Publications by authors named "Tommaso Martino De Pas"

12 Publications

  • Page 1 of 1

Pathological and clinical features of enteric adenocarcinoma of the thymus. A pooled analysis of cases from a reference center and systematic review of the literature.

Cancer Treat Rev 2021 Jan 3;92:102133. Epub 2020 Dec 3.

Division of Medical Oncology for Melanoma & Sarcoma, IEO, European Institute of Oncology IRCCS, Milan, Italy.

Background: Primary enteric adenocarcinoma of the thymus (EAT) is a recently proposed rare subtype of thymic carcinoma. Unlike thymic carcinomas with squamous histology, for which clinical guidelines are available, little knowledge is available regarding the clinical and pathological features of EAT, and there is no consensus on the best treatment algorithm for such tumors.

Methods: We performed a systematic review of the literature, searching for all cases of EAT reported. We also retrospectively reviewed all cases of EAT treated at the European Institute of Oncology (IEO) between January 2000 and January 2020. Individual patient data were extracted and analyzed in order to delineate clinical and pathological features, as well as patients' prognosis and treatments outcome, evaluated in terms of Disease free Survival (DFS), Progression free survival (PFS) and overall survival (OS).

Results: Thirty-three cases (29 reported in literature and 4 new cases treated at IEO) of thymic adenocarcinoma deploying enteric differentiation as defined by WHO-criteria were analyzed. All tumors showed positive immunoreactivity for cytokeratin (CK) 20 and/or caudal type homeobox 2 (CDX2). Data on molecular profiling by next-generation sequencing were available in only 3 cases, and did not show actionable findings. At diagnosis, 11 pts had an early-stage (Masaoka I-II) and 22 a locally advanced (10 pts) or metastatic (12 pts) disease. Median-DFS of patients with localized disease was 12 months (95% CI, 7-19). Patients who received systemic chemotherapy were mostly treated with regimens commonly used for thymic epithelial tumors, with a discouraging PFS of 3-5 months for patients with stage IV disease. Median OS of the whole population was 34 months (95% CI, 24-NA:. mOS was not reached for patients with stage I-II disease versus 34 months in stage III-IV (p < 0.05).

Conclusion: Available evidence suggests that EAT represents a distinct entity in the context of thymic epithelial tumors, characterized by aggressive clinical behavior, poor responsiveness to chemotherapy and dismal patients prognosis. More research is needed to better define optimal management strategies for patients with such rare disease.
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January 2021

The Activity of Chemotherapy in Inflammatory Myofibroblastic Tumors: A Multicenter, European Retrospective Case Series Analysis.

Oncologist 2020 11 12;25(11):e1777-e1784. Epub 2020 Jul 12.

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

Background: This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference centers.

Materials And Methods: Patients of any age, with histologically proven IMT, treated with anthracycline-based methotrexate plus/minus vinorelbine/vinblastine (MTX-V) or other chemotherapeutic regimens between 1996 and 2018 were retrospectively reviewed. Diagnosis was confirmed at the local level by an expert pathologist. Response was retrospectively assessed by local investigators by RECIST v1.1. Progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS) were computed by Kaplan-Meier method.

Results: Thirty-eight patients were included. Twenty-five patients (8 localized, 17 advanced disease) received an anthracycline-based regimen; 21 were evaluable for response. Overall response rate (ORR) was 10/21 (47.6%). At a 70.8-month median follow-up (FU), median RFS and median OS were not reached (NR) in patients with localized disease; median PFS and median OS were 6.3 (interquartile range [IQR]: 1.9-13.4) and 21.2 (IQR: 7.7-40.7) months in patients with advanced disease. Thirteen patients received MTX-V (4 localized, 9 advanced disease), all evaluable for response. ORR was 7/13 (53.8%). At a 56.6-month median FU, median RFS and median OS were 42.5 (IQR: 12.9-61.2) months and NR (no death events) in patients with localized disease, and NR (IQR: 24.9 to NR) and 83.4 months (IQR: 83.4 to NR) in patients with advanced disease. In the "other-regimens group," responses were seen in 3/4 patients treated with oral cyclophosphamide and 1/2 with docetaxel/gemcitabine.

Conclusion: Anthracycline-based and MTX-V regimens are very effective in IMT, with a similar ORR in both groups. MTX-V achieved a prolonged disease control. Responses were also seen with oral cyclophosphamide and docetaxel/gemcitabine, but few patients were treated with these schedules.

Implications For Practice: Inflammatory myofibroblastic tumor (IMT) is an ultrarare sarcoma with known sensitivity to anaplastic lymphoma kinase (ALK) inhibitors in ALK-fused cases, although ALK inhibitors are not licensed in the disease. The current knowledge on the activity of cytotoxic chemotherapy is limited. This multi-institutional retrospective study on pediatric and adult patients with IMT shows that cytotoxic chemotherapy, and in particular anthracycline-based and methotrexate plus/minus vinorelbine/vinblastine regimens, represents a treatment option and can be considered in IMT patients irrespectively from ALK status. This study provides a benchmark for future studies on new medical therapies.
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November 2020

Epstein-Barr virus in tumor-infiltrating B cells of myasthenia gravis thymoma: an innocent bystander or an autoimmunity mediator?

Oncotarget 2017 Nov 8;8(56):95432-95449. Epub 2017 Sep 8.

Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico "Carlo Besta", 20133 Milan, Italy.

The thymus plays a key role in myasthenia gravis (MG), a B cell-mediated autoimmune disorder affecting neuromuscular junction. Most MG patients have thymic abnormalities, including hyperplasia and thymoma, a neoplasm of thymic epithelial cells. Epstein-Barr virus (EBV) is associated with autoimmune diseases and tumors. Recently, we showed EBV persistence and reactivation in hyperplastic MG thymuses, suggesting that EBV might contribute to intra-thymic B cell dysregulation in MG patients. Here, we investigated EBV involvement in thymoma-associated MG, by searching for EBV markers in MG (n=26) and non-MG (n=14) thymomas. EBV DNA and EBV-encoded small nuclear RNA (EBER) 1 transcript were detected in 14/26 (53.8%) and 22/26 (84.6%) MG thymomas, and only in 3 of 14 (21.4%) non-MG thymomas. Latent EBNA2 and late gp350/220 lytic transcripts were undetectable in all, but one, thymomas, and early lytic BZLF1 transcript was absent in all samples, suggesting that early infection events and EBV reactivation were very rare in thymomas. EBER1 and 2-positive cells were detected in MG, but not in non-MG, thymomas, as well as cells expressing EBV latency proteins (EBNA1, LMP1, LMP2A), that were mainly of B cell phenotype, indicating EBV association with MG rather than with thymoma. Toll-like receptor (TLR) 3 transcriptional levels were higher in MG than non-MG thymomas and positively correlated with EBER1 levels, suggesting a role for EBERs in TLR3 activation. Our findings show that EBV is commonly present in thymoma-infiltrating B cells of myasthenic patients, indicating a contribution of EBV to B cell-mediated autoreactivity in MG associated with thymic tumor.
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November 2017

Safety and Immunogenicity of MAGE-A3 Cancer Immunotherapeutic with or without Adjuvant Chemotherapy in Patients with Resected Stage IB to III MAGE-A3-Positive Non-Small-Cell Lung Cancer.

J Thorac Oncol 2015 Oct;10(10):1458-67

*Thoracic Oncology Unit, Arnaud de Villeneuve Hospital/CHRU Montpellier, Montpellier, France; †Department of Pneumology, University Hospital, KU Leuven, Leuven, Belgium; ‡Medical Oncology, European Institute of Oncology, Milan, Italy; §Division of Hematology and Hematologic Malignancies, University of Utah Huntsman Cancer Institute, Salt Lake City, Utah; ¶Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany; ‖Department of Respiratory Medicine, Ziekenhuis Oost Limburg, Genk and LCRP Oncology Cluster, University of Hasselt, Hasselt, Belgium; #Department of Medical Oncologie, ICO R. Gauducheau, St-Herblain, France; **Department of Oncology, University Hospital S. Maria della misericordia, Udine, Italy; ††Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; ‡‡Northwest Lung Centre, University Hospitals of South Manchester, Manchester, United Kingdom; §§Thoracic Oncology-Pneumology Service, André Renard Clinic, Herstal, Belgium; ¶¶Clinic of Thoracic Surgery, Waldburg-Zeil Clinic, Wangen im Allgäu, Germany; and ‖‖GSK Vaccines, Rixensart, Belgium.

Introduction: To assess the safety and immunogenicity of MAGE-A3 immunotherapeutic in patients with stage IB-III MAGE-A3-positive non-small-cell lung cancer (NSCLC) who were or were not undergoing standard cisplatin/vinorelbine chemotherapy.

Methods: This open, prospective, multicenter, parallel-group phase I study (NCT00455572) enrolled patients with resected (cohorts 1-3) or unresectable (cohort 4) MAGE-A3-positive NSCLC. MAGE-A3 immunotherapeutic (300 μg recombinant MAGE-A3 formulated with AS15) was administered (eight doses, 3 weeks apart) concurrent with (cohort 1), after (cohort 2), or without (cohort 3) standard-adjuvant chemotherapy, or after standard radiotherapy and/or chemotherapy (cohort 4).

Results: Sixty-seven patients received greater than or equal to 1 dose of MAGE-A3 immunotherapeutic. Grade 3/4 adverse events (AEs) were reported for 16 out of 19 (84%), 2 out of 18 (11%), 5 out of 18 (28%), and 1 out of 12 (8%) patients in cohorts 1, 2, 3, and 4, respectively. Many grade 3/4 AEs in cohort 1 (e.g., neutropenia) were typical of chemotherapy. Six patients, including three in cohort 1, reported study treatment-related grade 3/4 AEs (injection-site reactions or musculoskeletal/back pain, which resolved within 5 days). One patient (in cohort 4) died, but this and the other serious adverse events were not study treatment related. MAGE-A3-specific antibody responses to immunotherapy were induced in all patients evaluated in all cohorts. MAGE-A3-specific CD4 T-cell responses to immunotherapy were detected in 4 out of 11 (36%), 4 out of 15 (27%), 2 out of 8 (25%), and 5 out of 6 (83%) evaluated patients in cohorts 1, 2, 3, and 4, respectively; and CD8 T-cell responses were only detected in four patients.

Conclusion: In resected and unresectable NSCLC patients and irrespective of whether standard chemotherapy was concurrent or not, MAGE-A3 immunotherapeutic is well tolerated and induces MAGE-A3-specific immune responses.
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October 2015

Antitumor activity of sorafenib and imatinib in a patient with thymic carcinoma harboring c-KIT exon 13 missense mutation K642E.

Onco Targets Ther 2014 8;7:697-702. Epub 2014 May 8.

Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy.

We report the case of a man with an advanced nonkeratinizing squamous cell thymic carcinoma harboring c-KIT exon 13 missense mutation K642E. This aberration is rare and has never been described previously in patients with thymic cancers. It has been found in a small number of cases of gastrointestinal stromal tumor and also in several cases of acral and mucosal melanomas. Some of the patients with gastrointestinal stromal tumor or melanoma harboring this rare mutation have had a tumor response when treated with imatinib. In contrast, in our case, the mutation was associated with primary resistance to full doses of imatinib but, at the same time, it was not a cause of resistance to sorafenib.
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May 2014

Stem cell transplantation effectively occludes bronchopleural fistula in an animal model.

Ann Thorac Surg 2014 Feb 25;97(2):480-3. Epub 2013 Dec 25.

Department of Health, Animal Science and Public Health, Università degli Studi di Milano, Milan, Italy.

Background: Bronchopleural fistula after lung resection still represents a challenging life-threatening complication for thoracic surgeons. Considering its extremely high mortality rate, an effective treatment is urgently required. Our project investigated the hypothesis of experimental bronchopleural fistula closure by bronchoscopic injection of autologous bone marrow-derived mesenchymal stem cells into the cavity of the fistula, evaluating its feasibility and safety in a large animal model.

Methods: An experimental bronchopleural fistula was created in 9 goats after right upper tracheal lobectomy. The animals were randomly assigned to two groups: one received autologous bone marrow-derived mesenchymal stem cell bronchoscopic transplantation; the other received standard bronchoscopic fibrin glue injection.

Results: All animals receiving bronchoscopic stem cell transplantation presented fistula closure by extraluminal fibroblast proliferation and collagenous matrix development; none (0%) died during the study period. All animals receiving standard treatment still presented bronchopleural fistula; 2 of them (40%) died. Findings were confirmed by pathology examination, computed tomography, and magnetic resonance imaging.

Conclusions: Bronchoscopic transplantation of bone marrow-derived mesenchymal stem cells effectively closes experimental bronchopleural fistula by extraluminal fibroblast proliferation and collagenous matrix development. Stem cells may play a crucial role in the treatment of postresectional bronchopleural fistula after standard lung resection. Although these results provide a basis for the development of clinical therapeutic strategies, the exact mechanism by which they are obtained is not yet completely clear; further studies are required to understand exactly how stem cells work in this field.
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February 2014

Targeting ALK in patients with advanced non small cell lung cancer: biology, diagnostic and therapeutic options.

Crit Rev Oncol Hematol 2014 Mar 26;89(3):358-65. Epub 2013 Sep 26.

European Institute of Oncology, Division of Thoracic Oncology, Italy.

The discovery of EML4-ALK fusion gene in a subgroup of patients with lung adenocarcinoma led to the development of a new class of agents, the ALK inhibitors, and dramatically improved the clinical outcome of these patients. The striking results from clinical trials with crizotinib, the first ALK inhibitor evaluated, allowed the accelerated approval of crizotinib from the USA Food and Drug Administration (FDA). Despite the high initial results, patients acquire resistance to crizotinib, and different next generation ALK kinase inhibitors have been developed. In the current review, we will analyze the biology of EML4-ALK gene, the acquired resistance mechanisms to crizotinib, the therapeutic strategies, currently under evaluation, designed to overcome crizotinib resistance, and the open issues that need to be addressed in order to improve outcome in ALK+ Non Small Cell Lung Cancer (NSCLC) patients.
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March 2014

EGFR tyrosine kinase inhibitors beyond focal progression obtain a prolonged disease control in patients with advanced adenocarcinoma of the lung.

Lung Cancer 2013 Sep 27;81(3):440-444. Epub 2013 Jun 27.

Thoracic and Sarcoma Oncology Unit, Division of New Drug Development and Clinical Pharmacology, Medical Oncology Department, European Institute of Oncology, Milano, Italy.

Introduction: Recent data show that EGFR pathway and its inhibition maintain their role after progression of disease during EGFR TKI therapy in NSCLCs. We conducted a retrospective study with the aim of evaluating efficacy and feasibility of prosecution of EGFR TKI therapy beyond focal progression associated to locoregional radiotherapy.

Methods: We retrospectively analyzed the data of all NSCLC patients treated with EGFR TKIs in our institution from 2004 to 2012. We included in the analysis patients that after a focal disease progression, meant as a single lesion RECIST progression, have been treated with definitive locoregional radiotherapy, associated to continuation of EGFR TKI therapy until further progression.

Results: 15 out of 147 patients (10%) satisfied inclusion criteria. The median progression free survival, measured from the date of focal progression until further progression of disease or death by any cause, was 10,9 months (range 3-32 months). The corresponding 6 and 12 months PFS rates were 73% and 33%, respectively.

Conclusion: The longer disease control observed in our patients suggests that continuation of EGFR TKI beyond focal progression associated to a locoregional treatment is an efficacious therapeutic strategy.
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September 2013

Moving towards molecular-guided treatments: erlotinib and clinical outcomes in non-small-cell lung cancer patients.

Future Oncol 2013 Mar;9(3):327-45

Medical Oncology Unit of Respiratory Tract & Sarcomas, New Drugs Development Division, European Institute of Oncology, Milan, Italy.

Erlotinib is an orally administered small-molecule inhibitor of EGF receptor (EGFR) tyrosine kinase that is approved for the treatment of non-small-cell lung cancer (NSCLC) and pancreatic cancer. Erlotinib was first approved for the treatment of unselected NSCLC patients with advanced disease after failure of at least one prior chemotherapy regimen, and it was subsequently demonstrated to also confer a significant clinical benefit as maintenance therapy after first-line platinum-based chemotherapy. In all clinical studies, erlotinib treatment was associated with a good safety profile. Activating mutations in the EGFR gene have emerged as the strongest predictive marker of response to tyrosine kinase inhibitors, erlotinib and gefitinib, independently of other clinical and molecular features. Results from recently published, randomized Phase III trials showed that first-line erlotinib significantly prolongs progression-free survival in patients with advanced EGFR mutation-positive NSCLC with favorable tolerability, compared with standard chemotherapy. EGFR mutation testing is a crucial factor in the decision-making process regarding the most appropriate initial treatment option for patients. Specific molecular alterations in crucial genes have been discovered and associated with resistance to erlotinib, limiting its efficacy. New targeted agents and combined-treatment strategies are now under evaluation in clinical trials of NSCLC patients following progression to tyrosine kinase inhibitors.
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March 2013

Erlotinib-induced breast cancer regression.

Ann Pharmacother 2006 Nov 24;40(11):2043-7. Epub 2006 Oct 24.

Medical Care Unit, Department of Medicine, European Institute of Oncology, Milan, Italy.

Objective: To report a case of erlotinib-induced breast cancer regression.

Case Summary: A 38-year-old woman developed bilateral locoregional malignant cutaneous lymphangitis following a right subcutaneous mastectomy and 3 months of adjuvant chemotherapy. After several systemic chemotherapy regimens, the lymphangitis worsened rapidly, with progressive skin ulceration. Morphine and dexamethasone were given, with suboptimal pain control. A chemotherapy regimen of gemcitabine and vinorelbine was started. After 2 full-dose administrations, while lymphangitis continued to worsen, erlotinib 150 mg/day was added to the regimen. After 10 weeks of treatment, pain subsided and analgesics were discontinued. Physical examination revealed a partial regression of malignant cutaneous lymphangitis and pulmonary metastases, with resolution of ulceration.

Discussion: There has been increased interest in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in the treatment of breast cancer. Gefitinib has shown a low level of efficacy, while preliminary clinical data on erlotinib were not conclusive and suggested lack of clinical activity. Molecular analysis of the tumor in our patient revealed a profile predictive of response to EGFR selective inhibitors in some patients with lung cancer.

Conclusions: The addition of erlotinib to our patient's chemotherapy regimen resulted in antitumor activity in breast cancer in which an activated EGFR pathway was demonstrated. This finding is consistent with available preclinical and clinical data on EGFR tyrosine kinase inhibitors across tumor types and supports the efforts to optimize EGFR selective inhibitors in treating breast cancer and other malignancies.
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November 2006

Pharmacogenetics of anticancer drug sensitivity in non-small cell lung cancer.

Pharmacol Rev 2003 Mar;55(1):57-103

Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy.

In mammalian cells, the process of malignant transformation is characterized by the loss or down-regulation of tumor-suppressor genes and/or the mutation or overexpression of proto-oncogenes, whose products promote dysregulated proliferation of cells and extend their life span. Deregulation in intracellular transduction pathways generates mitogenic signals that promote abnormal cell growth and the acquisition of an undifferentiated phenotype. Genetic abnormalities in cancer have been widely studied to identify those factors predictive of tumor progression, survival, and response to chemotherapeutic agents. Pharmacogenetics has been founded as a science to examine the genetic basis of interindividual variation in drug metabolism, drug targets, and transporters, which result in differences in the efficacy and safety of many therapeutic agents. The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes suspected of affecting drug response. However, these studies have yielded contradictory results because of the small number of molecular determinants of drug response examined, and in several cases this approach was revealed to be reductionistic. This limitation is now being overcome by the use of novel techniques, i.e., high-density DNA and protein arrays, which allow genome- and proteome-wide tumor profiling. Pharmacogenomics represents the natural evolution of pharmacogenetics since it addresses, on a genome-wide basis, the effect of the sum of genetic variants on drug responses of individuals. Development of pharmacogenomics as a new field has accelerated the progress in drug discovery by the identification of novel therapeutic targets by expression profiling at the genomic or proteomic levels. In addition to this, pharmacogenetics and pharmacogenomics provide an important opportunity to select patients who may benefit from the administration of specific agents that best match the genetic profile of the disease, thus allowing maximum activity.
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March 2003