Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and... more Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10−9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5′UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value&...
The Italian Sarcoma Group performed this retrospective analysis of patients with advanced soft ti... more The Italian Sarcoma Group performed this retrospective analysis of patients with advanced soft tissue sarcoma, pretreated with ≥1 anthracycline-based treatment, and treated with trabectedin every three weeks. Primary endpoint was to describe real-life use of trabectedin across Italy. Secondary endpoints included objective response rate (ORR) and safety. Overall, 512 patients from 20 Italian centers were evaluated. Leiomyosarcoma (37.7%)/liposarcoma (30.3%) were the most prevalent histological types (abbreviated as L-sarcoma). Patients received a median of four trabectedin cycles (range: 1–40), mostly as a second-line treatment (~60% of patients). The ORR was 13.7% superior (p < 0.0001) in patients with L-sarcoma compared with patients with non-L-sarcoma (16.6% vs. 9.0%). Median progression-free survival (PFS) was 5.1 months, whereas median overall survival (OS) was 21.6 months. Significantly better PFS and OS were observed in patients with L-sarcoma, those with objective response...
Purpose: Malignant pleural mesothelioma (MPM) is an aggressive cancer. Data are not available in ... more Purpose: Malignant pleural mesothelioma (MPM) is an aggressive cancer. Data are not available in prospective trials on correlations between genetic alterations and outcomes of therapies. In this study, we assessed the genetic profile of MPM patients (pts) in tissue samples. Patients and Methods: From December 2016 to July 2018 (end of enrolment), 164 pts were enrolled. We evaluated by targeted sequencing the mutational profile of a panel of 34 genes: ACTB, ACTG1, ACTG2, ACTR1A, BAP1, CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53, TXNRD1, UQCRC1, XRCC6. Genetic profiling was correlated with clinical and pathological variables. Results: Overall, 110 pts (67%) from both treatment arms had samples available for molecular analysis. Median age was 63 years (45–81), 25.5% (n = 28) were females, and 74.5% (n = 82) were males. Tumor histotype was 81.8% (n = 90...
Purpose: Perivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms for which t... more Purpose: Perivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms for which the role of systemic treatments is not established as there are no published prospective clinical trials or sufficiently large retrospective case series. The aim of this study is to clarify the activity of conventional chemotherapy and biological agents in advanced/metastatic PEComas. Experimental Design: This was an observational, retrospective, international study that included patients with advanced/ metastatic PEComa treated with systemic therapy at 5 European sarcoma reference centers and within the Italian Rare Cancer Network. Survival analyses were performed using the Kaplan-Meier method and the Cox hazards regression models. Results: A total of 53 patients were included. Cytotoxic chemotherapy regimens were active only in a small proportion of PEComas. Gemcitabine-based regimens [objective response rate (ORR): 20%, median progression-free survival (PFS): 3.4 months] seemed to have the same activity of anthracycline-based regimens (ORR: 13%, median PFS: 3.2 months). Antiangiogenic agents resulted in disease stabilization in some patients, with a number having density changes/tissue response on imaging, with an ORR of 8.3% and a median PFS of 5.4 months. mTOR inhibitors were the most active agents, with an ORR of 41% and a median PFS of 9 months. Conclusions: Our study provides data for the selection of systemic therapy in patients with advanced/metastatic PEComa: mTOR inhibitors are the most active agents. Antiangiogenics and chemotherapy with gemcitabine-based regimens or anthracycline-based regimens are options in further line, but with a lower response rate and PFS.
Conclusion: Tocilizumab is a therapeutic option for the management of irAEs for patients already ... more Conclusion: Tocilizumab is a therapeutic option for the management of irAEs for patients already on corticosteroids. There was no evidence of an adverse effect on overall survival with tocilizumab therapy.
Peripheral blood DNA methylation as potential biomarker of Malignant Pleural Mesothelioma in asbe... more Peripheral blood DNA methylation as potential biomarker of Malignant Pleural Mesothelioma in asbestos-exposed subjects.
Patients with recurrent/metastatic uterine leiomyosarcoma (U-LMS) have a dismal prognosis. This p... more Patients with recurrent/metastatic uterine leiomyosarcoma (U-LMS) have a dismal prognosis. This phase II study aims to evaluate trabectedin efficacy and safety in advanced U-LMS. Eligible patients had received ≥ one line of chemotherapy. Gemcitabine ± docetaxel naive patients were randomised to Arm A: trabectedin 1.3 mg/m or calibration Arm B: gemcitabine 900 mg/m and docetaxel 75 mg/m. Patients who had already received gemcitabine ± docetaxel directly entered Arm A. Primary end-point: 6-month progression-free rate (PFS-6). The null hypothesis that the true PFS-6 = 14% was tested against a one-sided alternative. This design yielded a 5% type I error rate and 90% power when the true PFS-6 is 25%. Overall, 126 patients entered Arm A (45 from randomisation and 81 directly) and 42 Arm B. Arm A patients characteristics: median age = 57; ≥2 previous chemotherapy lines = 37.4%; metastatic disease = 93%. The study met the condition for trabectedin activity: PFS-6 = 35.2% (95% CI: 26.2-45). ...
Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An... more Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop the tumor. Germline mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma. We hypothesized that other genes involved in hereditary cancer syndromes could be responsible for the inherited mesothelioma predisposition. We investigated the prevalence of germline variants in 94 cancer-predisposing genes in 93 MPM patients with a quantified asbestos exposure. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair. Patients carrying PTVs represented 9.7% of the panel and showed lower asbestos expo...
Background. The aim of this study was to report on sirolimus activity in a series of patients wit... more Background. The aim of this study was to report on sirolimus activity in a series of patients with hemangioendothelioma (HE) treated at the National Cancer Institute, Milan (Istituto Nazionale Tumori; INT) and within the Italian Rare Cancer Network (''Rete Tumori Rari''; RTR). Methods. We retrospectively reviewed patients with advanced and progressing epithelioid hemangioendothelioma (EHE) treated with sirolimus at the INT and/or within the RTR. Pathologic review and molecular analysis for WWTR1 rearrangement were performed. Sirolimus was administered until unacceptable toxicity or progression, with the dose being adjusted to reach target plasma levels
Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treat... more Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treatment options. Sarcomatoid/biphasic mesotheliomas are characterized by more aggressive behaviour and a poorer prognosis compared with the epithelioid subtype. To date prognostic and tailored therapeutic biomarkers are lacking. The present study analyzed the expression levels of MDM2 and HIF1alpha in different histologic subtypes from chemonaive MPM patients. Diagnostic biopsies of MPM patients from four Italian cancer centers were centrally collected and analyzed. MDM2 and HIF1alpha expression levels were investigated through immunohistochemistry and RT-qPCR. Pathological assessment of necrosis, inflammation and proliferation index was also performed. Molecular markers, pathological features and clinical characteristics were correlated to overall survival (OS) and progression free survival (PFS). Sixty MPM patients were included in the study (32 epithelioid and 28 non-epithelioid). Higher...
To investigate, retrospectively, the role of tumour histotype and antiangiogenic drugs for venous... more To investigate, retrospectively, the role of tumour histotype and antiangiogenic drugs for venous thromboembolism (VTE) development in advanced cancer patients treated in phase I studies. Patients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organisation) were considered. Data of 1415 patients were included in the analysis: 526 (37.2%) patients were males, median age was 57.3 years (range: 13-85). Fifty-six (3.96%) patients developed a VTE. At multivariate analysis gynaecologic (hazard ratio (HR): 2.8, 95% confidence interval (CI): 1.29-6.23, P=0.009) and gastrointestinal tumours (HR: 3.23, 95% CI: 1.18-8.87, P=0.023) as well as combination regimens of cytotoxic and antiangiogenic agents (HR: 2.6, 95% CI: 1.11-6.30, P=0.028), white blood cell >11,000 μl(-1) (HR: 2.59, 95% CI: 1.10-6.09, P=0.028) and haemoglobin<10 g dl(-1) (HR: 3.1, 95% CI: 1.07-8.94, P=0.037) were statistically correlated with VTE development. Venous thromboembolism wa...
This retrospective pooled analysis assessed the effect of age on the efficacy and safety of trabe... more This retrospective pooled analysis assessed the effect of age on the efficacy and safety of trabectedin in young and elderly patients with recurrent advanced soft tissue sarcoma (STS). Data from 350 adults with STS treated in five phase II trials with trabectedin were divided in the younger (<60 years; n=267) and the older cohort (≥60 years; n=83). The response rate did not differ with age (younger: 10.1% vs elderly 9.6%). No significant differences were found in median progression-free survival (PFS) in younger (2.5 months) and older (3.7 months) cohort with a comparable PFS rates at 3 (45.1% vs 55.1%) and 6 months (29.5% vs 36.4%). Similar median overall survival was observed in both cohorts (13.0 vs 14.0 months). Reversible neutropenia and aspartate aminotransferase/alanine aminotransferase elevation were the most common abnormalities. A higher incidence of grade 3/4 neutropenia (43.6% vs 60.2%) and fatigue (6.3% vs 14.4%) was observed in older patients. In 24 patients aged ≥7...
Soft tissue sarcomas are aggressive tumors representing <1% of all adult neoplasms. Aim of our st... more Soft tissue sarcomas are aggressive tumors representing <1% of all adult neoplasms. Aim of our study was to evaluate promyelocytic leukemia gene expression value as prognostic factor and as a factor predicting response to alkylating agents/antracycline-based first line therapy. One hundred eleven patients affected by locally advanced and metastatic soft tissue sarcoma were selected. PML expression was evaluated by immunohistochemical analysis in pathological samples and in the corresponding normal tissue from each case. PML immunohistochemical results were correlated with prognosis and with radiological response to alkylating agents/antracycline-based first line therapy. PML expression was significantly reduced in synovial sarcomas ( P < 0.0001), in myofibroblastic sarcomas ( P < 0.0001), angiosarcomas ( P < 0.0001), in leiomyosarcomas ( P ¼ 0.003), in mixoid liposarcomas ( P < 0.0001), and in dedifferentiated liposarcomas ( P < 0.0001). No significant difference was found for pleomorphic sarcoma [31.8 (95% CI: 16.7-41.0); P ¼ 0.21]. and pleomorphic liposarcomas ( P ¼ 0.51). Loss of PML expression was found to be statistically correlated with TTP ( P < 0.0001), median duration of response ( P ¼ 0.007), and OS ( P ¼ 0.02). No correlation was observed between PML expression and treatment efficacy. PML IHC expression is down-regulated in synovial sarcomas, myofibroblastic sarcomas, angiosarcomas, liposarcoma, and leiomyosarcomas and its expression correlated with prognosis.
Purpose This analysis determined the incidence of serious rhabdomyolysis events reported during t... more Purpose This analysis determined the incidence of serious rhabdomyolysis events reported during trabectedin treatment since the first phase I clinical trial in April 1996 up to September 2010. Methods Search was done in the Yondelis Ò Pharmacovigilance and Clinical Trials databases using a list of terms according to the Medical Dictionary for Regulatory Activities (MedDRA, v. 13.1), followed by a medical review of all cases retrieved. Total estimated sample was 10,841 patients: 2,789 from clinical trials; 3,926 from compassionate use programs; and 4,126 treated in the marketplace. Two groups were identified: (1) rhabdomyolysis and (2) clinically relevant creatine phosphokinase (CPK) increases without acute renal failure (ARF). Descriptive analysis included demographic, clinical/laboratory data, and contributing/confounding factors. Potential predictive factors were evaluated by multivariate stepwise logistic regression analysis. Possible changes of pharmacokinetics (PK) in patients with rhabdomyolysis were explored using a population PK model. Results The global incidence of rhabdomyolysis was 0.7 %, and most cases occurred in Cycle 2 of treatment. The incidence of fatal cases was 0.3 %. None of the variables evaluated to detect potential risk factors of rhabdomyolysis were predictive. Additionally, CPK increases (without ARF) were detected in 0.4 % of patients as an incidental finding with good prognosis. Conclusions Rhabdomyolysis is an uncommon event during trabectedin treatment. Multivariate analyses did not show any potential factor that could be predictive or represent a significantly higher risk of developing rhabdomyolysis. Nevertheless, close patient monitoring and adherence to drug administration guidelines may help to limit the incidence of this event.
What ' s known on the subject? and What does the study add? Sunitinib and sorafenib are orally ad... more What ' s known on the subject? and What does the study add? Sunitinib and sorafenib are orally administered multikinase inhibitors approved for the treatment of advanced RCC. The limited pharmacokinetics data on sunitinib and sorafenib suggest that haemodialysis does not signifi cantly alter plasma concentrations.
survival. This study aimed to quantify the impact of MPM histology on the use of surgery and surv... more survival. This study aimed to quantify the impact of MPM histology on the use of surgery and survival in a population-based analysis. Method: Overall survival (OS) of patients with stage I-III epithelioid, sarcomatoid, and biphasic MPM in the National Cancer Database from 2004 to 2015 was evaluated using Kaplan-Meier survival analysis and multivariable Cox proportional hazard models. Result: Of the 3,346 patients who met inclusion criteria, the histologic subtype was epithelioid in 2,326 patients (70%), biphasic in 482 patients (14%), and sarcomatoid in 538 patients (16%). Median survival was 16.2 [95% CI: 15.3 e 17.2] months in the epithelioid group, 10.9 [95% CI: 9.8 e 11.9] months in the biphasic group, and 5.3 [95% CI: 4.7 e 6.0] months in the sarcomatoid group (p<0.001). Cancer-directed surgery was utilized more often in epithelioid (31%, n¼718) and biphasic patients (38%, n¼181) compared to sarcomatoid patients (17%, n¼91) (p<0.001). Among patients who underwent surgery, median survival was significantly better for epithelioid (22.6 [95% CI: 21.2 e 24.8] months) and biphasic (14.7 [95% CI: 12.6 e 17.3] months) histologies compared to sarcomatoid histology (7.7 [95% CI: 6.4 e 8.6] months) (p<0.001). Surgery was associated with better survival in multivariable analysis for epithelioid (HR 0.81; [95% CI: 0.72 e 0.93], p¼0.002) and biphasic histologies (HR 0.69; [95% CI: 0.53 e 0.89], p¼0.004), but not for sarcomatoid type mesothelioma (HR 0.87; [95% CI: 0.65 e 1.16, p¼0.34). Further, the absolute difference in median survival between surgical and non-surgical therapy was more clinically significant for the epithelioid (22.6 vs 15.8 months; p <0.001 and biphasic (14.7 vs 10.4 months; p¼0.001) patients compared to the sarcomatoid (7.7 vs 7.2 months; p¼0.13). Conclusion: In this U.S. national analysis of patients with malignant pleural mesothelioma, surgery was most commonly used for epithelioid and biphasic histologies and was associated with a median survival of nearly 2 years and over 1 year, respectively. However, surgery was also used in almost 1 in 5 patients with sarcomatoid mesothelioma but was associated with a median survival of less than 8 months. These results suggest that the specific mesothelioma histology should be firmly established before surgery, and it is reasonable to aggressively treat select patients with epitheloid and biphasic mesothelioma with surgery, but that surgery should not be performed for most patients with sarcomatoid mesothelioma.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 11, 2017
Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy an... more Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), wh...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 10, 2015
To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (... more To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (DFSP)/ fibrosarcomatous (FS)-DFSP and on the impact of the treatment on tumor biology Experimental Design:Ten consecutive patients treated with IM from 2007 to 2015 for a metastatic relapse from DFSP/FS-DFSP were identified. FISH analysis for COL1A1-PDGFb was performed. Two IM-treated and 4 naïve FS-DFSP were transcriptionally profiled by RNAseq on HiScanSQ platform. Differential gene expression was analyzed with edgeR (Bioconductor), followed by hierarchical clustering and Principal Component Analysis (PCA). All cases featured fibrosarcomatous in the metastasis and retained the COL1A1-PDGFB. Best RECIST response was: 8 PR, 1 SD, 1 PD. Median PFS was 11 months. Five patients received surgery after IM and all relapsed. IM was restored in 4 patients with a new response. After IM, the most up-regulated genes included those encoding for immunoglobulins and those affecting functions and diffe...
Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and... more Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10−9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5′UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value&...
The Italian Sarcoma Group performed this retrospective analysis of patients with advanced soft ti... more The Italian Sarcoma Group performed this retrospective analysis of patients with advanced soft tissue sarcoma, pretreated with ≥1 anthracycline-based treatment, and treated with trabectedin every three weeks. Primary endpoint was to describe real-life use of trabectedin across Italy. Secondary endpoints included objective response rate (ORR) and safety. Overall, 512 patients from 20 Italian centers were evaluated. Leiomyosarcoma (37.7%)/liposarcoma (30.3%) were the most prevalent histological types (abbreviated as L-sarcoma). Patients received a median of four trabectedin cycles (range: 1–40), mostly as a second-line treatment (~60% of patients). The ORR was 13.7% superior (p < 0.0001) in patients with L-sarcoma compared with patients with non-L-sarcoma (16.6% vs. 9.0%). Median progression-free survival (PFS) was 5.1 months, whereas median overall survival (OS) was 21.6 months. Significantly better PFS and OS were observed in patients with L-sarcoma, those with objective response...
Purpose: Malignant pleural mesothelioma (MPM) is an aggressive cancer. Data are not available in ... more Purpose: Malignant pleural mesothelioma (MPM) is an aggressive cancer. Data are not available in prospective trials on correlations between genetic alterations and outcomes of therapies. In this study, we assessed the genetic profile of MPM patients (pts) in tissue samples. Patients and Methods: From December 2016 to July 2018 (end of enrolment), 164 pts were enrolled. We evaluated by targeted sequencing the mutational profile of a panel of 34 genes: ACTB, ACTG1, ACTG2, ACTR1A, BAP1, CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53, TXNRD1, UQCRC1, XRCC6. Genetic profiling was correlated with clinical and pathological variables. Results: Overall, 110 pts (67%) from both treatment arms had samples available for molecular analysis. Median age was 63 years (45–81), 25.5% (n = 28) were females, and 74.5% (n = 82) were males. Tumor histotype was 81.8% (n = 90...
Purpose: Perivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms for which t... more Purpose: Perivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms for which the role of systemic treatments is not established as there are no published prospective clinical trials or sufficiently large retrospective case series. The aim of this study is to clarify the activity of conventional chemotherapy and biological agents in advanced/metastatic PEComas. Experimental Design: This was an observational, retrospective, international study that included patients with advanced/ metastatic PEComa treated with systemic therapy at 5 European sarcoma reference centers and within the Italian Rare Cancer Network. Survival analyses were performed using the Kaplan-Meier method and the Cox hazards regression models. Results: A total of 53 patients were included. Cytotoxic chemotherapy regimens were active only in a small proportion of PEComas. Gemcitabine-based regimens [objective response rate (ORR): 20%, median progression-free survival (PFS): 3.4 months] seemed to have the same activity of anthracycline-based regimens (ORR: 13%, median PFS: 3.2 months). Antiangiogenic agents resulted in disease stabilization in some patients, with a number having density changes/tissue response on imaging, with an ORR of 8.3% and a median PFS of 5.4 months. mTOR inhibitors were the most active agents, with an ORR of 41% and a median PFS of 9 months. Conclusions: Our study provides data for the selection of systemic therapy in patients with advanced/metastatic PEComa: mTOR inhibitors are the most active agents. Antiangiogenics and chemotherapy with gemcitabine-based regimens or anthracycline-based regimens are options in further line, but with a lower response rate and PFS.
Conclusion: Tocilizumab is a therapeutic option for the management of irAEs for patients already ... more Conclusion: Tocilizumab is a therapeutic option for the management of irAEs for patients already on corticosteroids. There was no evidence of an adverse effect on overall survival with tocilizumab therapy.
Peripheral blood DNA methylation as potential biomarker of Malignant Pleural Mesothelioma in asbe... more Peripheral blood DNA methylation as potential biomarker of Malignant Pleural Mesothelioma in asbestos-exposed subjects.
Patients with recurrent/metastatic uterine leiomyosarcoma (U-LMS) have a dismal prognosis. This p... more Patients with recurrent/metastatic uterine leiomyosarcoma (U-LMS) have a dismal prognosis. This phase II study aims to evaluate trabectedin efficacy and safety in advanced U-LMS. Eligible patients had received ≥ one line of chemotherapy. Gemcitabine ± docetaxel naive patients were randomised to Arm A: trabectedin 1.3 mg/m or calibration Arm B: gemcitabine 900 mg/m and docetaxel 75 mg/m. Patients who had already received gemcitabine ± docetaxel directly entered Arm A. Primary end-point: 6-month progression-free rate (PFS-6). The null hypothesis that the true PFS-6 = 14% was tested against a one-sided alternative. This design yielded a 5% type I error rate and 90% power when the true PFS-6 is 25%. Overall, 126 patients entered Arm A (45 from randomisation and 81 directly) and 42 Arm B. Arm A patients characteristics: median age = 57; ≥2 previous chemotherapy lines = 37.4%; metastatic disease = 93%. The study met the condition for trabectedin activity: PFS-6 = 35.2% (95% CI: 26.2-45). ...
Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An... more Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop the tumor. Germline mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma. We hypothesized that other genes involved in hereditary cancer syndromes could be responsible for the inherited mesothelioma predisposition. We investigated the prevalence of germline variants in 94 cancer-predisposing genes in 93 MPM patients with a quantified asbestos exposure. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair. Patients carrying PTVs represented 9.7% of the panel and showed lower asbestos expo...
Background. The aim of this study was to report on sirolimus activity in a series of patients wit... more Background. The aim of this study was to report on sirolimus activity in a series of patients with hemangioendothelioma (HE) treated at the National Cancer Institute, Milan (Istituto Nazionale Tumori; INT) and within the Italian Rare Cancer Network (''Rete Tumori Rari''; RTR). Methods. We retrospectively reviewed patients with advanced and progressing epithelioid hemangioendothelioma (EHE) treated with sirolimus at the INT and/or within the RTR. Pathologic review and molecular analysis for WWTR1 rearrangement were performed. Sirolimus was administered until unacceptable toxicity or progression, with the dose being adjusted to reach target plasma levels
Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treat... more Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treatment options. Sarcomatoid/biphasic mesotheliomas are characterized by more aggressive behaviour and a poorer prognosis compared with the epithelioid subtype. To date prognostic and tailored therapeutic biomarkers are lacking. The present study analyzed the expression levels of MDM2 and HIF1alpha in different histologic subtypes from chemonaive MPM patients. Diagnostic biopsies of MPM patients from four Italian cancer centers were centrally collected and analyzed. MDM2 and HIF1alpha expression levels were investigated through immunohistochemistry and RT-qPCR. Pathological assessment of necrosis, inflammation and proliferation index was also performed. Molecular markers, pathological features and clinical characteristics were correlated to overall survival (OS) and progression free survival (PFS). Sixty MPM patients were included in the study (32 epithelioid and 28 non-epithelioid). Higher...
To investigate, retrospectively, the role of tumour histotype and antiangiogenic drugs for venous... more To investigate, retrospectively, the role of tumour histotype and antiangiogenic drugs for venous thromboembolism (VTE) development in advanced cancer patients treated in phase I studies. Patients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organisation) were considered. Data of 1415 patients were included in the analysis: 526 (37.2%) patients were males, median age was 57.3 years (range: 13-85). Fifty-six (3.96%) patients developed a VTE. At multivariate analysis gynaecologic (hazard ratio (HR): 2.8, 95% confidence interval (CI): 1.29-6.23, P=0.009) and gastrointestinal tumours (HR: 3.23, 95% CI: 1.18-8.87, P=0.023) as well as combination regimens of cytotoxic and antiangiogenic agents (HR: 2.6, 95% CI: 1.11-6.30, P=0.028), white blood cell >11,000 μl(-1) (HR: 2.59, 95% CI: 1.10-6.09, P=0.028) and haemoglobin<10 g dl(-1) (HR: 3.1, 95% CI: 1.07-8.94, P=0.037) were statistically correlated with VTE development. Venous thromboembolism wa...
This retrospective pooled analysis assessed the effect of age on the efficacy and safety of trabe... more This retrospective pooled analysis assessed the effect of age on the efficacy and safety of trabectedin in young and elderly patients with recurrent advanced soft tissue sarcoma (STS). Data from 350 adults with STS treated in five phase II trials with trabectedin were divided in the younger (<60 years; n=267) and the older cohort (≥60 years; n=83). The response rate did not differ with age (younger: 10.1% vs elderly 9.6%). No significant differences were found in median progression-free survival (PFS) in younger (2.5 months) and older (3.7 months) cohort with a comparable PFS rates at 3 (45.1% vs 55.1%) and 6 months (29.5% vs 36.4%). Similar median overall survival was observed in both cohorts (13.0 vs 14.0 months). Reversible neutropenia and aspartate aminotransferase/alanine aminotransferase elevation were the most common abnormalities. A higher incidence of grade 3/4 neutropenia (43.6% vs 60.2%) and fatigue (6.3% vs 14.4%) was observed in older patients. In 24 patients aged ≥7...
Soft tissue sarcomas are aggressive tumors representing <1% of all adult neoplasms. Aim of our st... more Soft tissue sarcomas are aggressive tumors representing <1% of all adult neoplasms. Aim of our study was to evaluate promyelocytic leukemia gene expression value as prognostic factor and as a factor predicting response to alkylating agents/antracycline-based first line therapy. One hundred eleven patients affected by locally advanced and metastatic soft tissue sarcoma were selected. PML expression was evaluated by immunohistochemical analysis in pathological samples and in the corresponding normal tissue from each case. PML immunohistochemical results were correlated with prognosis and with radiological response to alkylating agents/antracycline-based first line therapy. PML expression was significantly reduced in synovial sarcomas ( P < 0.0001), in myofibroblastic sarcomas ( P < 0.0001), angiosarcomas ( P < 0.0001), in leiomyosarcomas ( P ¼ 0.003), in mixoid liposarcomas ( P < 0.0001), and in dedifferentiated liposarcomas ( P < 0.0001). No significant difference was found for pleomorphic sarcoma [31.8 (95% CI: 16.7-41.0); P ¼ 0.21]. and pleomorphic liposarcomas ( P ¼ 0.51). Loss of PML expression was found to be statistically correlated with TTP ( P < 0.0001), median duration of response ( P ¼ 0.007), and OS ( P ¼ 0.02). No correlation was observed between PML expression and treatment efficacy. PML IHC expression is down-regulated in synovial sarcomas, myofibroblastic sarcomas, angiosarcomas, liposarcoma, and leiomyosarcomas and its expression correlated with prognosis.
Purpose This analysis determined the incidence of serious rhabdomyolysis events reported during t... more Purpose This analysis determined the incidence of serious rhabdomyolysis events reported during trabectedin treatment since the first phase I clinical trial in April 1996 up to September 2010. Methods Search was done in the Yondelis Ò Pharmacovigilance and Clinical Trials databases using a list of terms according to the Medical Dictionary for Regulatory Activities (MedDRA, v. 13.1), followed by a medical review of all cases retrieved. Total estimated sample was 10,841 patients: 2,789 from clinical trials; 3,926 from compassionate use programs; and 4,126 treated in the marketplace. Two groups were identified: (1) rhabdomyolysis and (2) clinically relevant creatine phosphokinase (CPK) increases without acute renal failure (ARF). Descriptive analysis included demographic, clinical/laboratory data, and contributing/confounding factors. Potential predictive factors were evaluated by multivariate stepwise logistic regression analysis. Possible changes of pharmacokinetics (PK) in patients with rhabdomyolysis were explored using a population PK model. Results The global incidence of rhabdomyolysis was 0.7 %, and most cases occurred in Cycle 2 of treatment. The incidence of fatal cases was 0.3 %. None of the variables evaluated to detect potential risk factors of rhabdomyolysis were predictive. Additionally, CPK increases (without ARF) were detected in 0.4 % of patients as an incidental finding with good prognosis. Conclusions Rhabdomyolysis is an uncommon event during trabectedin treatment. Multivariate analyses did not show any potential factor that could be predictive or represent a significantly higher risk of developing rhabdomyolysis. Nevertheless, close patient monitoring and adherence to drug administration guidelines may help to limit the incidence of this event.
What ' s known on the subject? and What does the study add? Sunitinib and sorafenib are orally ad... more What ' s known on the subject? and What does the study add? Sunitinib and sorafenib are orally administered multikinase inhibitors approved for the treatment of advanced RCC. The limited pharmacokinetics data on sunitinib and sorafenib suggest that haemodialysis does not signifi cantly alter plasma concentrations.
survival. This study aimed to quantify the impact of MPM histology on the use of surgery and surv... more survival. This study aimed to quantify the impact of MPM histology on the use of surgery and survival in a population-based analysis. Method: Overall survival (OS) of patients with stage I-III epithelioid, sarcomatoid, and biphasic MPM in the National Cancer Database from 2004 to 2015 was evaluated using Kaplan-Meier survival analysis and multivariable Cox proportional hazard models. Result: Of the 3,346 patients who met inclusion criteria, the histologic subtype was epithelioid in 2,326 patients (70%), biphasic in 482 patients (14%), and sarcomatoid in 538 patients (16%). Median survival was 16.2 [95% CI: 15.3 e 17.2] months in the epithelioid group, 10.9 [95% CI: 9.8 e 11.9] months in the biphasic group, and 5.3 [95% CI: 4.7 e 6.0] months in the sarcomatoid group (p<0.001). Cancer-directed surgery was utilized more often in epithelioid (31%, n¼718) and biphasic patients (38%, n¼181) compared to sarcomatoid patients (17%, n¼91) (p<0.001). Among patients who underwent surgery, median survival was significantly better for epithelioid (22.6 [95% CI: 21.2 e 24.8] months) and biphasic (14.7 [95% CI: 12.6 e 17.3] months) histologies compared to sarcomatoid histology (7.7 [95% CI: 6.4 e 8.6] months) (p<0.001). Surgery was associated with better survival in multivariable analysis for epithelioid (HR 0.81; [95% CI: 0.72 e 0.93], p¼0.002) and biphasic histologies (HR 0.69; [95% CI: 0.53 e 0.89], p¼0.004), but not for sarcomatoid type mesothelioma (HR 0.87; [95% CI: 0.65 e 1.16, p¼0.34). Further, the absolute difference in median survival between surgical and non-surgical therapy was more clinically significant for the epithelioid (22.6 vs 15.8 months; p <0.001 and biphasic (14.7 vs 10.4 months; p¼0.001) patients compared to the sarcomatoid (7.7 vs 7.2 months; p¼0.13). Conclusion: In this U.S. national analysis of patients with malignant pleural mesothelioma, surgery was most commonly used for epithelioid and biphasic histologies and was associated with a median survival of nearly 2 years and over 1 year, respectively. However, surgery was also used in almost 1 in 5 patients with sarcomatoid mesothelioma but was associated with a median survival of less than 8 months. These results suggest that the specific mesothelioma histology should be firmly established before surgery, and it is reasonable to aggressively treat select patients with epitheloid and biphasic mesothelioma with surgery, but that surgery should not be performed for most patients with sarcomatoid mesothelioma.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 11, 2017
Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy an... more Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), wh...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 10, 2015
To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (... more To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (DFSP)/ fibrosarcomatous (FS)-DFSP and on the impact of the treatment on tumor biology Experimental Design:Ten consecutive patients treated with IM from 2007 to 2015 for a metastatic relapse from DFSP/FS-DFSP were identified. FISH analysis for COL1A1-PDGFb was performed. Two IM-treated and 4 naïve FS-DFSP were transcriptionally profiled by RNAseq on HiScanSQ platform. Differential gene expression was analyzed with edgeR (Bioconductor), followed by hierarchical clustering and Principal Component Analysis (PCA). All cases featured fibrosarcomatous in the metastasis and retained the COL1A1-PDGFB. Best RECIST response was: 8 PR, 1 SD, 1 PD. Median PFS was 11 months. Five patients received surgery after IM and all relapsed. IM was restored in 4 patients with a new response. After IM, the most up-regulated genes included those encoding for immunoglobulins and those affecting functions and diffe...
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