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Biomedical subjects

P G Casali

Publications and source records attributed to P G Casali.

12 recordsLinked to original sources
PubMed2006

Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma.

Trabectedin is a marine-derived cytoxic alkaloid which has shown promising antitumour activity in a variety of human malignancies including sarcoma. Fifty-four patients with advanced sarcoma (age 43 yrs, range 18-70), all pretreated with prior chemotherapy, were enrolled on a named individual basis for treatment with trabectedin. Diagnosis was adult soft tissue sarcoma (STS) in 46 patients, Ewing's family tumour (EFT) in 4, and osteosarcoma (OS) in 4. The initial 23 patients (total number of courses administered: 68) did not receive premedication prior to trabectedin, while the other 31 patients (total number of courses administered: 134) received premedication with dexamethasone 4 mg po bid 24 hours before therapy. Incidence of toxicity (grade 3-4), expressed as percentage of courses, was as follows: in patients without dexamethasone, elevation of transaminases 34%, neutropenia 24% and thrombocytopenia 25%; in patients with prior dexamethasone, elevation of transaminases 2%, neutropenia 2% and no thrombocytopenia. The median received dose intensity of trabectedin was superimposable in the two groups (404 microg and 400 microg per week, respectively), as well as progression-free survival (19% at 6 months). Among STS patients, 9% had objective responses. In this unselected patient series, premedication with dexamethasone strongly reduced drug-induced hepatotoxicity and myelosuppression.

Adolescent↗
PubMed2006

Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients.

Imatinib-acquired resistance related to the presence of secondary point mutations has become a frequent event in gastrointestinal stromal tumors. Here, transient transfection experiments with plasmids carrying two different KIT-acquired point mutations were performed along with immunoprecipitation of total protein extracts, derived from imatinib-treated and untreated cells. The molecular mechanics/Poisson Boltzmann surface area computational techniques were applied to study the interactions of the wild-type and mutated receptors with imatinib at the molecular level. Biochemical analyses showed KIT phosphorylation in cells transfected with vectors carrying the specific mutant genes. Imatinib treatment demonstrated that T670I was insensitive to the drug at all the applied concentrations, whereas V654A was inhibited by 6 microM of imatinib. The modeling of the mutated receptors revealed that both substitutions affect imatinib-binding site, but to a different extent: T670I substantially modifies the binding pocket, whereas V654A induces only relatively confined structural changes. We demonstrated that T670I and V654A cause indeed imatinib-acquired resistance and that the former is more resistant to imatinib than the latter. The application of molecular simulations allowed us to quantify the interactions between the mutated receptors and imatinib, and to propose a molecular rationale for this type of drug resistance.

Antineoplastic Agents↗
PubMed2006

PDGFRalpha, PDGFRbeta and KIT expression/activation in conventional chondrosarcoma.

Chondrosarcomas represent 20% of all primary bone sarcomas, and many studies have attempted to unravel molecular targets for future development of new therapies. The aim of this study was to investigate the expression/activation of PDGFRalpha, PDGFRbeta and KIT receptor tyrosine kinases (RTKs) as potential therapeutic targets in conventional central primary chondrosarcomas (CCS). The expression of PDGFRalpha, PDGFRbeta and KIT RTKs was detected in 16 CCSs using immunohistochemistry (IHC), and their level of expression and activation status were analysed by immunoprecipitation and western blot experiments. PDGFRalpha, PDGFRbeta and KIT cDNAs were screened to verify the presence of activating mutations and the presence of the cognate ligands was analysed by means of RT-PCR. RTK gene amplification was further studied by means of fluorescence in situ hybridization (FISH) analysis. The immunophenotyping and biochemical analyses showed that the CCSs co-expressed PDGFRalpha and PDGFRbeta, with the latter showing definitively greater protein expression and phosphorylation levels. PDGFRbeta was expressed but not activated in control healthy joint cartilage, in line with no PDGFB detection. Conversely, the KIT gene product did not seem to play a relevant role. These findings, in the absence of activating mutations or an abnormal genomic profile and the presence of PDGFA and PDGFB expression, are consistent with an autocrine/paracrine loop activation of the corresponding receptors. The CCS gene profile described here offers a rationale for the use of RTK inhibitors alone or in combination with chemotherapy, and supports further investigation of RTKs and their downstream signals.

Bone Neoplasms↗
PubMed2005

Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: a series of patients treated at a single institution.

PURPOSE: To explore the prognostic effect of microscopic marginal status after surgery for extremity soft tissue sarcomas. PATIENTS AND METHODS: We analyzed 911 consecutive patients surgically treated throughout a 20-year span at a single referral center. Six hundred forty-two were first seen with a primary tumor, and 269, with a locally recurrent tumor. All patients underwent macroscopically complete resection. Microscopic marginal status was negative (tumor size > 1 mm) in 748 patients and positive (</= 1 mm) in 163 patients. Median follow-up was 107 months. RESULTS: Patients with primary disease had a lower disease-specific mortality in comparison to those first examined for recurrence (25% v 37%, respectively, at 10 years). Size, malignancy grade, depth, histotype, and local recurrence had a statistically significant prognostic effect at multivariable analysis, while microscopically positive surgical margins had not, though a trend in favor of negative margins was observed. However, an extra risk was observed for patients with positive margins after 3 to 5 years (hazard ratio, 1.8 after 5 years v 0.8 before 5 years). In patients treated for a local recurrence, the prognostic impact of positive margins was higher (hazard ratio, 1.6). CONCLUSION: Positive surgical margins had a weak adverse prognostic effect, which was more pronounced for those patients escaping an early relapse. This would seem to justify a policy of surgical adequacy in adult soft tissue sarcomas, though clinical decision making in borderline presentations for conservative surgery might be reasonably flexible and shared with the patient. Once a local relapse has occurred, the impact of local treatments seems more critical.

Adult↗
PubMed2004

Some lessons learned from imatinib mesylate clinical development in gastrointestinal stromal tumors.

Imatinib mesylate is a molecular-targeted agent, shown to be effective in chronic myeloid leukemia and gastrointestinal stromal tumors (GIST). The latter may currently serve as a model on which speculating how the future of molecular-targeted therapy in solid tumors will be. So far, some lessons have been learnt. 1) Molecular-targeted therapy can be effective in the advanced disease setting, resulting in major tumor responses. 2) Patterns of tumor responses may be peculiar, radiologically and pathologically. 3) Anti-tumor activity may be highly predictable by assessing tumor molecular biology. 4) The methodology of clinical development of molecular-targeted agents may differ from standard chemotherapy in some respects, because, say, the preclinical rationale may be stronger, thus increasing the Bayesian prior probability of efficacy, or the optimal dose cannot be determined separately from the assessment of activity and efficacy. 5) Molecular-targeted agents will hardly remain "orphan drugs", if effective. 6) While an obvious impact on survival in the advanced disease setting has been clearly demonstrated, the biologic and clinical impact of molecular-targeted therapy still needs to be elucidated. Its eradicating capabilities, as well as the implications of secondary resistance, are to be understood. 7) Integrated, multimodality approaches, including surgery, may still be of value in the molecular-targeted therapy era.

Benzamides↗
PubMed2003

Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution.

PURPOSE: To explore prognostic factors in surgically treated aggressive fibromatosis (extra-abdominal desmoid tumor). PATIENTS AND METHODS: A total of 203 consecutive patients treated with surgery over a 35-year period at a single referral center were retrospectively reviewed. One hundred twenty-eight were first seen at our institution with primary disease, whereas 75 had a recurrent tumor. All patients underwent macroscopically complete resection. Margins were rated as negative in 146 (97 with primary tumors, 49 with recurrences) and positive in 57 (31 in primary, 26 in recurrences) patients. Median follow-up was 135 months. RESULTS: Patients with primary disease had a better disease-free survival rate than those with recurrence (76% v 59% at 10 years). Presenting with a recurrence was also the strongest predictor of local failure in the multivariate analysis. In patients first treated for primary disease, size and site had prognostic significance, whereas microscopically positive surgical margins did not. In contrast, in patients with recurrence, there was a trend toward better prognosis if margins were negative (although this was not significant at multivariate analysis). CONCLUSION: Presence of microscopic disease does not necessarily affect long-term disease-free survival in patients with primary presentation of extra-abdominal desmoid tumors. Thus, function-sparing surgery may be a reasonable choice when feasible without leaving macroscopic residual disease. In patients with recurrences, positive margins may more clearly affect prognosis, potentially necessitating adjuvant radiation in selected cases.

Adolescent↗
PubMed2001

SYT-SSX fusion genes and prognosis in synovial sarcoma.

A case series of 64 synovial sarcomas was characterized for the SYT-SSX fusion transcripts and statistically analysed in order to correlate molecular data with prognosis and morphology. SYT-SSX1 fusion transcript appeared to be an independent, though not reaching statistical significance (P = 0.183), prognostic factor clearly associated with a reduced metastasis-free survival. Regarding the association between transcript type and histologic subtype we found, a borderline P value (P = 0.067) between the SYT-SSX1 transcript and the biphasic subtype which, subsequently expanding the analysis to 70 cases, turned out to be significant. However, we could not confirm the prediction value of the biphasic subtype for the presence of the SYT-SSX1 transcript since in our hands 6 out 33 (18%) biphasic tumours carried the SYT-SSX2 transcript.

Adolescent↗
PubMed2001

Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis.

BACKGROUND: This Phase II study was undertaken to assess the activity of methotrexate plus vinblastine in the treatment of patients with inoperable aggressive fibromatosis (AF) and to observe the evolution of the disease after such low-dose chemotherapy. METHODS: Thirty patients with a median age of 27 years who were affected by primary (20%) or recurrent (80%), advanced, inoperable AF were treated with weekly methotrexate at a dose of 30 mg/m(2) plus vinblastine at a dose of 6 mg/m(2) for a median interval of 1 year. Patients with recurrent disease had received surgery, radiotherapy, tamoxifen, and antracycline-based chemotherapy. Tumor response was assessed in all patients as well as time to disease progression. RESULTS: Eighteen patients (60%) showed stable disease or minor tumor shrinkage along with symptom relief. A partial response was detected in 12 patients (40%). No complete responses were observed, and no patients had tumor progression during treatment. Four patients received fewer than 15 cycles of chemotherapy, mainly because of severe myelotoxicity. One of these patients died of local disease progression 33 months later, and the other three patients were stable. After a median follow-up of 75 months, the 10-year actuarial progression free interval is 67%. CONCLUSIONS: Methotrexate plus vinblastine given every 7-10 days for several months is associated with prolonged stable disease in a substantial subset of patients with advanced (inoperable) aggressive fibromatosis.

Adult↗
PubMed2000

Outcome assessment in cancer management.

The goals of cancer treatment may be prevention, cure, or palliation. In each case, the length and quality of survival are the ultimate outcomes to assess when evaluating the success of treatment. Some surrogate or intermediate endpoints, however, may be considered, such as toxicity or the tumor response. The first section of this article considers traditional outcomes and endpoints and intermediate or surrogate endpoints for survival and quality of life. The second section specifically addresses the issue of the quality-of-life outcome, which has become increasingly important over the last 2 decades. The last section suggests that combining survival and quality of life may not be easy. Costs are increasingly important in management of diseases, and the outcomes of cancer treatment frequently are measured against them. Although the definitions of cost-effectiveness and cost-utility are mentioned at the end of this article, the article does not deal with the problems of decision making for health resource allocation.

Antineoplastic Agents↗