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.

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.

c-KIT and c-KIT ligand (SCF) in synovial sarcoma (SS): an mRNA expression analysis in 23 cases.

In a previous immunophenotypic molecular-based analysis it was shown that bcl2 over-expression characterizes the SS gene profile in addition to the non-random translocations. Here we show that the over-expression of an additional potentially antiapoptotic gene, the c-KIT gene, is associated with this tumour. Interestingly, whereas bcl2 over-expression appears to be restricted to the spindle cell tumoral component, c-kit mainly involves the epithelial component of biphasic SS. Twenty-three primary and metastatic samples from 21 patients were analysed by immunophenotyping (23/23), immunoprecipitations and Western blotting (3/23), and RT-PCR (23/23). Ten cases were biphasic and 13 monophasic in sub-type. Twelve, 10 and 1 case carried the SYT-SSX1, SYT-SSX2 and SYT-SSX4 fusion transcript, respectively. Co-presence of both c-Kit and SCF mRNA was observed in almost all cases (20/23), suggesting the occurrence of an autocrine loop. Immunophenotyping, confirmed by biochemical analyses, showed a modulation of c-Kit expression which was faint in the spindle and strong in the epithelial component, respectively. The study was complemented by c-Met/HGF receptor/ligand expression and c-Met protein analysis with results superimposable to those already reported. Since in each tumour, epithelial and spindle cell components harbour the same type of translocation t(X;18) the present findings suggest a shifting of the anti-apoptotic role from BCL2 to c-KIT gene during the transition from the uncommitted spindle to the differentiated epithelial cells.

A randomised phase II study on neo-adjuvant chemotherapy for 'high-risk' adult soft-tissue sarcoma.

The aim of this study was to examine the strategy, feasibility and outcome of neo-adjuvant chemotherapy, with doxorubicin and ifosfamide, in adult patients with 'high-risk' soft-tissue sarcomas. Patients with 'high-risk' soft-tissue sarcomas, defined as tumours > or =8 cm of any grade, or grade II/III tumours <8 cm, or grade II/III locally recurrent tumours, or grade II/III tumours with inadequate surgery performed in the previous 6 weeks and therefore requiring further surgery, were randomised between either surgery alone or three cycles of 3-weekly doxorubicin 50 mg/m(2) intravenous (i.v.) bolus and ifosfamide 5 g/m(2) (24 h infusion) before surgery. The type of surgery had to be planned at randomisation. Tumours were to be amenable to surgery by amputation, compartmental resection, wide or marginal excision. If chemotherapy was given, surgery had to be performed within 21 days after the last chemotherapy. Patients received postoperative radiotherapy in cases of marginal surgery, microscopically incomplete resection and no further possibility for surgery, and in cases of surgery because of local recurrence. 150 patients were entered into the study and 134 were eligible, 67 in each arm. The most frequent side-effects of chemotherapy were alopecia, nausea and vomiting (95%), and leucocytopenia (32%). One patient died of neutropenic fever after the first cycle of chemotherapy. Chemotherapy did not interfere with planned surgery and did not affect postoperative wound healing. Limb-salvage was achieved in 88%, amputation was necessary in 12% (all according to the plan at randomisation). The trial was closed after completion of phase II, since accrual was too slow to justify expanding the study into the scheduled phase III study. At a median follow-up of 7.3 years, the 5 year disease-free survival is estimated at 52% for the no chemotherapy and 56% for the chemotherapy arm (standard error: 7%) (P=0.3548). The 5 year overall survival for both arms is 64 and 65%, respectively (standard error 7%) (P=0.2204). Neo-adjuvant-chemotherapy with doxorubicin and ifosfamide at these doses and with this schedule was feasible and did not compromise subsequent treatment, surgery with or without radiotherapy. Although not powered to draw definitive conclusions on benefit, but with an at least 7 year median follow-up, the results render it less likely that major survival benefits will be achieved with this type of chemotherapy.

Analysis of the molecular species generated by MDM2 gene amplification in liposarcomas.

MDM2 gene is overexpressed in several tumors and its product may be processed into different isoforms, some of which have been demonstrated to possess transforming activity. In a panel of liposarcomas characterized by displaying 4 different combinations of mdm2/p53 immunoreactivity, molecular analysis of amplified MDM2 gene revealed a coexistence of mutated full-length MDM2 messenger RNAs, an out-of-frame splicing mRNA and finally aberrant spliced forms. Two of the latter are reported here for the first time. The molecular differences in this heterogeneous mRNA population seem to mirror distinct functional aspects of the altered encoded mdm2 proteins. In fact, besides the deleted transcripts defective in their ability to bind p53 and known to possess a transforming activity, here we describe both mutated full-length forms and deleted transcripts that still maintain the ability to bind p53 but, based on their mdm2+/p53+ immunophenotype, probably fail to signal its degradation. These aberrant forms, which are responsible for the accumulation and inactivation of p53, can contribute, together with the p53 independent transforming forms, to liposarcoma transforming pathway.

Identification of a novel spliced variant of the SYT gene expressed in normal tissues and in synovial sarcoma.

Synovial sarcoma (SS) is cytogenetically characterized by the translocation t(X;18)(p11.2-q11.2) generating a fusion between the SYT gene on chromosome 18 and one member of the SSX family gene (SSX1; SSX2; SSX4) on chromosome X. Here, we report for the first time that 2 forms of SYT mRNA are present in both normal tissues and SSs. By amplifying the full-length SYT cDNA of two SSs, we detected 2 bands, here designated N-SYT and I-SYT. The latter, previously undescribed, contains an in-frame insertion of 93 bp. Its sequencing revealed a 100% homology with the mouse SYT gene. These two SYT forms were present, although in different amounts, in all human normal tissues examined, including kidney, stomach, lung, colon, liver and synovia. Coexistence of N-SYT and I-SYT (both fused with SSX) was detected in a series of 59 SSs (35 monophasic and 24 biphasic) and in a SS cell line. A preliminary analysis of the differential expression levels of N-SYT and I-SYT in SSs revealed that the latter was consistently overexpressed, suggesting a role in SS pathogenesis.

Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial.

PURPOSE: Adjuvant chemotherapy for soft tissue sarcoma is controversial because previous trials reported conflicting results. The present study was designed with restricted selection criteria and high dose-intensities of the two most active chemotherapeutic agents. PATIENTS AND METHODS: Patients between 18 and 65 years of age with grade 3 to 4 spindle-cell sarcomas (primary diameter > or = 5 cm or any size recurrent tumor) in extremities or girdles were eligible. Stratification was by primary versus recurrent tumors and by tumor diameter greater than or equal to 10 cm versus less than 10 cm. One hundred four patients were randomized, 51 to the control group and 53 to the treatment group (five cycles of 4'-epidoxorubicin 60 mg/m(2) days 1 and 2 and ifosfamide 1.8 g/m(2) days 1 through 5, with hydration, mesna, and granulocyte colony-stimulating factor). RESULTS: After a median follow-up of 59 months, 60 patients had relapsed and 48 died (28 and 20 in the treatment arm and 32 and 28 in the control arm, respectively). The median disease-free survival (DFS) was 48 months in the treatment group and 16 months in the control group (P =.04); and the median overall survival (OS) was 75 months for treated and 46 months for untreated patients (P =.03). For OS, the absolute benefit deriving from chemotherapy was 13% at 2 years and increased to 19% at 4 years (P =.04). CONCLUSION: Intensified adjuvant chemotherapy had a positive impact on the DFS and OS of patients with high-risk extremity soft tissue sarcomas at a median follow-up of 59 months. Therefore, our data favor an intensified treatment in similar cases. Although cure is still difficult to achieve, a significant delay in death is worthwhile, also considering the short duration of treatment and the absence of toxic deaths.

The incremental prognostic value of pharmacological stress echo over exercise electrocardiography in women with chest pain of unknown origin.

AIMS: The value of exercise electrocardiography in evaluating women with suspected coronary artery disease is limited. Conversely, stress echocardiography is effective for both diagnostic and prognostic purposes in females. The purpose of the study was to determine the relative prognostic value of exercise electrocardiography and pharmacological stress echocardiography in a cohort of women with chest pain of unknown origin, in order to verify whether criteria could be established for the daily non-invasive evaluation of such a low-risk profile population. METHODS AND RESULTS: Exercise electrocardiography and pharmacological stress echocardiography (171 dipyridamole, 73 dobutamine) were performed in 244 women (age 60+/-10 years) with chest pain and known coronary artery disease. A positive result of exercise electrocardiography (ST-segment shift > or =1 mm at 80 ms after the J point) was detected in 95 patients; a positive result of stress echocardiography (new regional wall motion abnormalities) was observed in 33 patients. During follow-up (36+/-18 months), two deaths, five infarctions, seven unstable anginas, and 11 coronary revascularizations occurred. Using Cox analysis, the positive result of stress echocardiography (odds ratio=40.1) alone, was independently related to hard cardiac events (death, infarction). With spontaneous cardiac events (death, infarction, and unstable angina) as end-points, the multivariate prognostic predictors were a positive result of stress echocardiography (odds ratio=37.0), a family history of coronary artery disease (odds ratio=4.1), typical chest pain (odds ratio=3.7), and a positive exercise electrocardiography result with a rate-pressure product < or =20 000 (odds ratio=3.5). By adopting an interactive stepwise procedure, the prognostic value of stress echocardiography was incremental to that of clinical and exercise electrocardiography data. Nevertheless, the negative result of exercise electrocardiography and pharmacological stress predicted a very high and comparable (P=ns) 24-month survival rate when both hard and spontaneous cardiac events were taken as end-points. CONCLUSIONS: In women with chest pain, stress echocardiography is a strong and independent prognostic indicator, incremental to that shown by exercise electrocardiography. However, the two tests have a similar high negative predictive value in this population. Therefore, exercise electrocardiography has to be considered the initial approach and the only test when the result is negative, whereas stress echocardiography is warranted in selected conditions, including those in women with uninterpretable electrocardiograms, those unable to exercise maximally, and those with an ambiguous or ischaemic response to exercise electrocardiography.

Low grade fibromyxoid sarcoma. a further low-grade soft tissue malignancy characterized by a ring chromosome.

Supernumerary rings in the context of a simple karyotype characterize several low-grade malignant tumors of soft tissue and bone. Low-grade fibromyxoid sarcoma is an uncommon low-grade sarcoma, the cytogenetics of which has not yet been reported. Here we describe the first molecular-cytogenetic characterization of a pulmonary metastasis of low-grade fibromyxoid sarcoma. The histology of the primary and recurrent tumors was consistent with the diagnosis of low-grade fibromyxoid sarcoma of the usual type, whereas the pulmonary metastasis was of the "giant rosettes" variant. Cytogenetic analysis revealed a ring chromosome. Because gain of material of chromosomes 7 and 16 was detected by CGH, the ring chromosome is assumed to be composed of material from these respective chromosomes.

A novel zinc finger gene is fused to EWS in small round cell tumor.

Ewing sarcoma family of tumors share recurrent translocations that fuse EWS from 22q12 to five different members of transcription factors namely FLI-1, ERG, ETV1, E1AF and FEV. Different classes of DNA binding proteins, ATF1, WT1 and CHOP are fused to EWS generating distinct tumor phenotypes: clear cell sarcoma, desmoplastic small round cell tumor, and myxoid liposarcoma, respectively. We have cloned a novel gene located at 22q12 fused to EWS by a submicroscopic inversion of 22q in a small round cell sarcoma showing a translocation (t(1;22)(p36.1;q12). The gene, designated ZSG (Zinc finger Sarcoma Gene), is a putative Cys2-His2 zinc finger protein which contains a POZ transcriptional repressor-like domain at the N-terminus. The rearrangement involves intron 8 of EWS and exon 1 of ZSG creating a chimeric sequence containing the transactivation domain of EWS fused to zinc finger domain of ZSG. This product lacks the transcriptional repressor domain at the N-terminus of ZSG. A rearrangement of the second ZSG allele was also found in tumor cells. This is the first example of an intra-chromosomal rearrangement of chromosome 22, undetectable by cytogenetics, activating EWS in soft tissue sarcoma.

[The evaluation of the appropriateness of instrumental exams in cardiology. The case of echocardiography]. / La valutazione dell'appropriatezza degli esami strumentali in cardiologia. Il caso dell'ecocardiografia.

BACKGROUND: The aim of this study was to evaluate the appropriateness and utility rates of echocardiograms performed in 309 patients in an outpatient clinical setting. METHODS: Data were collected by means of a questionnaire filled in by the cardiologists who performed the examinations. Appropriateness was evaluated according to international guidelines and scored as class I: appropriate, class II: doubtful appropriateness, class III: inappropriate; the exam was deemed useful if it was able to influence the clinical decision-making; normalcy rate was also checked. The relationship between both the referring physicians and motivation of the exam and its appropriateness, and the relationship between appropriateness and both the normalcy rate and utility of the exam were assessed. RESULTS: An echocardiogram was requested by the cardiologist in 46% of patients; the more common reasons for the exam were arterial hypertension (26%), cardiac murmur (18%), palpitations (15%), and known coronary artery disease (10%). The echocardiogram was appropriate (class I) in 25% of patients, doubtfully appropriate (class II) in 39% of patients and inappropriate (class III) in 36% of patients. The appropriateness rate between the cardiologists was similar to that of other prescribing clinicians (p = NS). The highest class III rate was found in patients with hypertension, while the highest class I rate was found in patients with a cardiac murmur (p < 0.01). Normalcy rate was lower in class I than in class II and III exams (p < 0.001). The utility rate was higher in class I (76%) than in class II (13%) and III (< 1%) exams (p < 0.01). CONCLUSIONS: International guidelines can be used effectively and safely to identify (not to prescribe) the useless echocardiograms.

The expression of MDM2/CDK4 gene product in the differential diagnosis of well differentiated liposarcoma and large deep-seated lipoma.

Ordinary lipomas are cytogenetically characterized by a variety of balanced rearrangements involving chromosome segment 12q13-15, whereas well differentiated liposarcomas (WDL) show supernumerary ring and giant marker chromosomes, known to contain amplified 12q sequences. The tight correlation between the presence of ring chromosomes and both amplification and overexpression of MDM2 and CDK4 genes suggests the exploration of the possibility that immunocytochemistry (ICC) might assist in the differential diagnosis of lipoma-like well differentiated liposarcomas (LL-WDL) and large deep-seated lipomas (LDSL). For this purpose, 21 cases of the former and 19 cases of the latter tumours were analysed by ICC and, according to the availability of material, by molecular and cytogenetic approaches. All lipomas displayed a null MDM2/CDK4 phenotype, whereas all LL-WDL showed MDM2/CDK4 or CDK4 phenotypes. Southern blot analysis performed on 16 suitable cases, complemented by fluorescence in situ hybridization and classical cytogenetic analysis in 11 cases, was consistent with, and further supported the immunophenotyping data. In conclusion, MDM2/CDK4 product-based immunophenotyping appears to represent a valuable method for the categorization of arguable LDSL.

Soft tissue limb sarcomas: Italian clinical trials with hyperthermic antiblastic perfusion.

BACKGROUND: Of the different options for limb-sparing treatment for patients with soft tissue limb sarcomas (STLS), hyperthermic antiblastic perfusion (HAP) combined with surgery might be the most effective in terms of tumor resectability, local control, and aesthetic and functional results. The aim of this study was to identify the most safe, active, and effective perfusional regimen in order to improve multidisciplinary treatment for patients with advanced STLS. METHODS: The first trial undertaken (which involved 18 patients) was a Phase I study to assess the maximum tolerable dose of doxorubicin, the second (with 29 patients) was a Phase II study of HAP with doxorubicin, and the third (with 20 patients) was a Phase I-II study to assess the maximum tolerable dose and tumor response to doxorubicin combined with tumor necrosis factor (TNF). Statistical tests were performed on the whole series to evaluate the factors influencing local toxicity, tumor response, and local disease free and overall survival. RESULTS: Grade IV systemic toxicity was observed in only 2 cases (TNF >1 mg). Muscle temperature (>41.5 degrees C) was the limiting factor for locoregional toxicity. Limb-sparing surgery was feasible for 60 patients (92.3%). The highest tumor response was observed in the third trial, with complete histologic necrosis in 26.3% of cases. Muscle and tumor temperature (>41.5 degrees C) and the type of trial had a statistically significant influence on response. The local recurrence rate was influenced by tumor site, type of trial, maximum tumor temperature, and local toxicity, whereas the overall survival was influenced by the presence of metastasis, tumor grade, and response to treatment. CONCLUSIONS: These findings show that HAP with doxorubicin and TNF (< or =1 mg) at a muscle temperature of < or =41.5 degrees C is a safe, active, and effective perfusional regimen for the multidisciplinary treatment of patients with advanced STLS.

Hyperthermic antiblastic perfusion with alpha tumor necrosis factor and doxorubicin for the treatment of soft tissue limb sarcoma in candidates for amputation: results of a phase I study.

To improve the therapeutic effectiveness of hyperthermic antiblastic perfusion (HAP), the association of recombinant tumor necrosis factor alpha (rTNF alpha), doxorubicin, and true hyperthermia (41 degrees C) was employed for the treatment of soft tissue limb sarcoma. A dose-escalation study according to Fibonacci's modified scheme was conducted, starting with a rTNF alpha dose of 0.5-3.3 mg. The doxorubicin doses (0.7 and 1.4 mg for the upper and lower limbs, respectively) and temperature level (41 degrees C) remained unchanged. Eighteen patients have been treated thus far: 9 males and 9 females of a mean age of 33 years (range: 24-71 years). The tumor was located in the upper limb in one patient and in the lower limbs in seventeen. Only 16 patients were evaluable, as 2 refused further treatment after the perfusion. In terms of local toxicity, a grade I limb reaction was observed in 3 patients, a grade II or III in 10 patients, and a grade IV in 5 patients, showing a strict correlation between the TNF dose and the grade of limb reaction. In fact, a grade III-IV limb reaction was observed in 66.6% of the patients treated with > 1 mg of rTNF alpha. The maximum tolerable dose in association with doxorubicin and true hyperthermia (41 degrees C) was 2.4 mg. Eleven patients showed a good pathological response (> 75%) and five patients showed a partial response (> 25%-< 75%). In no case was stable or progressive disease observed. The postperfusional tumor shrinkage permitted limb-sparing surgery in 75% of the patients, all of whom were candidates for amputation before HAP. No recurrences have been observed thus far. Two patients developed regional disease: one presented with a skip femur metastasis that disappeared after radiotherapy and systemic chemotherapy; the second developed regional node involvement, requiring a radical node dissection. Another patient had pulmonary metastases, 2 months after the HAP, which were resected. At a median follow-up of 12 months, all the patients are living without disease. The results of this phase I study suggest that the association of rTNF alpha, doxorubicin, and true HAP (41 degrees C) by regional perfusion is feasible and safe at a maximum tolerable rTNF alpha dose of 2.4 mg. However, because no correlation was found between the amount of rTNF alpha and the tumor response, 1 mg is recommended as the dose able to provide a high tumor necrosis rate and low local and systemic toxicity. This association appears to play an important role in the neoadjuvant treatment of soft tissue limb sarcoma.

[Variation in the evoked ventricular potentials after the implantation of an endocardiac catheter; the correlation with stimulation thresholds]. / Variazione dei potenziali ventricolari evocati dopo l'impianto di un catetere endocardico; correlazione con le soglie di stimolazione.

BACKGROUND: The drop in T wave amplitude of the ventricular pace-evoked response (VER) is a well-recognized and reliable mean of detecting localized conditions of myocardial hypoxia. In patients who undergo pacemaker implantation, the post-implant change at the electrode-tissue interface consists of an early inflammatory reaction. The aim of this study was to establish whether the extent of the inflammatory reaction following an endocardial lead can be assessed by the changes in the T wave amplitude of VER. METHODS: Modifications in VER amplitude and the correlation between these changes and pacing threshold time-course were evaluated in 30 patients receiving an endocardial catheter. Telemetered endocardial recordings of T wave amplitude and pacing thresholds were measured at the time of implant and after 1, 2, 3, 7, 14 and 30 days. RESULTS: A biphasic time-course was observed for T wave, characterized by reduction in amplitude of 48% (p < 0.005) from baseline at day 3 and subsequent increment up to 84% (p = ns) of the baseline value at day 30. By using a linear regression analysis, a significant correlation between T wave changes and increment in pacing threshold was found (r = 0.81; p < 0.002). A higher pacing threshold increment was observed in patients having a decrease in VER amplitude > or = 1 mV at 3rd in comparison with patients with a decrease in VER amplitude < 1 mV (1.1 +/- 0.4 vs 0.2 +/- 0.2 V; p < 0.001). CONCLUSIONS: VER recordings during the first days after endocardial lead implantation may be a valuable means of assessing the extent of the inflammatory reaction developing at the electrode-tissue interface. This method may be useful for early identification of patients at risk of increases in pacing threshold and for evaluation of the biocompatibility of different leads.

Limited role of TP53 and TP53-related genes in myxoid liposarcoma.

AIMS: Circumstantial evidence suggests that genetic changes may lead to tumor progression within the myxoid liposarcoma tumors (MLTs) carrying non-random chromosomal translocation t(12;16). METHODS: To address this subject an immunophenotypic analysis, applying antibodies against proteins encoded by TP53, MDM2 and CDK4 genes, complemented by molecular analysis of eight suitable cases, was performed on 104 consecutive cases. Chromosomal translocations were assessed either by cytogenetic analysis or by RT-PCR in 9 suitable cases and chimeric transcripts were found in all cases but two pleomorphic liposarcomas. RESULTS: Based on immunophenotyping and tumor site, the case material consisted of three groups. The first one was made up of 92 non-retroperitoneal cases carrying a null p53, mdm2, cdk4 immunophenotype, which remained unchanged over the time of recurrences and along the gamut of histologic subtypes. The second group was represented by five p53+, mdm2-, cdk4- non-retroperitoneal cases, 4 of which were further analysed by PCR-SSCP for p53 mutation. The immunophenotypic profile of these cases, complemented by the molecular findings, supported a role of TP53 in tumor progression in three high-grade MLTs. The third group, consisting of 7 retroperitoneal cases, showed a heterogeneous immunophenotype, sharing immunophenotypic and molecular features with the well-differentiated/evoluted (dedifferentiated) liposarcoma group. CONCLUSIONS: TP53 mutations seem to play a role in tumor progression in a few cases of MLTs (2.8%) showing more aggressive histologic characteristics. The unexpected finding that a number of retroperitoneal LMTs display the immunophenotypic profile of the well differentiated/evoluted (dedifferentiated) liposarcomas, deserves further investigation.

Left ventricular size and function in patients with noninsulin-dependent diabetes and postinfarction total or subtotal coronary occlusions.

The aim of this study was to establish the effects of postinfarction total or subtotal coronary occlusion on left ventricular remodeling in patients with noninsulin-dependent diabetes (NIDD) compared with the effects in postinfarct nondiabetic patients. The authors selected 100 patients submitted to coronary angiography between 1 and 5 weeks after acute myocardial infarction (T0: 20.5+/-15.4 days) and classified into three groups: G1: NIDD with coronary occlusion/subocclusion (n=24), G2: controls with coronary occlusion/subocclusion (n=43), G3: controls without coronary occlusion/subocclusion (n=33). At time zero (T0) the following parameters were evaluated: end-systolic and end-diastolic volume indexes (ESVi, EDVi), ejection fraction (EF), echocardiographic wall motion score index (WMI), presence of left ventricular aneurysm, and triple-vessel coronary disease. The frequencies of major cardiovascular events were recorded during follow-up. Significantly greater ESVi and EDVi were noted in G2 compared with G3 (P<0.0001), while no significant differences were observed between NIDD patients and controls. Although left ventricular global and segmental dysfunctions were increased in diabetics, controls with coronary occlusion/subocclusion presented more pronounced EF reduction (P<0.0001 G2 vs G3) and higher elevation in WMI (P<0.005 G2 vs G3). Cardiac events during follow-up were elevated in G1 and G2, particularly as regards the occurrence of congestive heart failure. The authors conclude that NIDD seems to influence in a positive way left ventricular remodeling associated with postinfarct total or subtotal coronary occlusion.

Mutations of adenomatous polyposis coli (APC) gene are uncommon in sporadic desmoid tumours.

Desmoids are locally aggressive, non-metastasizing soft-tissue tumours, whose aetiology is still unclear. In patients affected with familial adenomatous polyposis (FAP), the incidence of desmoids is much higher than in the general population. The APC gene, which is responsible for FAP, is involved in the development of desmoids associated with this syndrome. In this study 16 sporadic and four FAP-related desmoids were analysed in order to investigate the possible involvement of APC in non-syndromic cases also. The 5' end (exons 1-11) and the coding portion of exon 15 of APC were screened using the in vitro synthesized-protein assay (IVSP). Exons 5, 6, 8-14, and a region of exon 15 spanning codons 1036-1634 were investigated by single-strand conformation polymorphism (SSCP) analysis. APC germline mutations were identified in all FAP patients, but not in sporadic cases. Somatic mutations were found in three FAP-associated desmoids (75%) and two sporadic tumours (12.5%). In one of the latter cases, both alleles were affected. These findings indicate a limited role of the gene in the development of desmoid tumours outside FAP.

Molecular abnormalities in liposarcoma: role of MDM2 and CDK4-containing amplicons at 12q13-22.

It has recently been shown that mdm2 overexpression with stabilization of p53 represents a characteristic of retroperitoneal well-differentiated-dedifferentiated, here renamed evolved (WD-E), liposarcomas at the immunocytochemical, molecular, and cytogenetic level. This make-up appears to be confined to half the cases in non-retroperitoneal well-differentiated liposarcomas. Since in different tumours MDM2 amplification involves amplicons encompassing flanking genes, such as CDK4, the possibility was investigated that in these tumours, CDK4 could act as an alternative or additional gene involved in the transformation mechanism. Forty-one retroperitoneal (R)/non-retroperitoneal (NR) well-differentiated-dedifferentiated (WD-DD) and 33 myxoid/round cell liposarcomas were reanalysed by immunocytochemical, molecular (nine cases) and fluorescence in situ hybridization (FISH) (one case) techniques. The results showed that all but one R WD-E cases carried the mdm2+, p53+, cdk4+ immunophenotype. In NR-WD liposarcomas, this immunophenotype was shared in five cases and the remainder showed mdm2+, p53-, cdk4+ in four and mdm2-, p53-, cdk4+ in one case, showing ring chromosomes by FISH analysis. TP53 mutations are confirmed to be closely correlated with NR-DD liposarcomas and no CDK4 involvement was found in the myxoid/round cell liposarcoma group. As well as confirming the synergistic effect of MDM2 and CDK4, these results are consistent with the concept that amplicon(s) excluding MDM2 may contribute to transformation and support a role of CDK4 in opposing p53 function, particularly in NR WD liposarcoma.