G. Grasselli - Academia.edu (original) (raw)
Papers by G. Grasselli
Seminars in Oncology
A pilot study of primary chemotherapy with bolus doxorubicin plus paclitaxel (Taxol; Bristol-Myer... more A pilot study of primary chemotherapy with bolus doxorubicin plus paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) infused over 3 hours was performed in 38 women with locally advanced and 41 with stage II/III breast cancer. Patients received four cycles of primary chemotherapy followed by surgery and treatment with cyclophosphamide/methotrexate/5-fluorouracil for six cycles. Preliminary data are available on 73 patients. Doxorubicin plus paclitaxel was well tolerated. Primary toxicity consisted of grade 1 or 2 reversible peripheral neuropathy and grade 3 alopecia. After a median follow-up of 13 months, none of the patients have developed cardiac toxicity or any significant alteration of the left ventricular ejection fraction, which was measured before treatment, at each cycle of doxorubicin plus paclitaxel, and every 3 months thereafter. Major clinical response of the breast tumor was observed in 88% of patients. At pathologic examination of the surgical specimen, 40% were pT1, 15% had no macroscopic tumor residue, and 7% had complete disappearance of invasive neoplastic cells. After a median follow-up of 17 months for patients with locally advanced breast cancer, freedom from progression was 67%, disease-free survival was 71%, and overall survival was 74%. The same end points were 100% for patients with stage II/III disease, with a shorter median follow-up of 10 months. In conclusion, doxorubicin plus paclitaxel is safe, feasible, and effective, and can be used as primary or adjuvant chemotherapy to assess its actual therapeutic role in women with early breast cancer.
Investigational new drugs, 2001
The taxanes' interaction with other anticancer drugs have been extensively investigated in in... more The taxanes' interaction with other anticancer drugs have been extensively investigated in in vitro and in animal models as well as in humans due to the outstanding antitumor activity in a broad range of malignancies. Paclitaxel and docetaxel are endowed of a rich and complex pharmacology whereby different pharmacodynamic effects are observed depending on the sequence of their administration in respect with the companion drug, and the type of drug that is combined. Pharmacokinetic interference is often but not always a basis of the pharmacodynamic effect. In addition, the vehicle of clinical formulation, especially Cremophor EL for paclitaxel, influence the pharmacological effect. Finally, new interaction based on as yet unknown mechanisms drive the two taxanes to multiple additive/synergistic relationships with new signal transduction drugs, such as modulators of the epidermal-growth-factor family of receptors and farnesyl-transferase inhibitors. The ongoing effort to better un...
Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2000
To define the maximum tolerated dose (MTD), the toxicity and pharmacokinetic profile of BBR3464, ... more To define the maximum tolerated dose (MTD), the toxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. Fourteen patients with advanced solid tumors not responsive to previous antitumor treatments received BBR 3464 on a daily x 5 schedule every twenty-eighth day. The drug was given as a one-hour infusion with pre-and post-treatment hydration (500 ml in one hour) and no antiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. A modified accelerated titration escalation design was used. Total and free platinum (Pt) concentrations in plasma and urine were assessed by ICP-MS on days 1 and 5 of the first cycle. Dose was escalated four times up to 0.17 mg/m2/day. Short-lasting neutropenia and diarrhea of late onset were dose-limiting and defined the MTD at 0.12 mg/m2. Nausea and vomiting were rare, neither neuro- nor renal toxic effects were observed. BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-life of several days. At 0.17 mg/m2 plas...
British Journal of Pharmacology, 2013
Glutamate transmission is dysregulated in both multiple sclerosis (MS) and experimental autoimmun... more Glutamate transmission is dysregulated in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. A characteristic of EAE is increased glutamate transmission associated with up-regulation of AMPA receptors. However, little is known about the role of NMDA receptors in the synaptic modifications induced by EAE.
Brain, Behavior, and Immunity, 2011
Synaptic dysfunction triggers neuronal damage in experimental autoimmune encephalomyelitis (EAE),... more Synaptic dysfunction triggers neuronal damage in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). While excessive glutamate signaling has been reported in the striatum of EAE, it is still uncertain whether GABA synapses are altered. Electrophysiological recordings showed a reduction of spontaneous GABAergic synaptic currents (sIPSCs) recorded from striatal projection neurons of mice with MOG (35À55) -induced EAE. GABAergic sIPSC deficits started in the acute phase of the disease (20-25 days post immunization, dpi), and were exacerbated at later time-points (35, 50, 70 and 90 dpi). Of note, in slices they were independent of microglial activation and of release of TNF-a. Indeed, sIPSC inhibition likely involved synaptic inputs arising from GABAergic interneurons, because EAE preferentially reduced sIPSCs of high amplitude, and was associated with a selective loss of striatal parvalbumin (PV)-positive GABAergic interneurons, which contact striatal projection neurons in their somatic region, giving rise to more efficient synaptic inhibition. Furthermore, we found also that the chronic persistence of pro-inflammatory cytokines were able, per se, to produce profound alterations of electrophysiological network properties, that were reverted by GABA administration.
Annals of Oncology, 2004
Background: This randomized phase II study was conducted to evaluate the efficacy of doxorubicin ... more Background: This randomized phase II study was conducted to evaluate the efficacy of doxorubicin and docetaxel (DOC) administered either as a combination, an alternating or a sequential regimen in women with metastatic breast cancer. Secondary objectives included overall response, time to progression, survival and safety.
Intensive Care Medicine Experimental, 2015
Minerva anestesiologica
After the first outbreak identified in Mexico in late March 2009, influenza A sustained by a modi... more After the first outbreak identified in Mexico in late March 2009, influenza A sustained by a modified H1N1 virus ("swine flu") rapidly spread to all continents. This article describes the first Italian case of life-threatening ARDS associated with H1N1 infection, treated with extracorporeal respiratory assistance (venovenous extracorporeal membrane oxygenation [ECMO]). A 24-year-old, previously healthy man was admitted to the Intensive Care Unit (ICU) of the local hospital for rapidly progressive respiratory failure with refractory impairment of gas exchange unresponsive to rescue therapies (recruitment manoeuvres, pronation and nitric oxide inhalation). An extracorporeal respiratory assistance (venovenous ECMO) was performed. It allowed a correction of the respiratory acidosis and made possible the transportation of the patient to the ICU (approximately 150 km from the first hospital). A nasal swab tested positive for H1N1 infection and treatment with oseltamivir was star...
Photonic Therapeutics and Diagnostics VI, 2010
In the adult nervous system, different population of neurons corresponds to different regenerativ... more In the adult nervous system, different population of neurons corresponds to different regenerative behavior. Although previous works show that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury1, we have hitherto no details about the real dynamics of fiber regeneration. We coupled two photon imaging to laser-induced lesions to perform in vivo multiphoton
Minerva anestesiologica, 2007
In critical care medicine there is still a paucity of evidence on how to manage most of the clini... more In critical care medicine there is still a paucity of evidence on how to manage most of the clinical problems commonly encountered in critically ill patients. Randomized controlled trials (RCTs) are the most powerful instruments to evaluate the efficacy of a therapeutic intervention and to generate evidence for clinical practice. Unfortunately, the design and conduct of RCTs in our field are particularly complicated, because of some intrinsic and structural problems (e.g. lack of reliable nosography, concomitant use of different therapies, problems in the definition of end-points besides mortality) that will be discussed in this review. Further challenges are represented by the lack of tradition of large ICU networks, difficulties in linking or integrating physiologic and therapeutic objectives in designing clinical protocols, scarcity of independent or non-profit funds. A particularly stimulating opportunity of development is represented also by the relationship of critical care to...
2011 International Workshop on Biophotonics, 2011
In the adult nervous system, different population of neurons corresponds to different regenerativ... more In the adult nervous system, different population of neurons corresponds to different regenerative behavior. Although previous works show that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury (1), we have hitherto no details about the real dynamics of fiber regeneration. We coupled two photon imaging to laser-induced lesions to perform in vivo
Multiphoton Microscopy in the Biomedical Sciences XIII, 2013
ABSTRACT In the adult nervous system, different populations of neurons correspond to different re... more ABSTRACT In the adult nervous system, different populations of neurons correspond to different regenerative behavior. Although previous works showed that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury1, we have hitherto no details about the real dynamics of fiber regeneration. We set up a model of singularly axotomized climbing fibers (CF) to investigate their reparative properties in the adult central nervous system (CNS) in vivo. Time lapse two-photon imaging has been combined to laser nanosurgery2, 3 to define a temporal pattern of the degenerative event and to follow the structural rearrangement after injury. To characterize the damage and to elucidate the possible formation of new synaptic contacts on the sprouted branches of the lesioned CF, we combined two-photon in vivo imaging with block face scanning electron microscopy (FIB-SEM). Here we describe the approach followed to characterize the reactive plasticity after injury.
Neurophotonics, 2013
In the adult nervous system, different neuronal classes show different regenerative behavior. Alt... more In the adult nervous system, different neuronal classes show different regenerative behavior. Although previous studies demonstrated that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury, we have hitherto no details about the real dynamics of fiber regeneration. We set up a model of singularly axotomized climbing fibers (CF) to investigate their reparative properties in the adult central nervous system (CNS) in vivo. Here we describe the approach followed to characterize the reactive plasticity after injury.
Minerva anestesiologica, 2011
The novel influenza A (H1N1) pandemic was associated with an epidemic of critical illness. We des... more The novel influenza A (H1N1) pandemic was associated with an epidemic of critical illness. We describe the clinical profiles of critically ill patients with severe complications due to microbiologically confirmed pandemic influenza A (H1N1) infection admitted to a medical ICU in Monza, Italy, over a 6-month period. From August 2009 to January 2010, 19 patients (13 adults and 6 children) required ICU admission. Nine subjects were referred to our hospital from other ICUs. In all patients, with the exception of a case of severe septic shock, the cause of ICU admission was acute respiratory failure. Other nonpulmonary organ failures were common. A trial of non-invasive ventilation was attempted in 13 cases and was successful in four of them. The majority of the patients required invasive mechanical ventilation. In the 7 most severely hypoxemic patients, we applied veno-venous ECLS, with a very high rate of success. The median ICU stay was 9 days (range 1-78 days). Sixteen out of 19 (84%...
Seminars in Oncology
A pilot study of primary chemotherapy with bolus doxorubicin plus paclitaxel (Taxol; Bristol-Myer... more A pilot study of primary chemotherapy with bolus doxorubicin plus paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) infused over 3 hours was performed in 38 women with locally advanced and 41 with stage II/III breast cancer. Patients received four cycles of primary chemotherapy followed by surgery and treatment with cyclophosphamide/methotrexate/5-fluorouracil for six cycles. Preliminary data are available on 73 patients. Doxorubicin plus paclitaxel was well tolerated. Primary toxicity consisted of grade 1 or 2 reversible peripheral neuropathy and grade 3 alopecia. After a median follow-up of 13 months, none of the patients have developed cardiac toxicity or any significant alteration of the left ventricular ejection fraction, which was measured before treatment, at each cycle of doxorubicin plus paclitaxel, and every 3 months thereafter. Major clinical response of the breast tumor was observed in 88% of patients. At pathologic examination of the surgical specimen, 40% were pT1, 15% had no macroscopic tumor residue, and 7% had complete disappearance of invasive neoplastic cells. After a median follow-up of 17 months for patients with locally advanced breast cancer, freedom from progression was 67%, disease-free survival was 71%, and overall survival was 74%. The same end points were 100% for patients with stage II/III disease, with a shorter median follow-up of 10 months. In conclusion, doxorubicin plus paclitaxel is safe, feasible, and effective, and can be used as primary or adjuvant chemotherapy to assess its actual therapeutic role in women with early breast cancer.
Investigational new drugs, 2001
The taxanes' interaction with other anticancer drugs have been extensively investigated in in... more The taxanes' interaction with other anticancer drugs have been extensively investigated in in vitro and in animal models as well as in humans due to the outstanding antitumor activity in a broad range of malignancies. Paclitaxel and docetaxel are endowed of a rich and complex pharmacology whereby different pharmacodynamic effects are observed depending on the sequence of their administration in respect with the companion drug, and the type of drug that is combined. Pharmacokinetic interference is often but not always a basis of the pharmacodynamic effect. In addition, the vehicle of clinical formulation, especially Cremophor EL for paclitaxel, influence the pharmacological effect. Finally, new interaction based on as yet unknown mechanisms drive the two taxanes to multiple additive/synergistic relationships with new signal transduction drugs, such as modulators of the epidermal-growth-factor family of receptors and farnesyl-transferase inhibitors. The ongoing effort to better un...
Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2000
To define the maximum tolerated dose (MTD), the toxicity and pharmacokinetic profile of BBR3464, ... more To define the maximum tolerated dose (MTD), the toxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. Fourteen patients with advanced solid tumors not responsive to previous antitumor treatments received BBR 3464 on a daily x 5 schedule every twenty-eighth day. The drug was given as a one-hour infusion with pre-and post-treatment hydration (500 ml in one hour) and no antiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. A modified accelerated titration escalation design was used. Total and free platinum (Pt) concentrations in plasma and urine were assessed by ICP-MS on days 1 and 5 of the first cycle. Dose was escalated four times up to 0.17 mg/m2/day. Short-lasting neutropenia and diarrhea of late onset were dose-limiting and defined the MTD at 0.12 mg/m2. Nausea and vomiting were rare, neither neuro- nor renal toxic effects were observed. BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-life of several days. At 0.17 mg/m2 plas...
British Journal of Pharmacology, 2013
Glutamate transmission is dysregulated in both multiple sclerosis (MS) and experimental autoimmun... more Glutamate transmission is dysregulated in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. A characteristic of EAE is increased glutamate transmission associated with up-regulation of AMPA receptors. However, little is known about the role of NMDA receptors in the synaptic modifications induced by EAE.
Brain, Behavior, and Immunity, 2011
Synaptic dysfunction triggers neuronal damage in experimental autoimmune encephalomyelitis (EAE),... more Synaptic dysfunction triggers neuronal damage in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). While excessive glutamate signaling has been reported in the striatum of EAE, it is still uncertain whether GABA synapses are altered. Electrophysiological recordings showed a reduction of spontaneous GABAergic synaptic currents (sIPSCs) recorded from striatal projection neurons of mice with MOG (35À55) -induced EAE. GABAergic sIPSC deficits started in the acute phase of the disease (20-25 days post immunization, dpi), and were exacerbated at later time-points (35, 50, 70 and 90 dpi). Of note, in slices they were independent of microglial activation and of release of TNF-a. Indeed, sIPSC inhibition likely involved synaptic inputs arising from GABAergic interneurons, because EAE preferentially reduced sIPSCs of high amplitude, and was associated with a selective loss of striatal parvalbumin (PV)-positive GABAergic interneurons, which contact striatal projection neurons in their somatic region, giving rise to more efficient synaptic inhibition. Furthermore, we found also that the chronic persistence of pro-inflammatory cytokines were able, per se, to produce profound alterations of electrophysiological network properties, that were reverted by GABA administration.
Annals of Oncology, 2004
Background: This randomized phase II study was conducted to evaluate the efficacy of doxorubicin ... more Background: This randomized phase II study was conducted to evaluate the efficacy of doxorubicin and docetaxel (DOC) administered either as a combination, an alternating or a sequential regimen in women with metastatic breast cancer. Secondary objectives included overall response, time to progression, survival and safety.
Intensive Care Medicine Experimental, 2015
Minerva anestesiologica
After the first outbreak identified in Mexico in late March 2009, influenza A sustained by a modi... more After the first outbreak identified in Mexico in late March 2009, influenza A sustained by a modified H1N1 virus ("swine flu") rapidly spread to all continents. This article describes the first Italian case of life-threatening ARDS associated with H1N1 infection, treated with extracorporeal respiratory assistance (venovenous extracorporeal membrane oxygenation [ECMO]). A 24-year-old, previously healthy man was admitted to the Intensive Care Unit (ICU) of the local hospital for rapidly progressive respiratory failure with refractory impairment of gas exchange unresponsive to rescue therapies (recruitment manoeuvres, pronation and nitric oxide inhalation). An extracorporeal respiratory assistance (venovenous ECMO) was performed. It allowed a correction of the respiratory acidosis and made possible the transportation of the patient to the ICU (approximately 150 km from the first hospital). A nasal swab tested positive for H1N1 infection and treatment with oseltamivir was star...
Photonic Therapeutics and Diagnostics VI, 2010
In the adult nervous system, different population of neurons corresponds to different regenerativ... more In the adult nervous system, different population of neurons corresponds to different regenerative behavior. Although previous works show that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury1, we have hitherto no details about the real dynamics of fiber regeneration. We coupled two photon imaging to laser-induced lesions to perform in vivo multiphoton
Minerva anestesiologica, 2007
In critical care medicine there is still a paucity of evidence on how to manage most of the clini... more In critical care medicine there is still a paucity of evidence on how to manage most of the clinical problems commonly encountered in critically ill patients. Randomized controlled trials (RCTs) are the most powerful instruments to evaluate the efficacy of a therapeutic intervention and to generate evidence for clinical practice. Unfortunately, the design and conduct of RCTs in our field are particularly complicated, because of some intrinsic and structural problems (e.g. lack of reliable nosography, concomitant use of different therapies, problems in the definition of end-points besides mortality) that will be discussed in this review. Further challenges are represented by the lack of tradition of large ICU networks, difficulties in linking or integrating physiologic and therapeutic objectives in designing clinical protocols, scarcity of independent or non-profit funds. A particularly stimulating opportunity of development is represented also by the relationship of critical care to...
2011 International Workshop on Biophotonics, 2011
In the adult nervous system, different population of neurons corresponds to different regenerativ... more In the adult nervous system, different population of neurons corresponds to different regenerative behavior. Although previous works show that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury (1), we have hitherto no details about the real dynamics of fiber regeneration. We coupled two photon imaging to laser-induced lesions to perform in vivo
Multiphoton Microscopy in the Biomedical Sciences XIII, 2013
ABSTRACT In the adult nervous system, different populations of neurons correspond to different re... more ABSTRACT In the adult nervous system, different populations of neurons correspond to different regenerative behavior. Although previous works showed that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury1, we have hitherto no details about the real dynamics of fiber regeneration. We set up a model of singularly axotomized climbing fibers (CF) to investigate their reparative properties in the adult central nervous system (CNS) in vivo. Time lapse two-photon imaging has been combined to laser nanosurgery2, 3 to define a temporal pattern of the degenerative event and to follow the structural rearrangement after injury. To characterize the damage and to elucidate the possible formation of new synaptic contacts on the sprouted branches of the lesioned CF, we combined two-photon in vivo imaging with block face scanning electron microscopy (FIB-SEM). Here we describe the approach followed to characterize the reactive plasticity after injury.
Neurophotonics, 2013
In the adult nervous system, different neuronal classes show different regenerative behavior. Alt... more In the adult nervous system, different neuronal classes show different regenerative behavior. Although previous studies demonstrated that olivocerebellar fibers are capable of axonal regeneration in a suitable environment as a response to injury, we have hitherto no details about the real dynamics of fiber regeneration. We set up a model of singularly axotomized climbing fibers (CF) to investigate their reparative properties in the adult central nervous system (CNS) in vivo. Here we describe the approach followed to characterize the reactive plasticity after injury.
Minerva anestesiologica, 2011
The novel influenza A (H1N1) pandemic was associated with an epidemic of critical illness. We des... more The novel influenza A (H1N1) pandemic was associated with an epidemic of critical illness. We describe the clinical profiles of critically ill patients with severe complications due to microbiologically confirmed pandemic influenza A (H1N1) infection admitted to a medical ICU in Monza, Italy, over a 6-month period. From August 2009 to January 2010, 19 patients (13 adults and 6 children) required ICU admission. Nine subjects were referred to our hospital from other ICUs. In all patients, with the exception of a case of severe septic shock, the cause of ICU admission was acute respiratory failure. Other nonpulmonary organ failures were common. A trial of non-invasive ventilation was attempted in 13 cases and was successful in four of them. The majority of the patients required invasive mechanical ventilation. In the 7 most severely hypoxemic patients, we applied veno-venous ECLS, with a very high rate of success. The median ICU stay was 9 days (range 1-78 days). Sixteen out of 19 (84%...