Biomedical subjects

Paolo G Casali

Publications and source records attributed to Paolo G Casali.

At least 19 recordsLinked to original sources

PubMed2006

Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas.

PURPOSE: We have previously shown the presence of an activated platelet-derived growth factor (PDGF) receptor (PDGFR) B and its ligand PDGFB in a limited number of patients with clinical and radiological responses to imatinib mesylate treatment. This article describes the results of comprehensive molecular/biochemical analyses of the three receptors targeted by the drug (PDGFRB, PDGFRA, and KIT) in a series of 31 chordoma patients. EXPERIMENTAL DESIGN: The presence and activation status of PDGFRB, PDGFRA, and KIT receptors were investigated by means of immunoprecipitation and Western blot analyses complemented by immunohistochemistry, their expression level was analyzed by means of real-time PCR, and the occurrence of activating point mutations was investigated by means of cDNA sequencing. The PDGFB, PDGFA, and stem cell factor cognate ligands were investigated by reverse transcription-PCR, and gene status was assessed by fluorescence in situ hybridization. RESULTS: The results show that PDGFRB was highly expressed and phosphorylated, whereas PDGFRA and KIT were less expressed but phosphorylated and thus activated. These findings, together with the absence of gain-of-function mutations and the presence of the cognate ligands, strongly support the hypothesis that the activation mechanism is the autocrine/paracrine loop. No role seems to be played by gene amplification. CONCLUSIONS: In the light of our findings, the clinical benefit observed in chordoma patients treated with imatinib seems to be attributable to the switching off of all three receptors.

Adult↗

PubMed2006

Advanced extremity soft tissue sarcoma: prognostic effect of isolated limb perfusion in a series of 88 patients treated at a single institution.

PURPOSE: To explore the prognostic impact of isolated limb perfusion (ILP) in locally advanced extremity soft tissue sarcomas (ESTS). METHODS: From August 1982 to April 2005, 1,119 patients affected by ESTS (girdle excluded) were observed and treated at our institution. Eighty-eight (7.9%) were judged non-resectable or locally advanced and underwent ILP. Thirty-seven patients received antiblastic alone (non-TNF-ILP) while 51 had anti-blastic + recombinant-tumor necrosis factor alpha (TNF-ILP). Local disease-free survival (LDFS) was calculated by the Kaplan-Maier method and was reported separately in the two subgroups. RESULTS: Limb salvage was achieved in 83% (73/88) of the patients. The observed overall (complete + partial) response rate was 59%. In the TNF-ILP group a complete response (CR) was achieved in 21 (41%) patients, while in the non-TNF ILP group a CR was obtained in seven (19%) cases (P < 0.05). Patients with in-transit metastases (epithelioid sarcomas and clear cell sarcomas) had a significantly worse long-term outcome (LDFS at 5 years was 40.9 vs 67.3%, P < 0.05). A trend towards a better LDFS at 5 years could be observed in the patients receiving TNF (63.6 vs 57.1%) and post-operative radiation therapy (RT) (79.3 vs 55.4%). CONCLUSIONS: Isolated limb perfusion is an active treatment. By adding TNF a better local control seems to be obtained, possibly due to a higher rate of CR. It should therefore be considered as a valid option for patients affected by limb-threatening STS, save for in-transit metastases from epithelioid and clear cell sarcoma. Post-operative RT should always be considered.

Adolescent↗

PubMed2006

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.

BACKGROUND: No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. METHODS: Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. FINDINGS: 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. INTERPRETATION: We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

Adult↗

PubMed2006

Malignant peripheral nerve sheath tumors: prognostic factors and survival in a series of patients treated at a single institution.

BACKGROUND: The authors explored the prognostic factors and clinical outcomes of patients who had malignant peripheral nerve sheath tumors (MPNST) with and without neurofibromatosis type 1 (NF-1). METHODS: Two hundred five patients with localized MPNST who underwent surgery at the Istituto Nazionale per lo Studio e la Cura dei Tumori (Milan, Italy) over 25 years were reviewed. Forty-six patients had concomitant NF-1 syndrome, and 159 patients did not. Local recurrence, distant metastases, and survival rates were studied. RESULTS: One hundred thirty patients presented with primary disease, and 75 patients had locally recurrent tumors. The disease-specific mortality rate was 43% at 10 years, with a continuously disease-free survival rate of no greater than 40%. Presentation with either primary or recurrent disease, tumor size, and tumor site (trunk vs. extremity) were the strongest independent predictors of survival. Margin status and radiation therapy also played a role, mostly related to their effect on local outcome. Pathologic grade influenced distant metastases, but only a trend for survival could be observed. No significant independent differences between patients with and without NF-1 were observed. CONCLUSIONS: To the authors' knowledge, this was among the largest single-institution series to date. The results confirmed that patients with MPNST share similar prognostic factors with patients who have other soft tissue sarcomas and have some of the worst clinical outcomes. The presence of NF-1 syndrome per se did not affect survival, but patients with NF-1 were more likely to have larger tumors. Therefore, such patients should be followed carefully to detect disease as early as possible.

Adolescent↗

PubMed2006

Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: a study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG).

The aim of this study was to identify prognostic factors for toxicity to treatment with imatinib. The study was based on 942 patients with gastrointestinal stromal tumours (GIST) randomised to receive imatinib at different doses. The correlation between toxicities occurring with a Common Toxicity Criteria (CTC) grade 2 or more (non-haematological) or grade 3 or 4 (haematological) and imatinib dose, age, sex, performance status, original disease site, site and size of lesions at trial entry, baseline haematological and biological parameters was investigated. Anaemia was correlated with dose and baseline haemoglobin level, and neutropaenia with baseline neutrophil count and haemoglobin level. The risk of non-haematological toxicities was dose dependent and higher in females (oedema, nausea, diarrhoea), and in patients of advanced age (oedema, rash fatigue), poor performance status (fatigue and nausea), prior chemotherapy (fatigue), tumour of identified gastrointestinal origin (diarrhoea) and small lesions (rash). A multivariate risk calculator that can be used in the clinic for individual patients is proposed.

Adult↗

PubMed2006

KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.

A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P<0.0001) and the relative risk of death by 190% (P<0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P<0.0001) and the relative risk of death by 76% (P=0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.

Adult↗

PubMed2006

Prognostic effect of re-excision in adult soft tissue sarcoma of the extremity.

BACKGROUND: We explored the outcome of patients with primary adult soft tissue sarcoma (STS) of the extremities undergoing re-excision after previous unplanned surgery. METHODS: A total of 597 consecutive adult patients with primary extremity STS were treated with conservative surgery at our institution over a 20-year time span. A total of 318 patients were referred after unplanned excisions, and the remaining 279 underwent primary resection at our center. The two groups significantly differed in tumor size and depth. The assessed end points were sarcoma-specific mortality, local recurrence, and distant metastasis. Univariable and multivariable analyses, adjusted for other prognostic factors, were performed in the competing risks framework. RESULTS: The adjusted 10-year cumulative incidences in re-excised and primarily operated patients were, respectively, 18.7% and 16.4% (P = .535) for local relapse, 17.6% and 20.2% (P = .541) for metastasis, and 20.4% and 22.4% (P = .645) for mortality. Among patients who underwent re-excision, evidence of microscopic residual disease on pathologic examination had a significant prognostic effect on multivariable analysis for distant metastases (P = .002). A trend for survival was detected as well. CONCLUSIONS: At a referral center with a liberal policy of re-excisions in adult primary STS of the extremities, the outcome of patients who underwent re-excision was similar to that of patients who had primary resections. Evidence of microscopic residual disease at re-excision was a marker of clinical aggressiveness.

Adult↗

PubMed2005

Dermatofibrosarcoma protuberans treated at a single institution: a surgical disease with a high cure rate.

PURPOSE: Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous sarcoma with autocrine overproduction of the platelet-derived growth factor (PDGF) beta-chain from gene rearrangement as a key pathogenetic factor, now susceptible of molecular-targeted therapy. The aim of this retrospective analysis was to explore the outcome of patients with primary or recurrent DFSP. PATIENTS AND METHODS: Two hundred eighteen patients surgically treated at the Istituto Nazionale per lo studio e la cura dei Tumori (Milan, Italy) over 20 years were reviewed. Local relapse, distant metastasis, and survival were studied. RESULTS: One hundred thirty-six patients (62.4%) presented with a primary DFSP, while 82 patients (37.6%) had a recurrent disease. In the primary group, margins were microscopically positive in 11.8%, while in the recurrent group they were positive in 14.6% (P =.613). In the primary group, patients undergoing re-excision after inadequate previous surgery had residual disease in 62% of cases. Reconstructive surgery was needed in 30%, significantly more frequently in patients with a recurrence or a head and neck tumor. The crude cumulative incidence of local relapses was 4% at 10 years, and 2% at 10 years for distant metastases. No significant difference was found between primary and recurrent patients, as well as between positive and negative margins. CONCLUSION: This being one of the largest mono-institutional series of DFSP, we confirm that long-term outcome is excellent, in terms of both local and distant control, after a wide excision with negative margins. Reconstructive surgery is often needed. Novel medical therapies will be of use in a limited subgroup of patients.

Adolescent↗

PubMed2005

Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study.

PURPOSE: The aim of this study was to identify factors predicting initial and late resistance of GI stromal tumor (GIST) patients to imatinib and to document the dose-response relationship in the prognostic subgroups. This study is based on the European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group randomized trial comparing two doses of imatinib in advanced disease. PATIENTS AND METHODS: Initial resistance was defined as progression within 3 months of randomization, and late resistance was defined as progression beyond 3 months. Investigated cofactors include imatinib dose, age, sex, performance status, original disease site, site and size of lesions at trial entry, and baseline hematologic and biologic parameters. RESULTS: Initial resistance was recorded for 116 (12%) of 934 assessable patients and was independently predicted by the presence of lung and absence of liver metastases, low hemoglobin level, and high granulocyte count. Among 818 patients who were alive and progression free at 3 months, 347 subsequent progressions were recorded, and late resistance was independently predicted by high baseline granulocyte count, primary tumor outside of the stomach, large tumor size, and low initial imatinib dose. The impact of initial dose on late resistance was mainly significant in patients with a high baseline granulocyte count (> 5.10(9)/L) and in patients with tumors of GI origin outside of the stomach and small intestine. CONCLUSION: Our study identifies patients for whom initial and/or long-term treatment needs to be improved and patients who require a high initial dose. Correlation of these results with immunohistochemistry and molecular parameters may further help to understand the biologic mechanisms of resistance.

Adult↗

PubMed2005

Validation and adaptation of a nomogram for predicting the survival of patients with extremity soft tissue sarcoma using a three-grade system.

BACKGROUND: A nomogram for predicting long term tumor-specific death in patients with soft tissue sarcoma (STS) was developed at the Memorial Sloan-Kettering Cancer Center (MSKCC). METHODS: To assess the performance of the MSKCC nomogram, 642 consecutive patients with extremity STS who underwent surgery over a 20-year span at a single referral center were analyzed. Nomogram predictions were based on tumor size, depth, site, patient age, histologic subtype, and grade. The latter, at variance with the system in use at the MSKCC, was classified as Grade 1-3 according to the French Federation of Cancer Centers Sarcoma Group (FNCLCC) system. The statistical approach used for nomogram performance assessment was that of "validation by calibration" proposed by Van Houwelingen. RESULTS: Graphic comparison of observed and predicted sarcoma-specific survival curves showed that predictions by the nomogram were quite accurate, within 10% of actual survival for all prognostic strata. Statistical analysis showed that such predictions could be improved by employing approximately 25% shrinkage to achieve good calibration. The contribution of histologic grade was highly significant in both univariate analysis (P < 0.001) and multivariate analysis (P < 0.001), and a survival trend across the 3 grade categories was observed. Based on those findings, a nomogram that included the FNCLCC histologic grade classification was produced. CONCLUSIONS: Results of the current study confirmed that the MSKCC nomogram is a valuable tool for individual prognostic assessment. A nomogram that included the FNCLCC histologic grade classification was proposed and was validated internally.

Adolescent↗

PubMed2005

Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg.

In the EORTC-ISG-AGITG trial 946 patients with advanced gastro-intestinal stromal tumours (GIST) were randomised to receive 400 or 800 mg of imatinib daily. An increase in progression free survival (PFS) was demonstrated for patients randomised to the high-dose arm. Patients randomised to low-dose could cross-over to high-dose upon progression. We evaluated the feasibility, safety and efficacy of this policy. Of the 241 patients available for follow-up, 133 patients (55%) crossed over to high-dose imatinib according to the protocol. Of these patients, 92% had not had a prior dose reduction. The cumulative incidence of subsequent dose reductions after cross-over was 17% after six months with 51% discontinuing therapy without requiring a dose reduction. The extent of anaemia and fatigue increased significantly after cross-over, whilst neutropenia was less severe than during low-dose treatment. Objective responses after cross-over included three patients (2%) with a partial response and 36 (27%) with stable disease. The median PFS after cross-over was 81 days, although 18.1% of patients were still alive and progression free one year after cross-over. We conclude that a cross-over to high-dose imatinib is feasible and safe in GIST patients who progress on low-dose therapy.

Adult↗

PubMed2005

Adjuvant chemotherapy for soft tissue sarcoma.

PURPOSE OF REVIEW: To review current state-of-the-art knowledge about adjuvant medical therapy in adult soft tissue sarcomas. RECENT FINDINGS: Most recent contributions have added nonrandomized evidence to previously available controlled clinical trials, which were undertaken from the 1970s. Again, results are conflicting, with a limited benefit suggested by some retrospective analyses and denied by others. While a delay in relapse is likely to occur in a fraction of patients treated with adjuvant chemotherapy, a permanent benefit has been more difficult to prove. This result is consistent with findings from previous clinical trials, which pointed to a slight benefit from Doxorubicin-based adjuvant chemotherapy and a possibly higher, although less evidence-based, benefit from anthracycline plus Ifosfamide regimens. SUMMARY: Overall, adjuvant chemotherapy may give some benefit in soft tissue sarcoma. If any, it is likely to be of limited degree, confined to the highest-risk patients, and requiring a fully active chemotherapy regimen. This was mainly shown for extremity soft tissue sarcoma but may also apply to other primary sites. The value of molecular-targeted therapy as an adjuvant for high-risk gastrointestinal stromal tumor patients is a different subject awaiting long-term results of ongoing trials.

Antineoplastic Agents↗

PubMed2004

Imatinib mesylate in chordoma.

BACKGROUND: To the authors' knowledge, no effective medical therapy currently is available for advanced chordoma. Imatinib mesylate is a tyrosine kinase inhibitor targeting platelet-derived growth factor receptor-beta (PDGFRB), BCR-ABL, and KIT. METHODS: Six patients with advanced chordoma were treated with imatinib mesylate at a dose of 800 mg daily. In all patients, the tumor was found to be positive for PDGFRB, and in four patients PDGFRB was shown to be phosphorylated/expressed. RESULTS: After a treatment period of > or = 1 year, overt tumor liquefaction was evident on computed tomography (CT) scan in the first patient. In previous months, a decrease in contrast enhancement on magnetic resonance imaging (MRI) and a decrease in glucose uptake on positron emission tomography (PET) were detected. Similar signs on MRI and PET were observed in subsequent patients, who had a shorter treatment period. One of these patients initially was removed from therapy and then was readmitted to therapy because of difficulties with regard to tumor response assessment; 1 month after the reinitiation of therapy, an overt decrease in tumor density was visible on CT scan in this patient. In four of five symptomatic patients, a subjective improvement was observed early in the course of treatment. The first patient died after 17 months, with a sizeable, mostly liquefied mass. Another patient died early, apparently of unrelated causes. The remaining patients were on therapy at the time of last follow-up. CONCLUSIONS: Imatinib mesylate has been found to have antitumor activity in patients with chordoma. This activity might be mediated by inactivation of PDGFRB. Tumor response manifests through patterns that are similar to those observed in patients with gastrointestinal stromal tumors who respond to molecular-targeted therapy, but evolves more slowly. The benefit to the patient entailed by this pattern of tumor response in chordoma needs to be elucidated, but may be limited in the presence of significant local disease.

Adult↗

PubMed2004

Synovial sarcoma: a retrospective analysis of 271 patients of all ages treated at a single institution.

BACKGROUND: The optimal treatment strategy for synovial sarcoma (SS) is subject to debate, and different strategies have been used for pediatric and adult patients. The current retrospective analysis examined a large group of patients of all ages who were treated at a single institution over a 30-year period. METHODS: The study included 271 patients who ranged in age from 5 years to 87 years; 255 had localized disease, which was macroscopically resected in 215 cases and deemed unresectable at diagnosis in 40 cases. Chemotherapy was administered to 41% of patients, corresponding to 76% of patients age or 16 years and < 20% of older patients; 28% of patients with macroscopically resected disease received chemotherapy on an adjuvant basis. RESULTS: The 5-year event-free survival rate for the study cohort as a whole was 37%, although this rate varied with age (66%, 40%, and 31% for patients age < or = 16 years, 17-30 years, and > 30 years, respectively). Chemotherapy was used more commonly for children than for adults. Among patients with surgically resected disease, the 5-year metastasis-free survival (MFS) rate was 60% for those who were treated with chemotherapy and 48% for those who were not; the benefit associated with chemotherapy use appeared to be greatest for patients age > or = 17 years who had tumors measuring > 5 cm (MFS, 47% [chemotherapy] vs. 27% [no chemotherapy]). In the subgroup of patients with measurable disease, the rate of tumor response to chemotherapy was approximately 48%. CONCLUSIONS: Although the authors await more convincing proof of the efficacy of adjuvant chemotherapy in the treatment of adult soft tissue sarcoma, they recommend that patients with high-risk SS (tumor size > 5 cm) be the first to be considered for this type of treatment.

Adolescent↗

PubMed2004

Retroperitoneal soft tissue sarcomas: patterns of recurrence in 167 patients treated at a single institution.

BACKGROUND: The objective of this study was to assess long-term prognosis and patterns of failure in patients with retroperitoneal soft tissue sarcoma who underwent surgery with curative intent at a single institution. Several series of patients with retroperitoneal sarcoma were reported, providing widely variable data regarding local and distant failure. METHODS: Overall, 167 consecutive patients who underwent surgery for retroperitoneal soft tissue sarcoma over a 20 year span at a single referral center were reviewed retrospectively. Eighty-two patients presented with primary disease, whereas 85 patients had recurrent locoregional tumors. Surgical resection was considered macroscopically complete in 147 of 167 patients (88%). RESULTS: Overall survival at 10 years after definitive surgery was approximately 27%, and the disease-free survival was approximately 16%. Only a minority of patients developed distant metastases. The risk of recurrence was correlated with whether patients underwent surgery for primary disease or for recurrent disease; the 10 year disease-free survival rate was 27% in the former group and 4.6% in the latter group. Histotype and malignancy grade were other prognostic factors, with the former found to be predictive of the pattern of failure and the latter predictive of overall survival. CONCLUSIONS: Local recurrence after primary surgery and high-grade malignancy were associated with the worst survival. Histologic subtype appeared to influence the pattern of recurrence, which mainly was local for patients with liposarcoma but was both local and distant for patients with the other histotypes.

Adolescent↗

PubMed2004

Expression of ligand-activated KIT and platelet-derived growth factor receptor beta tyrosine kinase receptors in synovial sarcoma.

PURPOSE: The use of tyrosine kinase receptor inhibitors is increasingly becoming a valuable therapeutic alternative in tumors carrying activated tyrosine kinase receptors. In a previous study, we described a coexpression of KIT and stem cell factor (SCF) mRNA in Synovial sarcomas, (SS) and in a limited number of cases, we demonstrated the presence of an activated receptor. Here, in a wider number of cases, we investigated the expression level and phosphorylation status of two structurally related tyrosine kinase receptors, KIT and platelet-derived growth factor receptor beta (PDGFRbeta), at the light of their role as possible targets of tyrosine kinase receptors inhibitor molecules. EXPERIMENTAL DESIGN: Forty-three SS cases were analyzed for KIT and PDGFRbeta expression/activation by immunoprecipitation/Western blotting experiments. The cognate ligands, SCF and PDGFB, were detected by reverse transcription-PCR. RESULTS: KIT was observed in 48 and 41% (45% total) whereas PDGFRbeta in 54 and 33% (45% total) of monophasic and biphasic SS cases, respectively. With respect to the fusion transcript type SYTSSX1 and SYTSSX2, KIT was more expressed in SYTSSX1 carrying cases (48 versus 38%), whereas PDGFRbeta resulted more frequently expressed in SYTSSX2 ones (54 versus 37%). When expressed, the receptors were phosphorylated. Their ligands were detected in all of the activated cases. CONCLUSIONS: About 70% of the cases express one of the two activated tyrosine kinase receptors with a mutually exclusive expression trend. Coexpression is not frequent and seems to be restricted to monophasic subtype. These data indicate that a consistent fraction of this tumor type could represent a good candidate for kinase inhibitor molecules effective on KIT and PDGFRbeta where their activation is sustained by an autocrine loop.

Blotting, Western↗

PubMed2004

A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient.

BACKGROUND & AIMS: Imatinib, a tyrosine kinase inhibitor of BCR-ABL, KIT, and platelet-derived growth factor receptor, is used in patients with chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). Primary and acquired resistance to the drug can occur in both diseases. Molecular mechanisms have been reported in CML and GIST for primary resistance, whereas extensive studies on the mechanisms responsible for secondary resistance have been almost exclusively reported for CML. METHODS: In a patient with advanced GIST undergoing imatinib therapy, an isolated progressing peritoneal mass was excised, along with 2 still-responding lesions. Complementary DNA and genomic DNA were analyzed by sequencing for c-Kit gene mutations. KIT receptor expression and phosphorylation status were assessed by immunoprecipitation and Western blot. Transient-transfection experiments were performed with mutagenized KIT constructs, and their activation status was assessed. RESULTS: In addition to an exon 11 mutation, shared among all of the analyzed lesions, a novel point mutation in c-Kit exon 14 resulting in T670I substitution was found only in the progressing lesion, which harbored a phosphorylated receptor, as opposed to the finding of an inactive receptor in responding lesions. Functional analyses showed that KIT/T670I is insensitive to imatinib and that T670I mutation, introduced in a receptor responding to imatinib, subverted its sensitivity to the drug. CONCLUSIONS: This new mutation was confined to the progressing lesion; the resulting amino acidic substitution, T670I, affecting the ATP/imatinib pocket of KIT, makes it insensitive to the drug. Interestingly, this substitution is a homologue to the T315I mutation already reported in CML, where it is responsible for acquired resistance to imatinib.

Abdominal Neoplasms↗

PubMed2003

Rhabdomyosarcoma in adults. A retrospective analysis of 171 patients treated at a single institution.

BACKGROUND: The goal of the current study was to clarify treatment outcomes for adult patients with rhabdomyosarcoma (RMS). Published series have reported definitively worse results for adults with RMS compared with children with RMS. This finding casts doubt on whether RMS is the same disease in adults as it is in children. METHODS: Of 190 patients with RMS who were age 18 years or older and whose cases were recorded over a 25-year span in the pathology database of the Istituto Nazionale Tumori (Milan, Italy), 171 could be analyzed retrospectively for treatment outcome. The authors attempted to stratify patients according to the degree to which they had been treated appropriately, based on current treatment guidelines for childhood RMS. RESULTS: The overall rate of response to chemotherapy was 85%. For the entire series, 5-year event-free survival and 5-year overall survival (OS) were 28% and 40%, respectively. Among the 110 patients with embryonal, alveolar, or 'not otherwise specified' RMS, 5-year OS was 46%; however, 5-year OS was 61% for patients within this group (39% of the total) who had high scores for appropriate treatment. CONCLUSIONS: The current series parallels other published series in that it confirms the finding of a relatively poor long-term outcome for adult patients with RMS. However, for patients whose treatment adhered to the current guidelines for treatment of children, outcome was similar to what has been reported in pediatric series. In addition, the rate of response to chemotherapy for the entire series was similar to the rate typically observed among children. These findings suggest that adults and children with RMS should receive similar treatment. Treatment protocols adopted from pediatric programs but tailored to adults could increase adults' chances of receiving appropriate treatment; prospective studies are needed to test this idea.

Adult↗