P. Ferrucci - Academia.edu (original) (raw)
Papers by P. Ferrucci
American Journal of Infection Control, 2012
Central venous access port-related bloodstream infection (CVAP-BSI) is associated with morbidity ... more Central venous access port-related bloodstream infection (CVAP-BSI) is associated with morbidity and mortality in patients with cancer. This study examined the incidence rates and risk factors for CVAP-BSI in adult patients with digestive cancer. This prospective observational cohort study was performed from 2007 to 2011 in 2 oncology units of a university hospital. Incidence rate was expressed as number of CVAP-BSI per 1,000 catheter-days. A Cox regression model was used to identify risk factors for CVAP-BSI. A total of 315 patients were included. CVAP-BSI occurred in 41 patients (13.0%). The overall incidence rate was 0.76/1,000 catheter-days. The rate was higher in patients with esophageal cancer (1.28. P = .05) and pancreatic cancer (1.24; P = .007). Risk factors independently associated with CVAP-BSI were World Health Organization performance status between 2 and 4, catheter utilization-days in the previous month, pancreatic cancer, and parenteral nutrition. Coagulase-negative Staphylococci and enterobacteria were the main microorganisms isolated. In adult patients with digestive cancer, pancreatic cancer, cumulative catheter utilization-days, World Health Organization performance status, and parenteral nutrition were identified as independent risk factors for CVAP-BSI. Patients with any of these risk factors could be candidates for preventive strategies.
British Journal of Haematology, 1999
A number of clinical studies have demonstrated the prognostic significance of angiogenesis and an... more A number of clinical studies have demonstrated the prognostic significance of angiogenesis and angiogenic growth factors in solid tumours; however, very little is known about the relevance of these parameters in haematological malignancies. We evaluated circulating levels of angiogenic growth factors and endostatin in 36 non-Hodgkin's lymphoma (NHL) patients. Baseline vascular endothelial growth factor (VEGF) levels of patients in complete remission (CR) after a median follow-up of 21 months were significantly lower than those of patients with progressive disease (P = 0.016). Event-free survival (EFS) rate was significantly higher in patients who had baseline VEGF and basic-fibroblast growth factor (b.FGF) levels below the median values of 147 and 19.5 pg/ml (P = 0.018 and 0.039 by log-rank test, respectively). Conversely, the levels of endostatin, angiogenin and leptin were not different in CR patients compared to relapsed patients and did not correlate with EFS. Our data suggest that b-FGF and, particularly, VEGF might be considered prognostic factors in NHL staging and management.
Blood Reviews, 1993
The chromosome breakpoints of the acute promyelocytic leukemia (APL)-specific 15;17 translocation... more The chromosome breakpoints of the acute promyelocytic leukemia (APL)-specific 15;17 translocation have recently been isolated. They are localized on a previously unknown gene, PML, on chromosome 15 and in the gene that encodes the alpha retinoic acid receptor (RAR alpha) on 17. The translocation, which is balanced and reciprocal, leads to the formation of two fusion genes, PML/RAR alpha and RAR alpha/PML. Both are expressed in APL. The PML/RAR alpha gene codes for two abnormal proteins: the PML/RAR alpha fusion protein and an abnormal PML protein, the RAR alpha/PML gene encodes the RAR alpha/PML fusion protein. Experiments to investigate the biological activity of the abnormal translocation products are in progress. Preliminary results suggest that the PML/RAR alpha fusion protein is responsible for two important properties of the APL phenotype: the differentiation block characteristic of the leukemic blasts and the high sensitivity of the blasts to the differentiative action of retinoic acid (RA) both in vivo and in vitro. The mechanism through which PML/RAR alpha exerts its biological function remains unknown. However, there is accumulating evidence that it acts by interfering with normal endogenous pathways of both RAR alpha and PML. The RAR alpha receptor is implicated in regulating the myeloid differentiation induced by RA. Although the physiological function of PML is not known, it is probably a transcription factor. Definition of the molecular architecture of the t(15;17) has furnished further tools for: (1) molecular diagnosis of APL and (2) highly sensitive evaluation of the neoplastic clone during antileukaemic therapy. The molecular identification of residual APL disease after anti-leukaemia therapy allows patients at risk of relapse to be identified.
International Journal of Oncology, 2007
The incidence and prognostic relevance of bone marrow (BM) and leukapheresis (PBPC) tumor cell co... more The incidence and prognostic relevance of bone marrow (BM) and leukapheresis (PBPC) tumor cell contamination (TCC) in breast cancer patients is still to be circumstantiated. We developed a new comprehensive gene expression panel to study cytokeratins (CK), maspin (MAS) and mammaglobin (MAM) as possible predictors of prognosis. Forty-eight patients undergoing high dose chemotherapy (HDCT) and PBPC support were enrolled and analyzed for TCC on 116 PBPC apheresis and 96 BM obtained at basal conditions. All of the patients were evaluated by reverse transcriptase nested PCR (RT-PCR) for MAM and MAS gene expression and by immunocytochemistry (ICC) and nested RT-PCR to evaluate CK expression. PBPC and BM frequency of CK-positive (+) cells was 12-13% by ICC and 71-73% by RT-PCR respectively. Sixty-seven percent of CK ICC + samples were MAM RT-PCR + and 89% of them were MAS RT-PCR +. PBPC and BM frequency of MAM + cells was 21% and 31% respectively, while for MAS + cells it was 48% and 52% respectively by RT-PCR. After 71 mo median FU, 16 patients (33%) relapsed and 14 (88%) had BM/PBPC TCC. No marker had an impact on overall survival (OS) but MAS expression on BM and MAM expression on PBPC correlated with a statistically significant improved (p=0.05) and worsened RFS (p=0.06) respectively. These data confirm the activity of MAM as a negative prognostic factor and show for the first time that MAS could work as a tumor suppressor gene even in a clinical setting, since it protects from recurrence.
Blood, Oct 1, 1998
All-trans-retinoic acid (RA) treatment induces morphological remission in acute promyelocytic leu... more All-trans-retinoic acid (RA) treatment induces morphological remission in acute promyelocytic leukemia (APL) patients carrying the t(15;17) and expressing the PML/RARalpha product by inducing terminal differentiation of the leukemic clone. RA treatment induces downregulation of PML/RARalpha and reorganization of the PML-nuclear bodies. These events have been proposed to be essential for the induction of APL cell differentiation by RA. Here, we show that in the APL-derived NB4 cell line as well as in myeloid precursor U937 cells expressing the PML/RARalpha (U937/PR9) and in blasts from APL patients, the PML/RARalpha fusion protein is cleaved by a caspase 3-like activity induced by RA treatment. In fact, a caspase 3-like activity is detectable in PML/RARalpha expressing cells after RA treatment, and selective caspase inhibitor peptides are able to prevent the RA-induced degradation of the fusion protein in vivo and in vitro. Using recombinant caspases and PML/RARalpha deletion mutants...
Cancer research, 1994
We have analyzed the differentiation program of a U937 promonocytic leukemia clone transduced wit... more We have analyzed the differentiation program of a U937 promonocytic leukemia clone transduced with the acute promyelocytic leukemia specific PML/RAR alpha fusion gene, the expression of which is under the control of the inducible metallothionine (MT) I promoter (MTPR9 clone). MTPR9 cells treated with Zn2+ hence exhibit levels of PML-RAR alpha protein as high as fresh acute promyelocytic leukemia blasts. In the absence of Zn2+, i.e., upon low level PML/RAR alpha expression, 1,25-dihydroxyvitamin D3 (D3) and particularly D3 plus transforming growth factor beta 1 (TGF-beta 1) induced terminal differentiation of MTPR9 cells (as observed in "wild-type" U937 cells), on the basis of morphology, membrane antigen pattern, and functional criteria. Conversely, in the presence of Zn2+, D3 and D3 plus TGF-beta 1 failed to induce terminal differentiation, as evaluated by the above parameters. Interestingly, retinoic acid (RA) treatment suppresses the differentiation blockade induced by ...
Leukemia, 1994
Acute promyelocytic leukaemia is characterized by an expansion of haematopoietic precursors arres... more Acute promyelocytic leukaemia is characterized by an expansion of haematopoietic precursors arrested at the promyelocytic stage (1). The differentiation block can be reversed by retinoic acid, which induces blast differentiation both in vitro (2) and in vivo (3-4). Acute promyelocytic leukaemia is also characterized by a 15;17 chromosome translocation (5) with breakpoints within the retinoic acid alpha receptor (RAR alpha) gene on 17 and within the PML gene, that encodes a putative transcription factor of unknown function (6-7), on 15 (8-10). As a consequence of the translocation a PML/RAR alpha gene is formed. It is transcriptionally active and encodes a PML/RAR alpha fusion protein detectable in all APL cases (11-14). We expressed the PML/RAR alpha protein in U937 myeloid precursor cell line and show that they: 1) lose the capacity to differentiate under the action of different stimuli (vitamin D3, transforming growth factor beta 1); ii) acquire enhanced sensitivity to retinoic ac...
Leukemia & Lymphoma, 2003
Blood
Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT ... more Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT or for those pts relapsing after ABMT. Zevalin has been already demonstrated active in elderly pts with resistant-primary refractory DLBCL at dose of 0.4 mCi/kg, however duration of response is short. Increasing RIT dose intensity might improve efficacy. There are no data about the use of Zevalin at myeloablative dosage. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. Three Zevalin dose-levels were fixed: 0.8, 1.2, 1.5 mCi/kg; from April 2004 to July 2005 12pts were enrolled, 4pts at each dose level. Median age was 66,5 ys (28–73), 83% male. All pts had stage III/IV at diagnosis; 7DLBCL; 3MCL, 1FL, 1transformed MZL. 7pts had received more than 3 previous CT regimens. All pts had received prior rituximab, 3pts RT, 6pts HD-CT. BM was negative in all pts before RIT. 1Week prior to Zevalin all pts underwent do...
Journal of Clinical Oncology
7587 Background: Therapeutic options are limited in the treatment of relapsing NHL pts not suitab... more 7587 Background: Therapeutic options are limited in the treatment of relapsing NHL pts not suitable to HDCT. 90Yttrium ibritumomab tiuxetan (Zevalin) is active in DLBCL at 0.4 mCi/kg, but duration of response is usually short. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. From 04/04 to 11/05, 14 pts were enrolled. Median age was 68ys. 13/14 pts had advanced stage disease (III/IV) at diagnosis. 8 DLBCL, 4 MCL, 1 FL G3, 1 transformed MZL. Median number of prior therapies were 3, including rituximab, RT and HD-CT. Methods: 3 dose levels were fixed: 0.8, 1.2, 1.5 mCi/kg. 4 pts received 0.8, 4 pts 1.2 and 6 pts 1.5 mCi/kg. 1wk prior to Zevalin all pts underwent dosimetry: if no abnormal uptake was observed they received the planned dose. On d13 pts received PBSC previously harvested. On d28 from reinfusion (+41 from Zevalin) engraftment was considered to be delayed if ANC <1.0×109/L or PLT<20.0×109...
Clinical and Translational Oncology
Purpose The aim of this study is to verify if baseline hematological markers, in patients with ad... more Purpose The aim of this study is to verify if baseline hematological markers, in patients with advanced melanoma receiving BRAF inhibitor (BRAFi)-based therapies, are independently associated with progression free survival (PFS) and overall survival (OS). Methods We retrospectively analyzed 90 patients with metastatic melanoma harboring BRAF V600 mutation, who received treatment with either BRAFi alone or combined with a MEK inhibitor (MEKi) at the recommended dosages. Study population included 28 women and 62 men. Median age was 53 years. Seventy-three (82%) patients presented with M1c disease, 49 (56%) had elevated LDH and 54 (60%) had three or more metastatic sites. Results The median PFS was 9.1 and 3.5 months, respectively, for patients with baseline NLR < 5 and NLR ≥ 5, while median OS was 17.2 and 5.5 months, respectively, for patients with NLR < 5 and NLR ≥ 5. Multivariate analysis confirmed that baseline NLR < 5 was significantly associated with half risk of relapse (HR = 0.49; 95% CI = 0.28–0.85; p = 0.01) and half risk of death (HR = 0.46; 95% CI = 0.23–0.76; p = 0.004), independent of age, sex, stage, LDH > 2xULN, previous treatments, concomitant use of steroids and type of therapy. In patients with LDH ≥ ULN, NLR < 5 remained significantly and independently associated with improved PFS (HR = 0.28; 95% CI = 0.13–0.62; p = 0.002,) and OS (HR = 0.23; 95% CI = 0.10–0.55; p = 0.001). Conclusions These biomarkers are easily reproducible, affordable and costless and NLR could help to identify patients who have the best benefit from BRAF inhibitors.
Annals of Oncology
Background: Pembro þ D þ T had promising antitumor activity and acceptable tolerability in phase ... more Background: Pembro þ D þ T had promising antitumor activity and acceptable tolerability in phase 1 of KEYNOTE-022 (NCT02130466). Methods: In the double-blind phase 2 part of KEYNOTE-022, pts with treatment (tx)naive BRAF V600E/K-mutant stage III/IV melanoma were randomly assigned (stratified by ECOG PS [0/1)]; LDH level [>1.1 vs 1.1Â ULN]) to pembro 2 mg/kg Q3W þ D
Journal of Clinical Oncology
8536 Background: Advanced MM pts' poor prognosis is not improved by the neither of the 2 FDA ... more 8536 Background: Advanced MM pts' poor prognosis is not improved by the neither of the 2 FDA approved agents, DTIC and IL-2 (median survival-time < 9 month [mo]; 5-yr survival-rate < 5%). Single-agent DTIC has average response-rate of 10% and median response-duration of 5-6 mo, being poly-CTh never proven to be superior. To improve such sober results, different DTIC- combinations have been proposed. MM in vitro models showed VEGF transcription up-regulation by DTIC, suggesting DTIC/anti-VEGF combination as an intriguing exploiting path. Methods: Between July 2006-September 2009, at IEO, Milan, 40 CTh-naive advanced MM pts underwent CTh with DTIC (800 mg/mq q4w) + B (10 mg/kg q2w), being disease evaluated at each access by physical examination and every 3 cycles by whole-body (wb) CT-scan, according to RECIST criteria. Response rate, median TTP and safety were analyzed. Results: 36/40 pts were evaluated at the analysis-time, with 4 screening failures (3 pts: brain metastasis detection at the pre-study wb C...
Journal of Clinical Oncology, 2010
8589 Background: A new, promising application of bleomycin was discovered and developed by Mir in... more 8589 Background: A new, promising application of bleomycin was discovered and developed by Mir in 1991, combining the drug with electroporation. This new technique was called electrochemotherapy (ECT). The new treatment is based on the increased bleomycin delivery into tumor cells after cell membrane permeabilization by electric pulses administered locally at the site of superficial tumor localizations. Since 1991 more than 300 articles were published on the argument and experiences from many institutes in Europe seems to be very promising. Actually ECT is used for the treatment of cutaneous and subcutaneous tumoral lesions from different tumoral types. Favorable results in treating superficial metastatic lesions have been published with a complete response rate for treated nodules raging from 70% to 90%. Methods: In our Institute we treated 75 consecutive patients from 2006 to 2009 for superficial cancer lesions, especially metastatic melanomas (58 patients) and squamous or large basal cell carcinomas (1...
Annals of Oncology, 2016
Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront ... more Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need. Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out. The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P &amp;amp;amp;lt; 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR. Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials.
European Journal of Cancer, 2015
ABSTRACT The purpose of this study was to set up a prognostic model for the identification of sur... more ABSTRACT The purpose of this study was to set up a prognostic model for the identification of survival predictors specific for melanoma patients treated with ipilimumab. The following prospectively collected data were utilised: patient and primary tumour characteristics, relapse-free-interval, site and number of metastases, previous therapies and level of serum biomarkers (lactic dehydrogenase (LDH), C-reactive protein, β2-microglobulin, vascular endothelial growth factor (VEGF), IL2, IL6, S-100, alkaline phosphatase (ALP), transaminases, leucocyte count, lymphocytes subpopulations). A multivariate prognostic model was developed using the Cox regression model fitted to the data of 113 consecutive metastatic patients treated with ipilimumab (3mg/kg, q3w) at Veneto Institute of Oncology (IOV). External validation was obtained using the data of 69 and 34 patients treated at European Oncology Institute (IEO) and University of Torino (UT), respectively. Median survival was 9.7, 4.9 and 7.1months from first ipilimumab administration at IOV, IEO and UT, respectively. Both higher baseline levels of LDH (Hazard Ratio [HR] v=1.36, 95% Confidence Interval [CI] 1.16-1.58, P<.001) and neutrophils (HR=1.76, 95% CI 1.41-2.10, P<.001) were associated with worse prognosis. Model performance was satisfactory both upon internal validation (Dxy=0.42) and external validation (Dxy=0.40). Serum LDH and neutrophil count discriminated patients who lived more (low neutrophils and low LDH) or less (high LDH or neutrophils) than 24months. Serum LDH and neutrophil count were significant independent prognostic factors. This externally validated prognostic nomogram, could help clinicians to identify the patients who would benefit most from ipilimumab and consequently to improve resource allocation. These easily available biomarkers deserve further validation. Copyright © 2015 Elsevier Ltd. All rights reserved.
Cancer Research, 2015
Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Ipil... more Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Ipilimumab, a recently approved immunomodulatory drug, improves the survival of metastatic melanoma patients. Despite documented, durable objective responses, a significant number of patients fails to obtain clinical benefit from treatment. The aim of this study was to identify a criterion to select patients best suited to receive this drug. Methods: Sixty-nine metastatic melanoma patients treated at the European Institute of Oncology with 3 mg/kg ipilimumab, were evaluated. Neutrophil to lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts. Progression free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox models were applied. Findings were independently validated on a cohort of 27 patients treated with 10 mg/kg ipilimumab at the University Hospital of Siena and on a cohort of 88 treated in Rome. Results: Best overall response and disease control rates were 9% and 27%, respectively. Median PFS and OS were 3 and 5 months, respectively. Pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in univariate and multivariate analyses. Patients with baseline NLR<5 had a significantly improved PFS (HR = 0.38; 95% CI: 0.22-0.66; P = 0.0006) and OS (HR = 0.24; 95% CI: 0.13-0.46; P<0.0001) compared with those with a NLR≥5. Conclusions: Our findings show that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve as a selection criterion for this therapy. Citation Format: Pier Francesco Ferrucci, Sara Gandini, Angelo Battaglia, Salvatore Alfieri, Laura Pala, Annamaria Di Giacomo, Giovanni Amato, Gian Carlo Antonini Cappellini, Diana Giannarelli, Emilia Cocorocchio, Chiara Martinoli. Baseline neutrophil to lymphocyte ratio as a selection criterion for ipilimumab treatment in metastatic melanoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-115. doi:10.1158/1538-7445.AM2015-LB-115
The EMBO journal, Jan 16, 1996
The block of terminal differentiation is a prominent feature of acute promyelocytic leukemia (APL... more The block of terminal differentiation is a prominent feature of acute promyelocytic leukemia (APL) and its release by retinoic acid correlates with disease remission. Expression of the APL-specific PML/RARalpha fusion protein in hematopoietic precursor cell lines blocks terminal differentiation, suggesting that PML/ RARalpha may have the same activity in APL blasts. We expressed different PML/RARalpha mutants in U937 and TF-1 cells and demonstrated that the integrity of the PML protein dimerization and RARalpha DNA binding domains is crucial for the differentiation block induced by PML/RARalpha, and that these domains exert their functions only within the context of the fusion protein. Analysis of the in vivo dimerization and cell localization properties of the PML/RARalpha mutants revealed that PML/RARalpha--PML and PML/RARalpha--RXR heterodimers are not necessary for PML/RARalpha activity on differentiation. We propose that a crucial mechanism underlying PML/RARalpha oncogenic act...
American Journal of Infection Control, 2012
Central venous access port-related bloodstream infection (CVAP-BSI) is associated with morbidity ... more Central venous access port-related bloodstream infection (CVAP-BSI) is associated with morbidity and mortality in patients with cancer. This study examined the incidence rates and risk factors for CVAP-BSI in adult patients with digestive cancer. This prospective observational cohort study was performed from 2007 to 2011 in 2 oncology units of a university hospital. Incidence rate was expressed as number of CVAP-BSI per 1,000 catheter-days. A Cox regression model was used to identify risk factors for CVAP-BSI. A total of 315 patients were included. CVAP-BSI occurred in 41 patients (13.0%). The overall incidence rate was 0.76/1,000 catheter-days. The rate was higher in patients with esophageal cancer (1.28. P = .05) and pancreatic cancer (1.24; P = .007). Risk factors independently associated with CVAP-BSI were World Health Organization performance status between 2 and 4, catheter utilization-days in the previous month, pancreatic cancer, and parenteral nutrition. Coagulase-negative Staphylococci and enterobacteria were the main microorganisms isolated. In adult patients with digestive cancer, pancreatic cancer, cumulative catheter utilization-days, World Health Organization performance status, and parenteral nutrition were identified as independent risk factors for CVAP-BSI. Patients with any of these risk factors could be candidates for preventive strategies.
British Journal of Haematology, 1999
A number of clinical studies have demonstrated the prognostic significance of angiogenesis and an... more A number of clinical studies have demonstrated the prognostic significance of angiogenesis and angiogenic growth factors in solid tumours; however, very little is known about the relevance of these parameters in haematological malignancies. We evaluated circulating levels of angiogenic growth factors and endostatin in 36 non-Hodgkin's lymphoma (NHL) patients. Baseline vascular endothelial growth factor (VEGF) levels of patients in complete remission (CR) after a median follow-up of 21 months were significantly lower than those of patients with progressive disease (P = 0.016). Event-free survival (EFS) rate was significantly higher in patients who had baseline VEGF and basic-fibroblast growth factor (b.FGF) levels below the median values of 147 and 19.5 pg/ml (P = 0.018 and 0.039 by log-rank test, respectively). Conversely, the levels of endostatin, angiogenin and leptin were not different in CR patients compared to relapsed patients and did not correlate with EFS. Our data suggest that b-FGF and, particularly, VEGF might be considered prognostic factors in NHL staging and management.
Blood Reviews, 1993
The chromosome breakpoints of the acute promyelocytic leukemia (APL)-specific 15;17 translocation... more The chromosome breakpoints of the acute promyelocytic leukemia (APL)-specific 15;17 translocation have recently been isolated. They are localized on a previously unknown gene, PML, on chromosome 15 and in the gene that encodes the alpha retinoic acid receptor (RAR alpha) on 17. The translocation, which is balanced and reciprocal, leads to the formation of two fusion genes, PML/RAR alpha and RAR alpha/PML. Both are expressed in APL. The PML/RAR alpha gene codes for two abnormal proteins: the PML/RAR alpha fusion protein and an abnormal PML protein, the RAR alpha/PML gene encodes the RAR alpha/PML fusion protein. Experiments to investigate the biological activity of the abnormal translocation products are in progress. Preliminary results suggest that the PML/RAR alpha fusion protein is responsible for two important properties of the APL phenotype: the differentiation block characteristic of the leukemic blasts and the high sensitivity of the blasts to the differentiative action of retinoic acid (RA) both in vivo and in vitro. The mechanism through which PML/RAR alpha exerts its biological function remains unknown. However, there is accumulating evidence that it acts by interfering with normal endogenous pathways of both RAR alpha and PML. The RAR alpha receptor is implicated in regulating the myeloid differentiation induced by RA. Although the physiological function of PML is not known, it is probably a transcription factor. Definition of the molecular architecture of the t(15;17) has furnished further tools for: (1) molecular diagnosis of APL and (2) highly sensitive evaluation of the neoplastic clone during antileukaemic therapy. The molecular identification of residual APL disease after anti-leukaemia therapy allows patients at risk of relapse to be identified.
International Journal of Oncology, 2007
The incidence and prognostic relevance of bone marrow (BM) and leukapheresis (PBPC) tumor cell co... more The incidence and prognostic relevance of bone marrow (BM) and leukapheresis (PBPC) tumor cell contamination (TCC) in breast cancer patients is still to be circumstantiated. We developed a new comprehensive gene expression panel to study cytokeratins (CK), maspin (MAS) and mammaglobin (MAM) as possible predictors of prognosis. Forty-eight patients undergoing high dose chemotherapy (HDCT) and PBPC support were enrolled and analyzed for TCC on 116 PBPC apheresis and 96 BM obtained at basal conditions. All of the patients were evaluated by reverse transcriptase nested PCR (RT-PCR) for MAM and MAS gene expression and by immunocytochemistry (ICC) and nested RT-PCR to evaluate CK expression. PBPC and BM frequency of CK-positive (+) cells was 12-13% by ICC and 71-73% by RT-PCR respectively. Sixty-seven percent of CK ICC + samples were MAM RT-PCR + and 89% of them were MAS RT-PCR +. PBPC and BM frequency of MAM + cells was 21% and 31% respectively, while for MAS + cells it was 48% and 52% respectively by RT-PCR. After 71 mo median FU, 16 patients (33%) relapsed and 14 (88%) had BM/PBPC TCC. No marker had an impact on overall survival (OS) but MAS expression on BM and MAM expression on PBPC correlated with a statistically significant improved (p=0.05) and worsened RFS (p=0.06) respectively. These data confirm the activity of MAM as a negative prognostic factor and show for the first time that MAS could work as a tumor suppressor gene even in a clinical setting, since it protects from recurrence.
Blood, Oct 1, 1998
All-trans-retinoic acid (RA) treatment induces morphological remission in acute promyelocytic leu... more All-trans-retinoic acid (RA) treatment induces morphological remission in acute promyelocytic leukemia (APL) patients carrying the t(15;17) and expressing the PML/RARalpha product by inducing terminal differentiation of the leukemic clone. RA treatment induces downregulation of PML/RARalpha and reorganization of the PML-nuclear bodies. These events have been proposed to be essential for the induction of APL cell differentiation by RA. Here, we show that in the APL-derived NB4 cell line as well as in myeloid precursor U937 cells expressing the PML/RARalpha (U937/PR9) and in blasts from APL patients, the PML/RARalpha fusion protein is cleaved by a caspase 3-like activity induced by RA treatment. In fact, a caspase 3-like activity is detectable in PML/RARalpha expressing cells after RA treatment, and selective caspase inhibitor peptides are able to prevent the RA-induced degradation of the fusion protein in vivo and in vitro. Using recombinant caspases and PML/RARalpha deletion mutants...
Cancer research, 1994
We have analyzed the differentiation program of a U937 promonocytic leukemia clone transduced wit... more We have analyzed the differentiation program of a U937 promonocytic leukemia clone transduced with the acute promyelocytic leukemia specific PML/RAR alpha fusion gene, the expression of which is under the control of the inducible metallothionine (MT) I promoter (MTPR9 clone). MTPR9 cells treated with Zn2+ hence exhibit levels of PML-RAR alpha protein as high as fresh acute promyelocytic leukemia blasts. In the absence of Zn2+, i.e., upon low level PML/RAR alpha expression, 1,25-dihydroxyvitamin D3 (D3) and particularly D3 plus transforming growth factor beta 1 (TGF-beta 1) induced terminal differentiation of MTPR9 cells (as observed in "wild-type" U937 cells), on the basis of morphology, membrane antigen pattern, and functional criteria. Conversely, in the presence of Zn2+, D3 and D3 plus TGF-beta 1 failed to induce terminal differentiation, as evaluated by the above parameters. Interestingly, retinoic acid (RA) treatment suppresses the differentiation blockade induced by ...
Leukemia, 1994
Acute promyelocytic leukaemia is characterized by an expansion of haematopoietic precursors arres... more Acute promyelocytic leukaemia is characterized by an expansion of haematopoietic precursors arrested at the promyelocytic stage (1). The differentiation block can be reversed by retinoic acid, which induces blast differentiation both in vitro (2) and in vivo (3-4). Acute promyelocytic leukaemia is also characterized by a 15;17 chromosome translocation (5) with breakpoints within the retinoic acid alpha receptor (RAR alpha) gene on 17 and within the PML gene, that encodes a putative transcription factor of unknown function (6-7), on 15 (8-10). As a consequence of the translocation a PML/RAR alpha gene is formed. It is transcriptionally active and encodes a PML/RAR alpha fusion protein detectable in all APL cases (11-14). We expressed the PML/RAR alpha protein in U937 myeloid precursor cell line and show that they: 1) lose the capacity to differentiate under the action of different stimuli (vitamin D3, transforming growth factor beta 1); ii) acquire enhanced sensitivity to retinoic ac...
Leukemia & Lymphoma, 2003
Blood
Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT ... more Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT or for those pts relapsing after ABMT. Zevalin has been already demonstrated active in elderly pts with resistant-primary refractory DLBCL at dose of 0.4 mCi/kg, however duration of response is short. Increasing RIT dose intensity might improve efficacy. There are no data about the use of Zevalin at myeloablative dosage. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. Three Zevalin dose-levels were fixed: 0.8, 1.2, 1.5 mCi/kg; from April 2004 to July 2005 12pts were enrolled, 4pts at each dose level. Median age was 66,5 ys (28–73), 83% male. All pts had stage III/IV at diagnosis; 7DLBCL; 3MCL, 1FL, 1transformed MZL. 7pts had received more than 3 previous CT regimens. All pts had received prior rituximab, 3pts RT, 6pts HD-CT. BM was negative in all pts before RIT. 1Week prior to Zevalin all pts underwent do...
Journal of Clinical Oncology
7587 Background: Therapeutic options are limited in the treatment of relapsing NHL pts not suitab... more 7587 Background: Therapeutic options are limited in the treatment of relapsing NHL pts not suitable to HDCT. 90Yttrium ibritumomab tiuxetan (Zevalin) is active in DLBCL at 0.4 mCi/kg, but duration of response is usually short. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. From 04/04 to 11/05, 14 pts were enrolled. Median age was 68ys. 13/14 pts had advanced stage disease (III/IV) at diagnosis. 8 DLBCL, 4 MCL, 1 FL G3, 1 transformed MZL. Median number of prior therapies were 3, including rituximab, RT and HD-CT. Methods: 3 dose levels were fixed: 0.8, 1.2, 1.5 mCi/kg. 4 pts received 0.8, 4 pts 1.2 and 6 pts 1.5 mCi/kg. 1wk prior to Zevalin all pts underwent dosimetry: if no abnormal uptake was observed they received the planned dose. On d13 pts received PBSC previously harvested. On d28 from reinfusion (+41 from Zevalin) engraftment was considered to be delayed if ANC <1.0×109/L or PLT<20.0×109...
Clinical and Translational Oncology
Purpose The aim of this study is to verify if baseline hematological markers, in patients with ad... more Purpose The aim of this study is to verify if baseline hematological markers, in patients with advanced melanoma receiving BRAF inhibitor (BRAFi)-based therapies, are independently associated with progression free survival (PFS) and overall survival (OS). Methods We retrospectively analyzed 90 patients with metastatic melanoma harboring BRAF V600 mutation, who received treatment with either BRAFi alone or combined with a MEK inhibitor (MEKi) at the recommended dosages. Study population included 28 women and 62 men. Median age was 53 years. Seventy-three (82%) patients presented with M1c disease, 49 (56%) had elevated LDH and 54 (60%) had three or more metastatic sites. Results The median PFS was 9.1 and 3.5 months, respectively, for patients with baseline NLR < 5 and NLR ≥ 5, while median OS was 17.2 and 5.5 months, respectively, for patients with NLR < 5 and NLR ≥ 5. Multivariate analysis confirmed that baseline NLR < 5 was significantly associated with half risk of relapse (HR = 0.49; 95% CI = 0.28–0.85; p = 0.01) and half risk of death (HR = 0.46; 95% CI = 0.23–0.76; p = 0.004), independent of age, sex, stage, LDH > 2xULN, previous treatments, concomitant use of steroids and type of therapy. In patients with LDH ≥ ULN, NLR < 5 remained significantly and independently associated with improved PFS (HR = 0.28; 95% CI = 0.13–0.62; p = 0.002,) and OS (HR = 0.23; 95% CI = 0.10–0.55; p = 0.001). Conclusions These biomarkers are easily reproducible, affordable and costless and NLR could help to identify patients who have the best benefit from BRAF inhibitors.
Annals of Oncology
Background: Pembro þ D þ T had promising antitumor activity and acceptable tolerability in phase ... more Background: Pembro þ D þ T had promising antitumor activity and acceptable tolerability in phase 1 of KEYNOTE-022 (NCT02130466). Methods: In the double-blind phase 2 part of KEYNOTE-022, pts with treatment (tx)naive BRAF V600E/K-mutant stage III/IV melanoma were randomly assigned (stratified by ECOG PS [0/1)]; LDH level [>1.1 vs 1.1Â ULN]) to pembro 2 mg/kg Q3W þ D
Journal of Clinical Oncology
8536 Background: Advanced MM pts' poor prognosis is not improved by the neither of the 2 FDA ... more 8536 Background: Advanced MM pts' poor prognosis is not improved by the neither of the 2 FDA approved agents, DTIC and IL-2 (median survival-time < 9 month [mo]; 5-yr survival-rate < 5%). Single-agent DTIC has average response-rate of 10% and median response-duration of 5-6 mo, being poly-CTh never proven to be superior. To improve such sober results, different DTIC- combinations have been proposed. MM in vitro models showed VEGF transcription up-regulation by DTIC, suggesting DTIC/anti-VEGF combination as an intriguing exploiting path. Methods: Between July 2006-September 2009, at IEO, Milan, 40 CTh-naive advanced MM pts underwent CTh with DTIC (800 mg/mq q4w) + B (10 mg/kg q2w), being disease evaluated at each access by physical examination and every 3 cycles by whole-body (wb) CT-scan, according to RECIST criteria. Response rate, median TTP and safety were analyzed. Results: 36/40 pts were evaluated at the analysis-time, with 4 screening failures (3 pts: brain metastasis detection at the pre-study wb C...
Journal of Clinical Oncology, 2010
8589 Background: A new, promising application of bleomycin was discovered and developed by Mir in... more 8589 Background: A new, promising application of bleomycin was discovered and developed by Mir in 1991, combining the drug with electroporation. This new technique was called electrochemotherapy (ECT). The new treatment is based on the increased bleomycin delivery into tumor cells after cell membrane permeabilization by electric pulses administered locally at the site of superficial tumor localizations. Since 1991 more than 300 articles were published on the argument and experiences from many institutes in Europe seems to be very promising. Actually ECT is used for the treatment of cutaneous and subcutaneous tumoral lesions from different tumoral types. Favorable results in treating superficial metastatic lesions have been published with a complete response rate for treated nodules raging from 70% to 90%. Methods: In our Institute we treated 75 consecutive patients from 2006 to 2009 for superficial cancer lesions, especially metastatic melanomas (58 patients) and squamous or large basal cell carcinomas (1...
Annals of Oncology, 2016
Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront ... more Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need. Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out. The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P &amp;amp;amp;lt; 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR. Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials.
European Journal of Cancer, 2015
ABSTRACT The purpose of this study was to set up a prognostic model for the identification of sur... more ABSTRACT The purpose of this study was to set up a prognostic model for the identification of survival predictors specific for melanoma patients treated with ipilimumab. The following prospectively collected data were utilised: patient and primary tumour characteristics, relapse-free-interval, site and number of metastases, previous therapies and level of serum biomarkers (lactic dehydrogenase (LDH), C-reactive protein, β2-microglobulin, vascular endothelial growth factor (VEGF), IL2, IL6, S-100, alkaline phosphatase (ALP), transaminases, leucocyte count, lymphocytes subpopulations). A multivariate prognostic model was developed using the Cox regression model fitted to the data of 113 consecutive metastatic patients treated with ipilimumab (3mg/kg, q3w) at Veneto Institute of Oncology (IOV). External validation was obtained using the data of 69 and 34 patients treated at European Oncology Institute (IEO) and University of Torino (UT), respectively. Median survival was 9.7, 4.9 and 7.1months from first ipilimumab administration at IOV, IEO and UT, respectively. Both higher baseline levels of LDH (Hazard Ratio [HR] v=1.36, 95% Confidence Interval [CI] 1.16-1.58, P<.001) and neutrophils (HR=1.76, 95% CI 1.41-2.10, P<.001) were associated with worse prognosis. Model performance was satisfactory both upon internal validation (Dxy=0.42) and external validation (Dxy=0.40). Serum LDH and neutrophil count discriminated patients who lived more (low neutrophils and low LDH) or less (high LDH or neutrophils) than 24months. Serum LDH and neutrophil count were significant independent prognostic factors. This externally validated prognostic nomogram, could help clinicians to identify the patients who would benefit most from ipilimumab and consequently to improve resource allocation. These easily available biomarkers deserve further validation. Copyright © 2015 Elsevier Ltd. All rights reserved.
Cancer Research, 2015
Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Ipil... more Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Ipilimumab, a recently approved immunomodulatory drug, improves the survival of metastatic melanoma patients. Despite documented, durable objective responses, a significant number of patients fails to obtain clinical benefit from treatment. The aim of this study was to identify a criterion to select patients best suited to receive this drug. Methods: Sixty-nine metastatic melanoma patients treated at the European Institute of Oncology with 3 mg/kg ipilimumab, were evaluated. Neutrophil to lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts. Progression free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox models were applied. Findings were independently validated on a cohort of 27 patients treated with 10 mg/kg ipilimumab at the University Hospital of Siena and on a cohort of 88 treated in Rome. Results: Best overall response and disease control rates were 9% and 27%, respectively. Median PFS and OS were 3 and 5 months, respectively. Pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in univariate and multivariate analyses. Patients with baseline NLR<5 had a significantly improved PFS (HR = 0.38; 95% CI: 0.22-0.66; P = 0.0006) and OS (HR = 0.24; 95% CI: 0.13-0.46; P<0.0001) compared with those with a NLR≥5. Conclusions: Our findings show that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve as a selection criterion for this therapy. Citation Format: Pier Francesco Ferrucci, Sara Gandini, Angelo Battaglia, Salvatore Alfieri, Laura Pala, Annamaria Di Giacomo, Giovanni Amato, Gian Carlo Antonini Cappellini, Diana Giannarelli, Emilia Cocorocchio, Chiara Martinoli. Baseline neutrophil to lymphocyte ratio as a selection criterion for ipilimumab treatment in metastatic melanoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-115. doi:10.1158/1538-7445.AM2015-LB-115
The EMBO journal, Jan 16, 1996
The block of terminal differentiation is a prominent feature of acute promyelocytic leukemia (APL... more The block of terminal differentiation is a prominent feature of acute promyelocytic leukemia (APL) and its release by retinoic acid correlates with disease remission. Expression of the APL-specific PML/RARalpha fusion protein in hematopoietic precursor cell lines blocks terminal differentiation, suggesting that PML/ RARalpha may have the same activity in APL blasts. We expressed different PML/RARalpha mutants in U937 and TF-1 cells and demonstrated that the integrity of the PML protein dimerization and RARalpha DNA binding domains is crucial for the differentiation block induced by PML/RARalpha, and that these domains exert their functions only within the context of the fusion protein. Analysis of the in vivo dimerization and cell localization properties of the PML/RARalpha mutants revealed that PML/RARalpha--PML and PML/RARalpha--RXR heterodimers are not necessary for PML/RARalpha activity on differentiation. We propose that a crucial mechanism underlying PML/RARalpha oncogenic act...