Biomedical subjects

Giovanni Franchin

Publications and source records attributed to Giovanni Franchin.

12 recordsLinked to original sources

PubMed2005

Pulse steroids: how much is enough?

High dose pulse intravenous steroids with 1 g of methylprednisolone (MEP) given daily, usually for three days, is an accepted practice to treat severe manifestations of systemic lupus erythematosus (SLE) or systemic vasculitides, despite the lack of definitive data. Most studies addressing the efficacy of high dose glucocorticoids (GCs) have been uncontrolled, retrospective or did not compare different doses. A limited number of studies comparing different doses of GCs suggest that lower doses of MEP given as intravenous pulse therapy might be as effective as the very high doses currently used. In addition, while early reports did not find serious adverse effects related to very high doses of steroids, several more recent studies indicate a high risk of serious infections proportional to the current or cumulative dose of GCs. While we await more conclusive studies addressing these questions, one might wonder whether we could be using too much of a good thing.

Clinical Trials as Topic↗

PubMed2005

Role of Rho family GTPases in CCR1- and CCR5-induced actin reorganization in macrophages.

The beta-chemokines, MIP-1alpha/CCL3, MIP-1beta/CCL4, and RANTES/CCL5, play a critical role in the selective accumulation and activation of macrophages in inflamed tissues. Herein, we demonstrate that the binding of each of these beta-chemokines to their cognate receptors, CCR1 and CCR5, in either macrophages or in CCR1- or CCR5-transfected CHO cells, induced actin reorganization and the formation of lamellipodia that are characteristic of the activation of the Rho family GTPase, Rac. A dominant negative mutant of Rac, but not dominant negative mutants of RhoA or Cdc42, blocked MIP-1alpha-induced lamellipodia formation. Moreover, this MIP-1alpha-induced Rac activation and consequent lamellipodia formation is Gi- and phosphoinositide-3 kinase (PI3K)-mediated. Thus, Rac activation is critical for both CCR1- and CCR5-triggered signaling cascades mediating beta-chemokine-induced reorganization of the actin cytoskeleton, a process essential for effective recruitment and activation of macrophages in inflammation.

Actins↗

PubMed2005

Neoadjuvant accelerated chemotherapy followed by hyperfractionated radiation therapy in patients with operable, locally advanced head and neck carcinoma.

A prospective phase II trial was carried out to evaluate an accelerated chemotherapy (CT) regimen followed by hyperfractionated radiation therapy (RT) in previously untreated Stage III-IV, operable (total laryngectomy), head and neck cancer patients. The current study evaluates overall survival, loco-regional control, organ preservation rates and toxicity. Between April 1997 and December 2002, 68 patients with advanced head and neck cancer were treated with 3 cycles of induction CT (cisplatin and 5-fluorouracil; days 1, 14, and 28) followed by hyperfractionated RT (7440 cGy/62 fractions). Sixty patients received the planned RT-CT treatment. Two months after the end of RT, 96% of patients had a clinical complete remission of the primary and 66% of the neck disease. At a median follow-up of 32 months, the 3-year overall and disease-free survival rates were 66% and 76%, respectively. Seven patients recurred on the primary site, 1 on the neck and 2 patients only had distant metastases. The organ preservation rate was 73%. Acute grade 3-4 mucositis occurred in 75% of patients and an 18% rate of CT-related cardiotoxicity was reported. The accelerated CT-RT regimen achieves a high rate of larynx preservation albeit with considerable toxicity. The current prospective clinical trial was approved by the Ethics Committee of the Centro di Riferimento Oncologico (C.R.O.) on May 27, 1996, # CRO-02-96. Written informed consent was required from all patients entering the study.

Adult↗

PubMed2005

Treatment of head and neck cancer in elderly patients: state of the art and guidelines.

Although the majority of head and neck cancers occur between the fifth and sixth decade, their onset in patients older than 60 years is not a rare event. A peculiar characteristic of almost all case series is the lower prevalence of radical treatments among elderly as compared to younger patients, in particular surgery and combined treatment of surgery plus radiation therapy or chemotherapy and radiation therapy. Radiotherapy is a feasible treatment in elderly patients, also in very advanced age groups and, in the era of organ preservation, chemotherapy combined with RT has a paramount importance. Therapeutical planning must be based not only on tumor characteristics, but also on the physiological, rather than the chronological age the patient. The main clinical problem is, therefore, the selection of patients to be administered anticancer treatment. In patients aged 70 or older, complete geriatric assessment and a multidisciplinary approach are the crucial points.

Aged↗

PubMed2005

Thoracic radiation therapy and concomitant low-dose daily paclitaxel in non-small cell lung cancer: a phase I study.

The primary objective of the current study was to determine the maximum tolerated dose of paclitaxel (PTX) that could be added daily to radiation therapy (RT) in patients with non-small cell lung cancer (NSCLC). The secondary objective was to achieve a plasma concentration of PTX estimated to exert a radiosensitizing effect. Eighteen patients with locally advanced NSCLC were treated. 60 Gy of RT were given in 2 Gy fractions, 5 days per week. A daily dose of PTX was delivered by 4-h i.v. infusion before RT. The initial dose level of PTX was 9 mg/m2/day, escalated by 1 mg at each additional patient triplet. Two out of 6 patients experienced acute dose limiting toxicity (DLT) at the 12 mg/m2/day PTX dose level. PTX continuously greater than 10 nM, the estimated radiosensitizing condition, was achieved at the PTX dose level of 12 mg/m2/day. PTX at doses up to 11 mg/m2/day may be safely added to a conventional conformal RT course. Both DLT and the estimated radiosensitizing plasma exposure to PTX were encountered at the 12 mg/m(2)/day dose level.

Aged↗

PubMed2003

Radiotherapy for patients with early-stage glottic carcinoma: univariate and multivariate analyses in a group of consecutive, unselected patients.

BACKGROUND: Radiotherapy (RT) has a remarkable success rate in the treatment of patients with glottic carcinoma. The objectives of the current study were to assess the results in a group of consecutive patients with comparable characteristics who were treated with RT (6-megavolt photon linear accelerator) and to determine the prognostic factors that may influence local control in patients with early-stage glottic carcinoma. The impact on local control of tobacco smoking and second primary malignancies also was investigated. METHODS: Four hundred ten patients with T1-T2 squamous cell carcinoma of the glottis who were treated between 1986 and 2001 were analyzed retrospectively with regard to local control and overall survival. Potential prognostic factors for local control were evaluated with univariate and multivariate models. The impact of technologic advances also was evaluated. RESULTS: The 5-year and 10-year overall survival rates were 83% and 63.5%, respectively. The overall 10-year local control rate for patients with T1-T2 glottic carcinoma was 89%. The median time to recurrence was 7 months. Univariate analysis showed that tumor category, tumor size, macroscopic appearance of the lesion, RT fraction size, persistent edema, year of RT treatment, unchanged dysphonia, and surgical option all had a significant influence on local control; whereas multivariate analysis showed that only persistent dysphonia and year of RT treatment were significantly associated with increased local control. A 22.2% rate of second primary malignancies was reported: second primary tumors were the major cause of death in the patients studied. Only 2 patients died of laryngeal carcinoma; 304 patients were alive with their disease in complete remission, 1 patient was alive with recurrent laryngeal carcinoma after undergoing salvage surgery, and 103 patients died of either intercurrent disease or a second primary tumor. CONCLUSIONS: The use of a 6-megavolt photon linear accelerator achieved a high rate of local control in patients with T1-T2 glottic carcinoma. Dysphonia and the year of RT treatment were the most important prognostically significant factors for patient outcome. The occurrence of a second primary tumor was the most frequent cause of death, especially among patients who did not stop smoking after a diagnosis of glottic carcinoma.

Adult↗

PubMed2003

beta-Chemokine production in CD40L-stimulated monocyte-derived macrophages requires activation of MAPK signaling pathways.

CD40 ligand is a cell surface molecule on CD4(+) T cells that interacts with its receptor, CD40, on antigen presenting cells to mediate humoral and cellular immune responses. Our previous studies demonstrated that a trimeric soluble form of CD40L (CD40LT) activates macrophages to produce beta-chemokines and decrease CCR5 and CD4 cell surface expression, thus inducing resistance to HIV-1 infection. However, the mechanism(s) by which CD40LT mediates these effects in primary macrophages remains unclear. In this report, we demonstrate that CD40LT induces synthesis of beta-chemokines through the activation of MAPK signaling pathways. Treatment of macrophages with CD40LT results in a rapid activation of p38 and ERK1/2 mitogen-activated protein kinases. Inhibitors of these MAPKs blocked beta-chemokine production, while protein kinase A and C inhibitors had little or no effect. We also provide evidence that CD40LT stimulates beta-chemokine production directly, as well as indirectly via a TNF-alpha-dependent mechanism. At the early time points, CD40LT directly stimulated beta-chemokine production, whereas at later time points the effect was mediated to some extent by TNF-alpha. In conclusion, our results suggest that CD40-CD40L interactions are important for the activation of monocyte-derived macrophage antiviral response affecting both viral replication and the recruitment of immune cells.

CD40 Ligand↗

PubMed2003

Macrophages and lymphocytes differentially modulate the ability of RANTES to inhibit HIV-1 infection.

The beta-chemokines MIP-1alpha, MIP-1beta, and RANTES inhibit HIV-1 infection of CD4+ T cells by inhibiting interactions between the virus and CCR5 receptors. However, while beta-chemokine-mediated inhibition of HIV-1 infection of primary lymphocytes is well documented, conflicting results have been obtained using primary macrophages as the virus target. Here, we show that the beta-chemokine RANTES inhibits virus entry into both cellular targets of the virus, lymphocytes and macrophages. However, while virus entry is inhibited at the moment of infection in both cell types, the amount of virus progeny is lowered only in lymphocytes. In macrophages, early-entry restriction is lost during long-term cultivation, and the amount of virus produced by RANTES-treated macrophages is similar to the untreated cultures, suggesting an enhanced virus replication. We further show that at least two distinct cellular responses to RANTES treatment in primary lymphocytes and macrophages contribute to this phenomenon. In lymphocytes, exposure to RANTES significantly increases the pool of inhibitory beta-chemokines through intracellular signals that result in increased production of MIP-1alpha and MIP-1beta, thereby amplifying the antiviral effects of RANTES. In macrophages this amplification step does not occur. In fact, RANTES added to the macrophages is efficiently cleared from the culture, without inducing synthesis of beta-chemokines. Our results demonstrate dichotomous effects of RANTES on HIV-1 entry at the moment of infection, and on production and spread of virus progeny in primary macrophages. Since macrophages serve as a reservoir of HIV-1, this may contribute to the failure of endogenous chemokines to successfully eradicate the virus.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Dual effects of macrophage inflammatory protein-1alpha on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease.

Recent data have implicated macrophage inflammatory protein-1alpha (MIP-1alpha) in multiple myeloma (MM)-associated osteolysis. However, it is unclear whether the chemokine's effects are direct, to enhance osteolysis, or indirect and mediated through a reduction in tumor burden, or both. It is also unclear whether MIP-1alpha requires other factors such as receptor activator of nuclear factor-kappaB ligand (RANKL) for its effects on bone. In murine 5TGM1 (Radl) myeloma-bearing mice, administration of neutralizing anti-MIP-1alpha antibodies reduced tumor load assessed by monoclonal paraprotein titers, prevented splenomegaly, limited development of osteolytic lesions, and concomitantly reduced tumor growth in bone. To determine the effects of MIP-1alpha on bone in vivo, Chinese hamster ovary (CHO) cells secreting human MIP-1alpha (CHO/MIP-1alpha) were inoculated into athymic mice. Mice bearing intramuscular CHO/MIP-1alpha tumors developed lytic lesions at distant skeletal sites, which occurred earlier and were larger than those in mice with CHO/empty vector (EV) tumors. When experimental metastases were induced via intracardiac inoculation, mice bearing CHO/MIP-1alpha tumors developed hypercalcemia and significantly more osteolytic lesions than mice bearing CHO/EV tumors, with intramedullary CHO/MIP-1alpha tumors associated with significantly more tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Injection of recombinant MIP-1alpha over calvariae of normal mice evoked a striking increase in osteoclast formation, an effect dependent on RANK/RANKL signaling because MIP-1alpha had no effect in RANK-/- mice. Together, these results establish that MIP-1alpha is sufficient to induce MM-like destructive lesions in bone in vivo. Because, in the 5TGM1 model, blockade of osteoclastic resorption in other situations does not decrease tumor burden, we conclude that MIP-1alpha exerts a dual effect in myeloma, on osteoclasts, and tumor cells.

Animals↗

PubMed2003

Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial.

PURPOSE: To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. METHODS AND MATERIALS: Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week). RESULTS: No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. CONCLUSIONS: The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.

Adult↗

PubMed2002

Active site residues of cyclophilin A are crucial for its signaling activity via CD147.

Cyclophilin A (CyPA), a ubiquitously distributed intracellular protein, is a peptidylprolyl cis-trans-isomerase and the major target of the potent immunosuppressive drug cyclosporin A. Although expressed predominantly as an intracellular molecule, CyPA is secreted by cells in response to inflammatory stimuli and is a potent neutrophil and eosinophil chemoattractant in vitro and in vivo. The mechanisms underlying CyPA-mediated signaling and chemotaxis are unknown. Here, we identified CD147 as a cell surface receptor for CyPA and demonstrated that CD147 is an essential component in the CyPA-initiated signaling cascade that culminates in ERK activation. Both signaling and chemotactic activities of CyPA depended also on the presence of heparans, which served as primary binding sites for CyPA on target cells. The proline 180 and glycine 181 residues in the extracellular domain of CD147 were critical for signaling and chemotactic activities mediated by CD147. Also crucial were active site residues of CyPA, because rotamase-defective CyPA mutants failed to initiate signaling events. These results establish cyclophilins as natural ligands for CD147 and suggest an unusual, rotamase-dependent mechanism of signaling.

Amino Acid Sequence↗

PubMedDate not supplied

Long-term results of conventional radiotherapy versus accelerated hyperfractionated radiotherapy versus concomitant radiotherapy and chemotherapy in locoregionally advanced carcinoma of the oropharynx.

AIMS AND BACKGROUND: To compare conventional fractionation (CF) radiation therapy (RT), arm A, versus a split-course accelerated hyperfractionated schedule (S-AHF), arm B, versus CFRT plus concomitant chemotherapy (CT), arm C, in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx. METHODS AND STUDY DESIGN: Between January 1993 and June 1998, 192 previously untreated patients with stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were enrolled in a multicenter randomized phase III trial (ORO 93-01). In arms A and C, 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks. In arm B, the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day, five days a week, with a planned two-week split at 38.4 Gy. In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil (CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v. on days 1 to 4 every 28 days). RESULTS: No statistically significant difference was found in five-year overall survival (P = 0.39): 21% for arm A, 21% for arm B, and 40% for arm C. Similarly, there was no statistically significant difference in terms of five-year relapse-free survival: 15% for arm A, 17% for arm B, and 36% for arm C. There was a slight trend towards better five-year locoregional control (P = 0.07) for the combined arm: patients without locoregional relapse were 48% in arm C, 21% in arm A and 18% in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined (P = 0.02; arm A+B 20%; arm C 48%). Distant metastases were fairly balanced in the three arms (A: 14; B: 9; C: 11), with a tendency towards more frequent isolated distant metastasis development in arm C (8 of 11 [72%] versus 7 of 23 [30%] in arms A+B). Five-year second-tumor-free survival was 85%. The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption (five lung, two esophagus, two oral cavity, one larynx, one pancreas, one hepatocarcinoma, one myeloma). Arm C showed slightly more G3+ late side effects involving subcutaneous tissues and mucosa, although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient. The occurrence of persistent G3 xerostomia was comparable in the three treatment arms. CONCLUSIONS: The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance, but combined treatment almost doubled the five-year overall survival, relapse-free survival and locoregional control rate. Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy. The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death.

Aged↗