maintained even after 6 months of treatment.

Discussion And Conclusions: Mechanisms and strategies for managing CRF are not fully understood. This work aimed at investigating the possible role of S-adenosylmethionine supplementation in improving fatigue scores in a specific setting of cancer patients, using a FACIT-F questionnaire, a well-validated quality of life instrument widely used for the assessment of CRF in clinical trials.
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http://dx.doi.org/10.1159/000517376DOI Listing
October 2021

Adjuvant imatinib in GIST patients harboring exon 9 KIT mutations: results from a multi-institutional European retrospective study.

Clin Cancer Res 2021 Oct 6. Epub 2021 Oct 6.

Medical Oncology Department, Hogar.

Purpose: The effect of high-dose imatinib (800 mg/d) on survival in the adjuvant treatment of patients with resected KIT exon-9 mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopathological variables with survival was evaluated in a large multi-institutional European cohort.

Methods: Data from 185 patients were retrospectively collected in 23 European GIST reference centers. Propensity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Univariate and multivariate unweighted and weighted Cox proportional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival.

Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated to the survival outcomes (RFS: HR 1.24, 95% CI 0.79-1.94; mRFS: HR 1.69, 95% CI 0.92-3.10; IFFS: HR 1.35, 95% CI 0.79-2.28). The variables consistently associated with worse survival outcomes were high mitotic index and non-gastric tumor location.

Conclusion: In this retrospective series of KIT exon 9-mutated GIST patients treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1665DOI Listing
October 2021

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas.

Cells 2021 06 17;10(6). Epub 2021 Jun 17.

The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.

Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies.
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http://dx.doi.org/10.3390/cells10061533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235236PMC
June 2021

Impact of Previous Nephrectomy on Clinical Outcome of Metastatic Renal Carcinoma Treated With Immune-Oncology: A Real-World Study on Behalf of Meet-URO Group (MeetUro-7b).

Front Oncol 2021 8;11:682449. Epub 2021 Jun 8.

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Immune-Oncology (IO) improves Overall Survival (OS) in metastatic Renal Cell Carcinoma (mRCC). The prognostic impact of previous Cytoreductive Nephrectomy (CN) and radical nephrectomy (RN), with curative intent, in patients treated with IO is not well defined. The aim of our paper is to evaluate the impact of previous nephrectomy on outcome of mRCC patients treated with IO.

Methods: 287 eligible patients were retrospectively collected from 16 Italian referral centers adhering to the MeetUro association. Patients treated with IO as second and third line were included, whereas patients treated with IO as first line were excluded. Kaplan-Meier method and log-rank test were performed to compare Progression Free Survival (PFS) and OS between groups. In our analysis, both CN and RN were included. The association between nephrectomy and other variables was analyzed in univariate and multivariate setting using the Cox proportional hazard model.

Results: 246/287 (85.7%) patients had nephrectomy before IO treatment. Median PFS in patients who underwent nephrectomy (246/287) was 4.8 months (95%CI 3.9-5.7) vs 3.7 months (95%CI 1.9-5.5) in patients who did not it (HR log rank 0.78; 95%CI 0.53 to 1.15; = 0.186). Median OS in patients who had previous nephrectomy (246/287) was 20.9 months (95%CI 17.6-24.1) 13 months (95%CI 7.7-18.2) in patients who did not it (HR log rank 0.504; 95%CI 0.337 to 0.755; = 0.001). In the multivariate model, nephrectomy showed a significant association with OS (HR log rank 0.638; 95%CI 0.416 to 0.980), whereas gland metastases were still associated with better outcome in terms of both OS (HR log rank 0.487; 95%CI 0.279 to 0.852) and PFS (HR log rank 0.646; 95%CI 0.435 to 0.958).

Conclusions: IO treatment, in patients who had previously undergone nephrectomy, was associated with a better outcome in terms of OS. Further prospective trials would assess this issue in order to guide clinicians in real word practice.
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http://dx.doi.org/10.3389/fonc.2021.682449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217989PMC
June 2021

Deep Learning Algorithm Trained with COVID-19 Pneumonia Also Identifies Immune Checkpoint Inhibitor Therapy-Related Pneumonitis.

Cancers (Basel) 2021 Feb 6;13(4). Epub 2021 Feb 6.

Departmental Faculty of Medicine and Surgery, Unit of Diagnostic Imaging and Interventional Radiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy.

Background: Coronavirus disease 2019 (COVID-19) pneumonia and immune checkpoint inhibitor (ICI) therapy-related pneumonitis share common features. The aim of this study was to determine on chest computed tomography (CT) images whether a deep convolutional neural network algorithm is able to solve the challenge of differential diagnosis between COVID-19 pneumonia and ICI therapy-related pneumonitis.

Methods: We enrolled three groups: a pneumonia-free group ( = 30), a COVID-19 group ( = 34), and a group of patients with ICI therapy-related pneumonitis ( = 21). Computed tomography images were analyzed with an artificial intelligence (AI) algorithm based on a deep convolutional neural network structure. Statistical analysis included the Mann-Whitney U test (significance threshold at < 0.05) and the receiver operating characteristic curve (ROC curve).

Results: The algorithm showed low specificity in distinguishing COVID-19 from ICI therapy-related pneumonitis (sensitivity 97.1%, specificity 14.3%, area under the curve (AUC) = 0.62). ICI therapy-related pneumonitis was identified by the AI when compared to pneumonia-free controls (sensitivity = 85.7%, specificity 100%, AUC = 0.97).

Conclusions: The deep learning algorithm is not able to distinguish between COVID-19 pneumonia and ICI therapy-related pneumonitis. Awareness must be increased among clinicians about imaging similarities between COVID-19 and ICI therapy-related pneumonitis. ICI therapy-related pneumonitis can be applied as a challenge population for cross-validation to test the robustness of AI models used to analyze interstitial pneumonias of variable etiology.
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http://dx.doi.org/10.3390/cancers13040652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914551PMC
February 2021

Identification of Aneuploid Circulating Tumor Cells in Soft-Tissue Sarcoma Patients: A Pilot Study.

Oncology 2020 20;98(12):893-896. Epub 2020 Aug 20.

Medical Oncology, University Campus Bio-Medico, Rome, Italy.

Background: Circulating tumor cells (CTCs) have been identified and shown to have prognostic and predictive roles in several types of carcinoma. More recently, aneuploid CTCs have become subject of a growing interest, as aneuploidy is considered a hallmark of cancer often associated with poor prognosis. Here, we aimed to identify for the first time aneuploid CTCs in soft-tissue sarcoma (STS) patients and show supportive in silico evidence on the prognostic role of aneuploidy in mesenchymal cancers.

Methods: In our pilot study, we collected blood from 4 metastatic STS patients and 4 age- and sex-matched healthy controls. After sample processing, cells were cyto-centrifuged onto glass slides and FISH was performed using 5 probes. The in silico analysis was performed using data from The Cancer Genome Atlas cohort of STS patients, using the validated Aneuploidy Score. We divided the patients in two populations (aneuploidy-high, Ane-Hi, and aneuploidy-low, Ane-Lo) using the median value of the Aneuploidy Score as a cutoff. Kaplan-Meier curves associated with log-rank test were used to compare progression-free and overall survival between groups. GraphPad Prism 8.0 (La Jolla, CA, USA) was used for statistical analyses.

Results: Aneuploid CTCs were identified in all 4 STS patients and in none of the controls, with a median value of 4 (range 3-6) per 7 mL of blood. Ane-Hi patients showed a significantly worse progression-free and overall survival compared to Ane-Lo patients. The same trend was maintained when analyzing the data based on the different histologies.

Conclusions: We identified for the first time aneuploid CTCs in STS patients using fluorescence in situ hybridization in a surface marker-independent way. We also showed that the Aneuploidy Score has a prognostic value both in terms of progression-free survival and overall survival in STS patients using The Cancer Genome Atlas data, regardless of the histology.
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http://dx.doi.org/10.1159/000509326DOI Listing
December 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

COVID-19 pneumonia and immune-related pneumonitis: critical issues on differential diagnosis, potential interactions, and management.

Expert Opin Biol Ther 2020 09 2;20(9):959-964. Epub 2020 Jul 2.

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

Introduction: The COVID-19 pandemic occurred amid the cancer immunotherapy revolution. Immune checkpoint inhibitors (ICIs) have become the standard of care for several solid cancers and are associated with peculiar toxicities, including pneumonitis which has similar features to COVID-19 pneumonia.

Areas Covered: We summarize the main hallmarks of lung injury induced by ICIs and severe acute respiratory syndrome coronavirus 2 and discuss the critical aspects for differential diagnosis and management. Symptoms and radiological findings are often similar; conversely, treatments are quite different. Furthermore, we focus on potential interactions generating hypotheses that need confirmatory studies.

Expert Opinion: All cancer patients treated with immunotherapy should receive screening for SARS-CoV-2. This would improve the diagnosis and management of pneumonia and guide therapeutic choices. Furthermore, clinicians could estimate the risk/benefit of continuing ICI treatment in COVID-19 positive patients. Temporary withdrawal of the immunotherapy treatment pending resolution of viral infection may be a reasonable option in long-responders patients.
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http://dx.doi.org/10.1080/14712598.2020.1789097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441753PMC
September 2020

Current and Emerging Biomarkers Predicting Bone Metastasis Development.

Front Oncol 2020 3;10:789. Epub 2020 Jun 3.

Medical Oncology, Bio-Medico University of Rome, Rome, Italy.

Bone is one of the preferential sites of distant metastases from malignant tumors, with the highest prevalence observed in breast and prostate cancers. Patients with bone metastases (BMs) may experience skeletal-related events, such as severe bone pain, pathological fractures, spinal cord compression, and hypercalcemia, with negative effects on the quality of life. In the last decades, a deeper understanding of the molecular mechanisms underlying the BM onset has been gained, leading to the development of bone-targeting agents. So far, most of the research has been focused on the pathophysiology and treatment of BM, with only relatively few studies investigating potential predictors of risk for BM development. The ability to select such "high-risk" patients could allow early identification of those most likely to benefit from interventions to prevent or delay BM. This review summarizes several evidences for the potential use of specific biomarkers able to predict early the BM development.
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http://dx.doi.org/10.3389/fonc.2020.00789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283490PMC
June 2020

Correction to: Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples.

J Exp Clin Cancer Res 2020 06 24;39(1):120. Epub 2020 Jun 24.

Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13046-020-01615-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313142PMC
June 2020

Regression of Papillary Thyroid Cancer during Nivolumab for Renal Cell Cancer.

Eur Thyroid J 2020 May 15;9(3):157-161. Epub 2020 Apr 15.

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

Immune checkpoint inhibitors have been recently approved for cancer treatment. Nivolumab is a monoclonal antibody specific for programmed cell death-1 (PD-1) that modulates T-cell response. It was initially used for the treatment of malignant melanoma and then approved in other cancers, such as non-small cell lung cancer and clear cell renal cell carcinoma (ccRCC). So far, the activity of nivolumab in patients with thyroid malignancies has been reported in a single case of anaplastic thyroid cancer. Here, we report the case of a patient with ccRCC who developed a papillary thyroid carcinoma (PTC) under first-line sunitinib treatment. During nivolumab, the second-line treatment for ccRCC, we unexpectedly observed a complete regression of PTC.
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http://dx.doi.org/10.1159/000506107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265713PMC
May 2020

Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples.

J Exp Clin Cancer Res 2020 May 27;39(1):95. Epub 2020 May 27.

Department of Medical Oncology, Campus Bio-Medico University of Rome, Álvaro del Portillo, 21, 00128, Rome, Italy.

In a large number of cancer types, treatment selection depends on the presence of specific tumor biomarkers. Due to the dynamic nature of cancer, very often these predictive biomarkers are not uniformly present in all cancer cells. Tumor heterogeneity represents indeed one of the main causes of therapeutic failure, and its decoding remains a major ongoing challenge in the field.Liquid biopsy is the sampling and analysis of non-solid biological tissue often through rapid and non-invasive methods, which allows the assessment in real-time of the evolving landscape of cancer. Samples can be obtained from blood and most other bodily fluids. A blood-based liquid biopsy can capture circulating tumor cells and leukocytes, as well as circulating tumor-derived nucleic acids.In this review, we discuss the current and possibly future applications of blood-based liquid biopsy in oncology, its advantages and its limitations in clinical practice. We specifically focused on its role as a tool to capture tumor heterogeneity in metastatic cancer patients.
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http://dx.doi.org/10.1186/s13046-020-01601-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254767PMC
May 2020

Prognostic and predictive factors in pancreatic cancer.

Oncotarget 2020 Mar 10;11(10):924-941. Epub 2020 Mar 10.

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

Pancreatic cancer is one of the leading causes of cancer death worldwide. Its high mortality rate has remained unchanged for years. Radiotherapy and surgery are considered standard treatments in early and locally advanced stages. Chemotherapy is the only option for metastatic patients. Two treatment regimens, i. e. the association of 5-fluorouracil- irinotecan-oxaliplatin (FOLFIRINOX) and the association of nab-paclitaxel with gemcitabine, have been shown to improve outcomes for metastatic pancreatic adenocarcinoma patients. However, there are not standardized predictive biomarkers able to identify patients who benefit most from treatments. CA19-9 is the most studied prognostic biomarker, its predictive role remains unclear. Other clinical, histological and molecular biomarkers are emerging in prognostic and predictive settings. The aim of this review is to provide an overview of prognostic and predictive markers used in clinical practice and to explore the most promising fields of research in terms of treatment selection and tailored therapy in pancreatic cancer.
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http://dx.doi.org/10.18632/oncotarget.27518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075465PMC
March 2020

Prognostic clinical factors in patients affected by non-small-cell lung cancer receiving Nivolumab.

Expert Opin Biol Ther 2020 03 6;20(3):319-326. Epub 2020 Feb 6.

Unit of Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.

: Immune-checkpoint inhibitors have radically changed the treatment landscape of Non-Small-Cell Lung Cancer (NSCLC). It is still unclear whether specific clinical characteristics might identify those patients benefiting from immunotherapy more than others. The aim of this study was to identify clinical characteristics associated with disease-specific survival (DSS), time-to-treatment failure (TTF), objective responses (OR) and progressive disease (PD) in NSCLC patients treated with Nivolumab.: This was a multicenter retrospective study conducted on 294 patients treated with Nivolumab for advanced NSCLC.: Of the more than 50 variables analyzed, five showed a significant correlation with DSS: ECOG PS, size of the biggest brain metastasis, number of metastatic sites, toxicity, and malignant pleural effusion. Three variables significantly correlated with TTF: malignant pleural effusion, number of metastatic sites, number of liver metastases. Malignant pleural effusion was the only variable showing a significant correlation with OR, as well as the only one correlating with all the endpoints of the study.: This study identified clinical characteristics associated with survival and response during treatment with Nivolumab in NSCLC patients. The unfavorable association between malignant pleural effusion and objective response is a novel finding with important translational implications.
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http://dx.doi.org/10.1080/14712598.2020.1724953DOI Listing
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

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

New frontiers in the medical management of gastrointestinal stromal tumours.

Ther Adv Med Oncol 2019 17;11:1758835919841946. Epub 2019 May 17.

Medical Oncology, Università Campus Bio-Medico, Via Alvaro del Portillo 200, Rome, Italy.

The tyrosine kinase inhibitor (TKI) imatinib has radically changed the natural history of KIT-driven gastrointestinal stromal tumours (GISTs). Approved second-line and third-line medical therapies are represented by the TKIs sunitinib and regorafenib, respectively. While imatinib remains the cardinal drug for patients with GISTs, novel therapies are being developed and clinically tested to overcome the mechanisms of resistance after treatments with the approved TKI, or to treat subsets of GISTs driven by rarer molecular events. Here, we review the therapy of GISTs, with a particular focus on the newest drugs in advanced phases of clinical testing that might soon change the current therapeutic algorithm.
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http://dx.doi.org/10.1177/1758835919841946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535752PMC
May 2019

Unexpected benefit from an 'old' metronomic chemotherapy regimen in advanced chordoma.

BMJ Case Rep 2019 Jun 2;12(6). Epub 2019 Jun 2.

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

In this case report, we describe an older adult man affected by advanced chordoma progressing after treatment with cisplatin and imatinib. The patient was symptomatic for uncontrolled pain. We decided to treat the patient with metronomic cyclophosphamide, unexpectedly achieving long-lasting clinical and radiological benefit.
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http://dx.doi.org/10.1136/bcr-2018-228728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557366PMC
June 2019

Secondary KIT mutations: the GIST of drug resistance and sensitivity.

Br J Cancer 2019 03 22;120(6):577-578. Epub 2019 Feb 22.

Università Campus Bio-Medico, Rome, Italy.

Pharmacological targeting of KIT in gastrointestinal stromal tumours has dramatically changed the clinical outcome of this disease. Tyrosine kinase inhibitors are the cornerstone of this improvement, but resistance occurs through secondary KIT mutations. Studies aimed at improving our understanding of the molecular basis of sensitivity and resistance will soon allow us to further tailor our therapeutic strategies.
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http://dx.doi.org/10.1038/s41416-019-0388-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461933PMC
March 2019

PDGFRα inhibition in soft-tissue sarcomas: Have we gotten it all wrong?

EBioMedicine 2019 Feb 5;40:37-38. Epub 2019 Feb 5.

Medical Oncology, Università Campus Bio-Medico, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2019.01.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413760PMC
February 2019

Splicing molecular biology and novel therapies in diffuse malignant peritoneal mesothelioma.

EBioMedicine 2019 01 3;39:7-8. Epub 2019 Jan 3.

Medical Oncology, Università Campus Bio-Medico, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2018.12.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355435PMC
January 2019

A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations.

J Clin Oncol 2018 Oct 30:JCO2018790352. Epub 2018 Oct 30.

Sandra Pastorino, Mitsuru Emi, Masaki Nasu, Ian Pagano, Yasutaka Takinishi, Ryuji Yamamoto, Michael Minaai, Keisuke Goto, Mika Tanji, Angela Bononi, Andrea Napolitano, Giovanni Gaudino, Haining Yang, and Michele Carbone, University of Hawaii Cancer Center, Honolulu, HI; Yoshie Yoshikawa, Mitsuru Emi, Tomoko Hashimoto-Tamaoki, and Masaki Ohmuraya, Hyogo College of Medicine, Hyogo, Japan; Mary Hesdorffer, Mesothelioma Applied Research Foundation, Washington DC; Harvey I. Pass and Chandra Goparaju, New York University Langone Medical Center, New York, NY; Andrea Neopolitano, University Campus Bio-Medico, Rome, Italy; and Kavita Y. Sarin, Stanford University, Stanford, CA.

Purpose: We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years.

Patients And Methods: Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing.

Results: Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001).

Conclusion: We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.
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http://dx.doi.org/10.1200/JCO.2018.79.0352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162737PMC
October 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

Progress in the Management of Malignant Pleural Mesothelioma in 2017.

J Thorac Oncol 2018 05 8;13(5):606-623. Epub 2018 Mar 8.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address:

Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1-deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.
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http://dx.doi.org/10.1016/j.jtho.2018.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544834PMC
May 2018

Body Mass Index as a Risk Factor for Toxicities in Patients with Advanced Soft-Tissue Sarcoma Treated with Trabectedin.

Oncology 2018 6;95(1):1-7. Epub 2018 Mar 6.

Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy.

Objectives: Low body mass index (BMI) and/or low lean body mass have been shown to be risk factors for chemotherapy-related toxicities in a number of different cancers. However, no data are available regarding the role of BMI as a risk factor for developing toxicities related to the novel anticancer agent, trabectedin, in patients with soft-tissue sarcoma (STS). We evaluated the role of BMI as a risk factor for trabectedin-related toxicity in patients with STS.

Methods: Data from 51 patients with metastatic/advanced STS treated with trabectedin after progression on ≥1 anthracycline ± ifosfamide regimen were retrospectively reviewed.

Results: Eighteen patients (35.3%) were underweight, and the remainder were of normal bodyweight (45.1%) or overweight (19.6%). Neutropenia of any grade (77.8 vs. 33.3%) and grade 3-4 neutropenia (50.0 vs. 18.2%) occurred more frequently in the underweight versus normal/overweight patients (p = 0.025). Febrile neutropenia also occurred more frequently in underweight patients. Differences remained statistically significant after adjusting for other predictors of toxicity. There were no significant differences in other hematological and nonhematological toxicities between the groups.

Conclusions: The data suggest for the first time that BMI should be considered a risk factor for neutropenia in patients with STS treated with trabectedin.
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http://dx.doi.org/10.1159/000487266DOI Listing
July 2018

Olaratumab: PDGFR-α inhibition as a novel tool in the treatment of advanced soft tissue sarcomas.

Crit Rev Oncol Hematol 2017 Oct 15;118:1-6. Epub 2017 Jul 15.

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

Advanced soft tissue sarcomas are aggressive cancers with limited therapeutic options. Recently, inhibition of platelet-derived growth factor receptor (PDGFR)-α by the monoclonal antibody olaratumab showed promising clinical activity. If confirmed, this would be one of the first examples of targeted therapy effective in advanced soft tissue sarcomas therapy independently of the histologic subtype. Here, we reviewed the biology of the PDGF/PDGFR axis, particularly focusing on its role in cancer, and then we discussed on the effects of PDGFR-α inhibition in the therapy of advanced soft tissue sarcomas.
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http://dx.doi.org/10.1016/j.critrevonc.2017.06.006DOI Listing
October 2017

Germline BAP1 mutations induce a Warburg effect.

Cell Death Differ 2017 10 30;24(10):1694-1704. Epub 2017 Jun 30.

Thoracic Oncology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.

Carriers of heterozygous germline BAP1 mutations (BAP1) develop cancer. We studied plasma from 16 BAP1 individuals from 2 families carrying different germline BAP1 mutations and 30 BAP1 wild-type (BAP1) controls from these same families. Plasma samples were analyzed by liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS), ultra-performance liquid chromatography triple quadrupole mass spectrometry (UPLC-TQ-MS), and gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found a clear separation in the metabolic profile between BAP1 and BAP1 individuals. We confirmed the specificity of the data in vitro using 12 cell cultures of primary fibroblasts we derived from skin punch biopsies from 12/46 of these same individuals, 6 BAP1 carriers and 6 controls from both families. BAP1 fibroblasts displayed increased aerobic glycolysis and lactate secretion, and reduced mitochondrial respiration and ATP production compared with BAP1. siRNA-mediated downregulation of BAP1 in primary BAP1 fibroblasts and in primary human mesothelial cells, led to the same reduced mitochondrial respiration and increased aerobic glycolysis as we detected in primary fibroblasts from carriers of BAP1 mutations. The plasma and cell culture results were highly reproducible and were specifically and only linked to BAP1 status and not to gender, age or family, or cell type, and required an intact BAP1 catalytic activity. Accordingly, we were able to build a metabolomic model capable of predicting BAP1 status with 100% accuracy using data from human plasma. Our data provide the first experimental evidence supporting the hypothesis that aerobic glycolysis, also known as the 'Warburg effect', does not necessarily occur as an adaptive process that is consequence of carcinogenesis, but rather that it may also predate malignancy by many years and facilitate carcinogenesis.
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http://dx.doi.org/10.1038/cdd.2017.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596430PMC
October 2017

BAP1 regulates IP3R3-mediated Ca flux to mitochondria suppressing cell transformation.

Nature 2017 06 14;546(7659):549-553. Epub 2017 Jun 14.

University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii 96813 USA.

BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1) developed one and often several BAP1 malignancies in their lifetime, mostly malignant mesothelioma, uveal melanoma, and so on. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity. The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1 carriers cause reduction both of IP3R3 levels and of Ca flux, preventing BAP1 cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1 carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis.
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http://dx.doi.org/10.1038/nature22798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581194PMC
June 2017

Malignant Mesothelioma: Time to Translate?

Trends Cancer 2016 09;2(9):467-474

Department of Thoracic Oncology, University of Hawai i Cancer Center, 96826 Honolulu, HI, USA.

Malignant mesothelioma is an aggressive cancer largely associated with asbestos exposure. In this review, we will discuss the significant advancements in our understanding of its genetics and molecular biology and their translational relevance. Remarkable findings included the discovery of germline and somatic mutations of BRCA1 associated protein-1 (BAP1) in patients, and the genome-wide characterization of pathways altered in mesothelioma that could be potentially exploited to design novel therapeutic approaches. Nevertheless, the clinical translation of these molecular findings has been slow and insufficient. In order to rapidly move translation from the bench to the bedside, we believe that cooperative research efforts have to be further endorsed and promoted at all levels.
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http://dx.doi.org/10.1016/j.trecan.2016.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461959PMC
September 2016
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