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Purpose: To present a single-center experience with a mechanical hydrodynamic thrombectomy system (Hydrolyser) in native arteries, veins, and bypass grafts., Methods: The Hydrolyser is a 7F, double lumen, over-the-wire thrombectomy catheter. The device was used in 41 patients (22 males; mean age 68 years, range 40 to 90), with recent thromboses (aged 1 to 30 days, mean 8.7+/-8.5), measuring from 4 to 35 cm long (mean 17.7+/-9.5). The occlusions were located in native lower limb arteries (n = 28), bypass grafts (n = 8), superior venae cavae (n = 2), axillary vein (n = 1), and pulmonary arteries (n = 2)., Results: Immediate technical success (residual clot < 50% of lumen diameter) was achieved in 34 patients (83%): 22/28 native arteries (78%), 7/8 bypass grafts (87%), and all pulmonary arteries, superior venae cavae, and the axillary vein. The 7 failed patients were treated surgically (bypass graft or Fogarty balloon). Adjunctive procedureswere used to maximize luminal diameter: angioplasty (n = 29, with 13 immediate stent implantations), thromboaspiration (n = 17), and thrombolysis (n = 10). One case of distal embolism was the only complication (treated by thromboaspiration). At 30 days, 30 (73%) vessels remained patent., Conclusions: The Hydrolyser system is a promising concept for percutaneous thrombectomy. It is a quick, reliable, efficient device that may offer an alternative to thrombolysis and surgical thrombectomy.

The aim of this study was to report the authors' experience of a new auto-expandable nitinol stent covered by a thin layer of polyester, the Cragg Endopro System 1, for percutaneous internal revascularisation. One hundred and forty-two patients (120 men, 22 women; average age: 63.5 +/- 10 (38-88) received a total of 204 stents (58 iliac, 75 femoral, 9 politeal). The lesions were stenosis in 61 cases, occlusions in 61 cases and aneurysms in 20 cases. The mean length at the femoro-popliteal level was 14.2 +/- 2.4 cm (4-30), at iliac level 9.4 +/- 0.9 (3-15). Implantation was successful in 140/142 cases, a technical success in 136/142 cases (96%). There were 4 acute thromboses requiring surgery and 4 others treated successfully by thrombolysis. There were 18 secondary thromboses. Twenty-nine patients had pyrexia and pain in the treated limb for several days. Over a 27 months follow-up all the iliac stents remained patent; there were 8 restenoses unrelated to the stent, 7 of which were treated by a repeat angioplasty. The primary (PI) and secondary (PII) patency rates at 27 months were: iliac, PI = 97%, PII = 100%; global femoral, PI = 64%, PII = 76% (stenosis PI = 59%, PII = 81%; occlusions, PI = 65%, PII = 74%); lesions of less than 15 cm, PI = 68%, PII = 93%; lesions over 15 cm, PI = 54%, PII: 76%; aneurysms, PI and PII = 88%). The authors conclude that the Cragg Endopro System 1 stent is safe and effective in the treatment of long lesions and aneurysms with encouraging medium term results suggesting that it may be a real alternative to surgery.

Purpose: to present our clinical experience with a new mechanical hydrodynamic thrombectomy system (Hydrolyser), using the Venturi effect, applied for thrombus removal in native arteries, arterial grafts, venous system and pulmonary arteries (diameter > 5 mm)., Material and Methods: the Hydrolyser, a 7F, double lumen, over the wire catheter, was used in 50 patients (29 males, 21 females), mean age: 66.2 +/- 13.1 years (40-90). Mean occlusion time: 8.7 +/- 7.3 days (1-30), mean thrombus length: 17.7 +/- 10.2 cm (4-35). Thrombus' location: native arteries (35), arterial grafts (9), superior vena cava (2), axillary vein (2), pulmonary artery (2). Approach ways: arterial femoral antegrade (22), retrograde (7), contralateral (14), popliteal arterial (1), veinous femoral (5) and veinous brachial (1)., Results: Immediate technical success in 41 patients (82%): native arteries (27/35), arterial graft (7/9), pulmonary artery (2/2), superior vena cava (2/2) axillary vein (2/2). Percentage of thrombus estimated angiographically to be removed by the Hydrolyser: 72.5 +/- 22%. Adjunctive therapy: angioplasty (38, with 19 immediate stents implantations), thromboaspiration (17), reduced time fibrinolysis (11). One complication: distal embolism cured by thromboaspiration. In 9 patients the procedure failed, requiring surgery., Conclusion: the Hydrolyser system seems a promising concept for percutaneous thrombectomy. It is a quick reliable, efficient device. This technique may also offer an alternative to thrombolysis and surgical thrombectomy.

Purpose: To assess the use of a recently developed stent-graft system for treatment of occlusive lesions and aneurysms in the iliac and femoropopliteal arteries., Materials and Methods: The stent-graft consisted of a nitinol stent framework covered by a thin-walled polyester fabric. The device was used in 105 patients with symptomatic peripheral vascular disease. Implant locations were iliac artery (n = 38), femoral artery (n = 62), and popliteal artery (n = 5)., Results: Initial technical success was achieved in all patients except one with occlusive disease and one with aneurysmal disease. Residual stenosis after stent-graft implantation was 0.5% +/- 3. Mean ankle-brachial index increased from 0.53 to 0.98. Complications were hematoma (n = 3), pseudoaneurysm (n = 2), puncture site thrombosis (n = 1), early graft thrombosis (n = 8), graft misplacement (n = 1), distal embolization (n = 2), delayed thrombosis (n = 14), pain and fever (n = 27). At the iliac level, primary patency was 97% and secondary patency was 100%. At the femoral level, primary patency was 59% and secondary patency was 81%., Conclusion: Endoluminal bypass with a percutaneously delivered stent-graft is feasible. Technical results are good, and the number of complications is few at the iliac level. At the femoropopliteal level, patency is not as good and the number of complications is higher.

Purpose: To evaluate a new self-expanding nitinol coil stent in stenotic or occluded peripheral arteries., Methods: Seventy-three symptomatic patients (58 men; mean age 67 years) were treated with nitinol stents for lesions in the iliac artery (9 stenoses); superficial femoral artery (SFA) (39 stenoses, 6 occlusions); popliteal artery and tibioperoneal trunk (9 stenoses, 7 occlusions); and 3 bypass grafts. Mean diameter stenosis was 84.4% +/- 9.9% (range 75% to 100%), and mean lesion length was 45 +/- 23 mm (range 20 to 120 mm)., Results: Eighty-eight 40-mm-long stents with diameters between 5 and 8 mm were implanted percutaneously for suboptimal dilation (n = 45); dissection (n = 21); and restenosis (n = 7). All stents but one were implanted successfully; the malpositioned stent was removed, and another stent was successfully deployed. There were 3 (4.1%) failures due to thrombosis at 24 hours. During the mean 16-month follow-up (range to 44 months), 4 restenoses (3 femoral, 1 popliteal) have occurred; 2 were treated with repeat dilation and 2 underwent bypass. Primary and secondary patency rates at 18 months were 87% and 90%, respectively, for all lesions (iliac: 100% for both; femoral: 85% and 88%; popliteal: 87% and 100%)., Conclusions: This new nitinol stent seems to be safe and effective with favorable long-term results, even in distal SFA lesions and popliteal arteries. Its flexibility and resistance to external compression allow its placement in tortuous arteries and near joints.

Purpose: To evaluate the long-term results of stent placement in the renal arteries., Patients and Methods: From January 1990 to August 1994, 59 hypertensive patients underwent 64 stent placement procedures. Indications were residual stenosis after percutaneous transluminal renal angioplasty in 42 patients, restenosis in 20 patients, and acute dissection in two patients. Follow-up (mean, 14 months) was obtained in 54 patients. Six-month restenosis rates were based on results of arteriography, and even more long-term patency rates were based on duplex ultrasound., Results: Technical success was achieved in all patients. Major complications occurred in two patients. No minor or puncture-site complications were observed. The overall 6-month restenosis rate was 1.6% (2.9% for ostial lesions). Survival analysis with the Kaplan-Meier method showed primary and secondary patency rates of 92% +/- 3.6 and 98% +/- 1.9, respectively, at 1 year and 79% +/- 8.8 and 92% +/- 6.1, respectively, at 2 years. Seventy-six percent of hypertensive patients benefited from the procedure. However, renal function was not improved by stent placement., Conclusion: Stent placement in renal arteries is a useful adjunct to percutaneous transluminal angioplasty for atherosclerotic renal-artery stenoses.

The authors report two cases of spontaneous paroxysmal atrial fibrillation closely followed by syncopal ventricular tachycardia resulting in cardiac arrest requiring defibrillation. Both patients, men aged 62 and 64 years, had a past history of myocardial infarction without arrhythmias; atrial fibrillation occurred during severe myocardial ischaemia; coronary arteriography showed tight stenoses of the left main coronary artery with normal left ventricular function. Ventricular tachycardia (or fibrillation) during spontaneous paroxysmal atrial fibrillation is a rare occurrence. This sequence of events has been described in patients with accessory conduction pathways or in hypertrophic cardiomyopathy. It is an exceptionally rare complication of ischemic heart disease with only a very few previously reported cases. Myocardial ischaemia is probably the cause of the arrhythmia in together with irregularity of the ventricular contractions responsible for long cycle-short cycle sequences which are particularly arrhythmogenic and changes in sympathetic tone.

There are at least three loci involved in Wilms' tumor (WT) tumorigenesis: WT1 in 11p13, WT2 in 11p15.5, and WT3, as yet unmapped. A compilation of cytogenetic data published for 107 WT revealed that deletion of chromosome 16 and duplication of chromosome 12 occur as frequently as the well-documented 11p deletions. Allelic imbalance for chromosomes 16 and 12 was investigated in a series of 28 WT. By use of a large panel of restriction fragment length polymorphisms and (CA)n probes, we demonstrated loss of heterozygosity (LOH) for 16q in seven (25%) of the tumors. The whole length of 16q was involved in six of the tumors. Moreover, consistent with a previous report of 16q13 LOH in a sporadic WT and a constitutional breakpoint with a Beckwith-Wiedemann patient, we map a region of particular interest to between D16S308 and D16S320. The assumption that 16q LOH may be an early event was based on: 1) the detection of 16q LOH in one case of nephroblastomatosis; 2) the presence of a complete (clonal) 16q LOH in a tumor with partial (mosaic) 11p LOH; and 3) 16q LOH as the sole abnormality in one WT. By quantification of chromosome 12 allelic imbalance, we detected duplication in 18% of the total series and in 25% of the sporadic unilateral cases. The common region extended from the centromere to D12S7 in 12q21.1-q23. We also suggest that the various pathogenetically important loci are not equally involved in the different forms of WT and that their sequential involvement may differ.

Purpose: To define the long-term outcome of stent placement in iliac and femoropopliteal arteries., Materials and Methods: Three hundred ten patients received 418 balloon-expandable Palmaz stents. Two hundred thirty stents were implanted in iliac arteries of 184 patients, and 188 stents were implanted in femoropopliteal arteries in 126 patients. Restenosis rates were based on results of angiography performed 4-6 months after stent placement. Long-term patency rates were determined with duplex ultrasound., Results: Immediate procedural success was achieved in 309 patients. Acute thrombosis ( < 24 hours) occurred in five patients, and immediate clinical success in 288. The 30-day mortality and morbidity rates were 0% and 8%, respectively. Angiography performed at 6 months in 299 patients revealed restenosis rates of 0.5% in iliac lesions, 11% in superficial femoral artery (SFA) lesions, and 20% in popliteal lesions. Survival analysis revealed 4-year primary patency rates of 86% +/- 4.1 for iliac artery lesions, 65% +/- 7.5 for SFA lesions, and 50% +/- 17.7 for popliteal artery lesions. Most restenotic lesions were successfully treated with repeat angioplasty., Conclusion: Implantation of Palmaz stents in iliac arteries allows long-term primary patency to be maintained in most patients.

Purpose: In order to assess the role of percutaneous peripheral rotational ablation using Rotablator, 150 symptomatic patients (94 males, 56 females; mean age 73 +/- 1 years, range 42 to 90) having 212 complex peripheral vascular lesions were treated., Methods: Fifty percent of lesions were below the knee; 65% of patients had severe claudication, 11% moderate (24% were in stage III or IV Fontaine classification). The femoral lesions were significantly longer than those at other sites (5.7 +/- 0.4 versus 2.9 +/- 0.3 cm, p < 0.001). The mean length was 4.0 +/- 0.2 cm (range 1 to 20). All the lesions were considered complex; 93% of the lesions were clacified, and 63% were located at a bifurcation. Complementary balloon dilation (percutaneous transluminal angioplasty [PTA]) was significantly (p < 0.001) more frequent in femoropopliteal lesions (70 PTAs in 86 femoral arteries, 10 PTAs in 19 popliteal arteries) than in distal leg lesions (14 in 106 arteries)., Results: After Rotablator therapy alone, the percent stenosis decreased from 81.0% +/- 0.8% to 18.0% +/- 1.1%. The residual stenosis was greater at the femoral (44%) than at the distal level (19%) (p < 0.01). Adjunctive PTA (47 lesions) lowered residual stenosis to 10% at the femoral level and 3% at the distal level. Thirty-seven intraprocedural complications occurred (spasm, thrombosis, dissection, perforation, distal emboli, no reflow); seven procedures subsequently failed for an overall technical success of 97%. The mean follow-up period was 14.4 +/- 1.0 months (range 1 to 51). Among 125 patients having a follow-up period > or = 4 months, 114 patients representing 163 lesions underwent angiography. One hundred twenty-three lesions (76%) were patent, and 40 lesions (24%) showed restenosis (> or = 50% luminal narrowing) of 82.0% +/- 21%. The restenosis rate was higher in femoral (36%) than in distal (21%) or popliteal arteries (7%). Restenosis was more frequent for all lesions > or = 7 cm (p < 0.001) and for both above- and below-knee locations: 55% versus 19% for < 7 cm at the femoropopliteal level (p < 0.03), and 80% versus 18% at the distal level (p < 0.01)., Conclusions: In our experience, percutaneous peripheral rotational ablation has taken a pre-eminent position in the treatment of distal leg arteries, especially in complex lesions. Our results have led us to broaden its indications to complex vascular lesions < or = 6 cm. In particular, the use of this technique for treatment of runoff vessels should improve the long-term patency of proximal PTA and bypass grafts. This device has become indispensable in our laboratory, where Rotablator therapy comprises 15% of all PTA procedures.

Purpose: To evaluate the safety and efficacy of a new covered stent, the Cragg Endopro System 1, for intraluminal treatment of peripheral vascular disease in the iliac and femoropopliteal arteries., Methods: Forty symptomatic patients with predominantly lengthy stenotic (24) or occlusive (13) lesions or aneurysms (3) in the iliac (19), femoral (19), or popliteal (2) arteries were treated percutaneously with balloon angioplasty followed by implantation of the self-expanding nitinol Cragg stent covered by a woven polyester fabric coated with low-molecular-weight heparin. The mean length of femoropopliteal lesions was 13.0 +/- 1.8 cm, as compared to 6.7 +/- 0.8 cm (p < 0.01) for iliac lesions. Mean percent stenosis was 89% +/- 2% with no significant difference between the arterial segments., Results: With a total of 52 covered stents implanted, technical success was achieved in 98% (39/40 patients). One tortuous femoral artery aneurysm was not satisfactorily excluded to prevent leakage. Clinical success was seen in all patients with demonstrable improvements in the claudication stage and the ankle-brachial index from a mean 0.54 to 0.92. Three local complications (one hematoma, two false aneurysms) required surgical repair. One distal embolism, one acute thrombosis, and three subacute thromboses were encountered and successfully treated by thrombolysis and/or surgery. One patient with two iliac stents developed contralateral common iliac artery occlusion from a stent partially obstructing the aorta; placement of a covered stent in the blocked artery re-established normal flow. Over an 8-month follow-up with arteriographic re-examination, all iliac stents remained patent. At the femoropopliteal level, two stents were occluded at 4 months; one was successfully dilated, but the other required surgical bypass grafting. A third patient developed a stenotic lesion proximal to the stent; dilation restored adequate inflow to the stent., Conclusions: The Cragg Endopro System 1 appears to be effective as an "internal bypass" for iliac and femoropopliteal occlusive disease. More complications and restenosis were seen in femoropopliteal implantations; however, a change in postoperative medication may improve these results. Long-term results will determine if the Cragg Endopro System 1 can achieve a patency equal to conventional bypass grafting.

A family with an aggregation of adrenocortical carcinoma, rhabdomyosarcoma, osteosarcoma, and early onset breast cancer was referred to our laboratory. Because this aggregation was reminiscent of Li-Fraumeni syndrome, germ-line mutation of the p53 tumor suppressor gene was sought in the DNA of two affected members. The highly conserved regions spanning exons 5 to 8 of the p53 gene were screened by a previously validated denaturing gradient gel electrophoresis method. A single base pair deletion at codon 215 was detected in constitutional DNA of the two patients, and in the DNA extracted from an adrenocortical carcinoma tumor specimen of the propositus. This deletion is predicted to lead to the formation of a truncated p53 protein, a relatively rare event in Li-Fraumeni families. The spectrum of tumors observed in this family does not differ markedly from the spectrum observed in families with missense p53 mutations.

In order to assess the role of percutaneous peripheral rotational ablation using Rotablator (PPRA), 95 symptomatic patients (58 M, 37 F, m. age: 77 +/- 1 y) (r: 50-90 y) having 146 peripheral vascular lesions (PVL) were treated by PPRA. 59% were below the knee and 41% above. The runoff status (n of distal leg art. involved) was as follows: 3:52 pts, 2:23 pts, 1:14 pts, 0:6 pts. The femoral lesions were significantly longer than those at other sites (5.27 +/- 0.43 vs 2.97 +/- 0.3 cm) (p < 0.001). The mean length was 3.73 +/- 0.26 cm (r: 1-20 cm). Complementary PTA was significantly (p < 0.001) more frequent in femoro-popliteal (32 PTA/48 Fem, 5 PTA/12 Pop) than in distal leg lesions (10/86.). RESULTS. After PPRA alone (99 PVL) the stenosis % decreased from 81 +/- 0.75 to 18 +/- 1.1. The residual stenosis was greater at femoral (26 +/- 2.3%) than at distal leg level (16 +/- 1.2%) (p < 0.01). Complementary PTA (47 PVL) lowered residual stenosis from 44% to 13%. 52 complications (spasm, perforation, dissection, distal emboli, no reflow, others) were cured in 47 PVL. Thus our primary technical success per PVL was 97% and per pt 95%. The mean follow-up period was 11 +/- 1 mths (r: 1-37 m). Among 78 pts having a follow-up period > or = 4 mths, 74 pts representing 115 treated PVL underwent an angiography control (2 deaths, 2 lost for follow-up). 87 lesions (76%) showed no restenosis and 28 lesions (34%) showed restenosis of 83 +/- 2.4% (r: 50-100%). The restenosis rate was higher in femoral (12/21: 36%) than in distal (15/58: 21%) or popliteal arteries (1/8: 12%). Restenosis was more frequent for PVL > or = 7 cm (67% vs 16%) (p < 0.001) at all sites. This result together with the complication rate would seem to indicate that lesions > or = 6.7 cm would be a limitation for PPRA. CONCLUSIONS. In our experience Percutaneous Peripheral Rotational Ablation has taken a pre-eminent position in the treatment of distal leg arteries. Our results lead us to broaden its indications to complex vascular lesions. The possibility of runoff treatment should allow an improvement in the long-term patency of PTA and bypass grafts.

We applied a subtractive hybridization approach to isolate genes differentially expressed between mature kidney and Wilms' tumor. We constructed a complementary DNA library from a total mature kidney complementary DNA subtracted by an excess of mRNA from a Wilms' tumor, WAGR4, with a germline deletion of 11p13 and a somatic loss of alleles at 11p15. Six clones presenting a differential pattern of expression, positive with mRNA from the mature kidney and negative with mRNA from the Wilms' tumor WAGR4, were characterized. Among these clones were two as yet unknown expressed sequences (D11S877E and D15S109E) and four sequences from known genes: renal dipeptidase (DPEP1), alpha B-crystallin (CRYA2), uromodulin (UMOD), and plasma glutathione peroxidase (GPX2). The different patterns of expression of these genes in 11 Wilms' tumors, whether or not they are hereditary, reflect the well-documented pathogenetic heterogeneity for Wilms' tumors. We propose that these clones could be helpful for an improved histological characterization of Wilms' tumors.

The combined use of qualitative and quantitative analysis of 11p13 polymorphic markers together with chromosomal in situ suppression hybridization (CISS) with biotin labeled probes mapping to 11p allowed us to characterize a complex rearrangement segregating in a family. We detected a pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in the family: an insertion of brand 11p13-p14 carrying the genes for predisposition to Wilms' tumor, WT1, and for aniridia, AN2, into the long arm of chromosome 11 in 11q13-q14. Asymptomatic balanced carriers were observed over three generations. Classical cytogenetics had failed to detect this anomaly in the balanced carriers, who were first considered to be somatic mosaics for del(11)(p13). Two of these women gave birth to children carrying a deleted chromosome 11, most likely resulting from the loss of the 11p13 band inserted in 11q. Although in both cases the deletion encompassed exactly the same maternally inherited markers, there was a wide variation in clinical expression. One child, with the karyotype 46,XY, del(11)(p13p14), presented the full-blown WAGR syndrome with aniridia, mental retardation, Wilms' tumor, and pseudohermaphroditism, but also had proteinuria and glomerular sclerosis reminiscent of Drash syndrome. In contrast, the other one, a girl with the karyotype 46,XX,del(11)(p13), only had aniridia. Although a specific set of mutational sites has been observed in Drash patients, these findings suggest that the loss of one copy of the WT1 gene can result in similar genital and kidney abnormalities.

The percutaneous common femoral arterial approach is usually used for endovascular management of lower limb arterial disease. This approach is sometimes impracticable because the femoral artery is the site of severe calcific atheromatous lesions which prevent arterial puncture or, when the superficial femoral lesions are ostial or proximal, make it impossible to position the introducer and advance the guide wire. The popliteal artery then becomes very useful for treating these lesions by a retrograde approach. Similarly, superficial femoral lesions which cannot be successfully dilated by the anterograde femoral approach may justify retrograde catheterisation via the popliteal artery. Between May 1988 and August 1991, the authors used the retrograde popliteal approach in 30 cases. They obtained 24 successes, 12 of which were associated with the implantation of an endoprosthesis. There was 1 complication at the puncture site a popliteal arteriovenous fistula was created but was treated successfully by surgery.

Genomic imprinting has been implicated in the aetiology of an overgrowth cancer-prone syndrome, the Wiedemann-Beck-with syndrome (WBS). We have demonstrated uniparental disomy (UPD) for paternal chromosome 11p markers in 5 out of 25 sporadic cases (20%). Delineation of the extent of the disomy region may help in understanding the mechanism and the stage, meiotic or mitotic, of disomy formation in this disease and in associated tumours. Our current studies in WBS patients with seventeen 11p and one 11q markers reveal paternal isodisomy, not heterodisomy, in the five cases. For one case we demonstrate unambiguously that partial isodisomy for 11p and somatic mosaicism for UPD resulted from a post-fertilization event. The restriction of isodisomy to part of 11p in another case, and somatic mosaicism for UPD in three other cases, suggest a mitotic recombinational event that must have occurred after fertilization. Mosaic phenotypes reflect the timing of their origin and the fate of the cells involved, as well as the cell-specific pattern of imprinting. Somatic mosaicism for UPD in four cases may thus explain the incomplete forms of WBS. The association of hemihypertrophy in sporadic WBS and even some cases of isolated hemihypertrophy. This is in agreement with a recent report of paternal isodisomy for 11p markers in a patient with hemihypertrophy, Wilms' tumour and adrenocortical carcinoma. Moreover, the risk of developing a tumour seems higher (50%) for patients with paternal 11p UPD than for WBS patients in general (7.5%).

Specific tumor-associated rearrangements involving the regions 11p13 and 11p15 have been extensively documented. However, cytogenetic definition of the breakpoints occurring at the boundaries of these two regions was not precise enough to correlate with the molecular data. Using probes corresponding to the genes coding for MYOD1, CTSD, LDHA, and RBTN1 and to the anonymous sequence D11S776, we have reassessed the breakpoints of three hybrids (J1.10, BID7, and NYX3.1) and confirmed the localization or more precisely mapped these four genes and the anonymous DNA marker on different subregions of 11pter-->p13, including the smallest region of 11p15.5 duplicated in a patient with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is often associated with embryonal tumours (nephroblastoma, adrenocortical carcinoma, hepatoblastoma, and rhabdomyosarcoma). Several pedigrees have been reported strongly suggesting autosomal dominant inheritance and an excess of transmitting females was noticed in these families. We confirmed this excess using 19 published pedigrees and showed that this excess was for two reasons: first, reduced fecundity in affected males compared to females in a ratio of 1:4.6, and, second, a smaller risk of being affected in a ratio of 1:3 for subjects having inherited the gene from their father. These latter findings suggest genomic imprinting. Furthermore, considering these results together with other observations, such as the parental origin of the 15p15.5 duplication and the existence of uniparental disomy in some sporadic cases, we propose that overgrowth in BWS patients and malignant proliferation in associated tumours reflect an imbalance between paternal and maternal alleles.

The 11p15.5 region of human chromosome 11 seems to contain a locus or loci involved in congenital overgrowth anomalies as well as in the genesis of many tumours associated with the Beckwith-Wiedemann syndrome (BWS). Given the unusual differential parental allele involvement in the different aetiological forms of BWS and the loss of maternal alleles in associated tumours, we have now used 11p15.5 markers to determine the parental origin of chromosome 11 in eight sporadic cases of BWS. Probands in three informative families had uniparental paternal disomy for region 11p15.5. Further, an overall greatly increased frequency of homozygosity for several 11p15.5 markers in 21 sporadic BWS patients suggests that isodisomy probably accounts for an even higher proportion of BWS sporadic cases. This demonstrates that uniparental paternal disomy can be associated with a genetic cancer-predisposing syndrome.

The chromosomal assignment of genes responsible for malformation syndromes associated with increased susceptibility to malignancy could be determined owing to specific constitutional chromosomal abnormalities or to family studies. For certain types of tumors, somatic chromosomal rearrangements (loss of alleles) occur at the same locus indicating the presence of a recessive suppressor gene or an antioncogène. For other types of tumors chromosomal rearrangements involving regions different from the locus for predisposition suggest genetic heterogeneity and/or implication of genes for tumor progression. These genes which are also involved in development and regulation of differentiation and cell growth, may undergo a differential genomic imprinting.

The human gene encoding the myogenic determination factor myf3 (mouse MyoD1) has been mapped to the short arm of chromosome 11. Analysis of several somatic cell hybrids containing various derivatives with deletions or translocations revealed that the human MyoD (MYF3) gene is not associated with the WAGR locus at chromosomal band 11p13 nor with the loss of the heterozygosity region at 11p15.5 related to the Beckwith-Wiedemann syndrome. Subregional mapping by in situ hybridization with an myf3 specific probe shows that the gene resides at the chromosomal band 11p14, possibly at 11p14.3.

Loss of heterozygosity for 11p markers and preferential loss of maternal alleles have been described in Wilms tumor. In this report we describe the molecular characterization of the constitutional and somatic 11p rearrangements in a del(11p13) WAGR patient with Wilms tumor. Both rearrangements led to loss of maternal alleles for two different regions of 11p, namely, 11p13 and 11p14----p15. This result clearly suggests that Knudson's hypothesis of two hits at the same locus does not necessarily apply to Wilms tumor. Moreover, the loss of 11p15 maternal alleles in the tumor is not incompatible with maternal inheritance of predisposition at 11p13. The putative roles of these two loci are discussed.

Several studies support that retinoblastoma originates from a primitive neuroectodermal cell, the main argument being the expression of the neuron-specific enolase (NSE) by the retinoblastic cells. NSE was measured in the aqueous humor taken off: 1) in 19 patients with various eye disorders for which the diagnosis of retinoblastoma was definitely excluded (NSE = 5.0 +/- 7.7 micrograms/l); 2) at the time of the enucleation, in 7 cases of proved retinoblastoma (NSE = 83 to 17,900 micrograms/l); 3) in 2 cases of retinoblastoma held as cured for more than 5 years (NSE = 2.8 and 8.7 micrograms/l). The high level of NSE in the aqueous humor of the subjects with retinoblastoma is very significant, so that it can play a great part in the diagnosis, particularly in the case of atypic tumors. Specific indications of this determination may be considered for the survey of tumors under treatment or of the controlateral eye after a first tumor.

We have compared constitutional and tumor genotypes in nine cases of hereditary Wilms tumor (WT) and in three unrelated cases of familial adrenocortical carcinoma (ADCC). Since susceptibility to these tumors can be observed in malformation syndromes associated with a constitutional deletion of band 11p13 (WT) and with a constitutional duplication of band 11p15.5 (WT, ADCC), we investigated these two candidate regions by using 11p polymorphic markers. As expected, somatic chromosomal events, resulting in a loss of heterozygosity limited to region 11p15.5, were observed in the tumor of two familial cases of adrenocortical carcinoma. Surprisingly, however, analysis of the WT of two patients with a constitutional deletion of band 11p13, associated with aniridia, genitourinary abnormalities, and mental retardation (WAGR syndrome), revealed a loss of heterozygosity limited to region 11p15.5. These data therefore suggest that observation of a specific loss of heterozygosity may not necessarily point to the site of the initial germinal mutation. Together with previous similar observations of a loss of heterozygosity limited to 11p15.5 in breast cancer and in rhabdomyosarcoma, our data suggest that region 11p15.5 may carry a non-tissue-specific gene that could be involved in genetic predisposition, in tumor progression, or in both.

We have used a cDNA clone for Chinese hamster 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase to isolate a genomic recombinant for human HMG-CoA reductase. The identity of the gene was confirmed by partial sequence analysis. Several unique fragments that will be useful for restriction fragment length polymorphism (RFLP) studies were identified. In situ hybridisation of a 2.6 kb unique fragment of the gene to human metaphase chromosomes localised the human HMGCoA reductase gene to human chromosome 5q12.

A recombinant probe specific for the pro alpha 2 chain of human Type V collagen has been used for the localization of the corresponding gene (COL5A2) to chromosome 2. Regional mapping by in situ hybridization and analysis of DNA from human X rodent cell lines indicated that COL5A2 is confined within the segment 2q14----2q32, thus syntenic to the pro alpha 1 (III) collagen gene (COL3A1).

We used a cloned cDNA probe for the B subunit of human aldolase (ALDB) and Southern blotting techniques to analyse DNA from a series of rodent X human somatic cell hybrids for the presence of specific ALDB-related sequences. Our results provide evidence for the assignment of the gene for ALDB to chromosome 9. Moreover, by direct gene dosage determination in two patients with chromosome 9 unbalanced rearrangements and by in situ hybridization we refined the regional chromosomal assignment to 9q13----q32 and most probably to 9q21.3----9q22.2.

Type XI collagen is a minor and poorly characterized structural component of cartilage. Recently, cDNA and genomic clones coding for the pro alpha 1 chain of human Type XI collagen, formerly 1 alpha collagen, have been isolated and fully characterized. Here we have used one such probe to establish the chromosomal localization of the pro alpha 1 (XI) collagen gene (COL11A1) by hybridization to filter-bound DNA isolated from flow-sorted chromosomes and by in situ hybridization on metaphase chromosomes. This combination of approaches has enabled us to locate COL1A11 in the p21 region of chromosome 1. This represents the first mapping of a Type XI collagen gene and the first assignment of a collagen locus to chromosome 1. These studies also provide additional evidence for the nearly uniform dispersion of the human fibrillar collagen genes in the human genome.

A 1.1-kb cDNA clone for human 2,3-bisphosphoglycerate mutase (BPGM) (EC 2.7.5.4) was used to map the structural gene to metaphase chromosomes. In situ hybridization experiments localized the human BPGM gene to chromosome 7 and, more precisely, to region 7q34----7q22.

We have used a cDNA clone for human lecithin:cholesterol acyl transferase (LCAT) and Southern blotting techniques to identify the human LCAT gene in DNA from a series of rodent X human somatic cell hybrids. Our results are compatible with the location of the gene on human chromosome 16, and this has been confirmed using in situ hybridization of the LCAT cDNA to human metaphase chromosomes. These results confirm the earlier studies on LCAT-deficient patients, indicating that the structural gene for LCAT is on human chromosome 16q22.

We used cloned cDNA probes for the A alpha-, B beta-, and gamma-chains of human fibrinogen and Southern blotting techniques to analyze DNA from a series of rodent X human somatic cell hybrids for the presence of specific fibrinogen-related sequences. Our results provide evidence for the assignment of the three genes for fibrinogen to chromosome 4. Moreover, by direct gene-dosage determination in two patients with chromosome 4 unbalanced rearrangements, we refined the regional chromosomal assignment to 4q2, thus suggesting that these three genes whose expression is coordinately regulated are closely linked.

A few cases of Beckwith-Wiedemann syndrome (BWS) have in common a duplication of 11p15. Among the genes located in 11p15, c-Ha-ras 1 (HRAS1), insulin (INS), and insulin-like growth factor II (IGF2) may account for the clinical features and the increased risk for malignancy. Using eight 11p15 markers including HRAS1, INS and IGF2 we have studied eight sporadic and hereditary cases of BWS whether or not associated with a nephroblastoma. By gene dosage determination and family studies, we have shown the following: the eight patients examined had an apparent diploid representation of all of the eight markers studied, thus indicating that a microduplication of these markers or of the region characterized by these markers is not a common event in BWS; in a family with three affected sibs the genes for HRAS1 and INS/IGF2 did not cosegregate with BWS and therefore may not participate in the pathogenic processes here observed.

We have synthesised a mixed oligonucleotide 17 bases long and used it to isolate cDNA clones for apolipoprotein CI (apo CI) from an adult liver cDNA library. The partial sequence of one of these clones confirms its identity. We have used this probe and Southern blotting techniques to identify the human apo CI gene in DNA from a series of rodent X human somatic cell hybrids. Our results provide evidence for the assignment of this gene to human chromosome 19.

A cytogenetic study performed on 6 human renal cell carcinomas after short-term culture on extracellular matrix with serum-free medium showed aneuploidy without structural changes in 2 tumors and a rearrangement of the short arm of chromosome 3 in 4 tumors, including deletions and a translocation involving the 3p14 and 3p21 bands. Chromosomal in situ hybridization with a c-raf 1 probe demonstrated that in 2 renal cancers with del3(p14 or 21) the cellular oncogene had shifted from 3p25 to 3p14 as a result of an interstitial deletion.

The short arm of chromosome 11 carries genes involved in malformation syndromes, including the aniridia/genitourinary abnormalities/mental retardation (WAGR) syndrome and the Beckwith-Wiedemann syndrome, both of which are associated with an increased risk of childhood malignancy. Evidence comes from constitutional chromosomal aberrations and from losses of heterozygosity, limited to tumor cells, involving regions 11p13 and 11p15. In order to map the genes involved more precisely, we have fused a mouse cell line with cell lines from patients with constitutional deletions or translocations. Characterization of somatic cell hybrids with 11p-specific DNA markers has allowed us to subdivide the short arm into 11 subregions, 7 of which belong to band 11p13. We have thus defined the smallest region of overlap for the Wilms' tumor locus bracketed by the closest proximal and distal breakpoints in two of these hybrids. The region associated with the Beckwith-Wiedemann syndrome spans the region flanked by two 11p15.5 markers, HRAS1 and HBB. These hybrids also represent useful tools for mapping new markers to this region of the human genome.

To define more precisely, in molecular terms, the region involved in Beckwith-Wiedemann syndrome (BWS), we have studied patients with BWS and a constitutional duplication of 11p15 using eight 11p15 markers. In the first case with a de novo duplication and extra material on 11p, the region spanning pter to CALCA, excluded, was duplicated. In the second case, the rearrangement was characterized using somatic cell hybrids established with lymphocytes from the father who carried a balanced translocation t(11;18)(p15.4;p11.1). The breakpoint lay exactly in the same region. It could thus be inferred that the two sons, who were the first cases reported of BWS with dup11p15 and adrenocortical carcinoma (ADCC), carried a duplication similar to that observed in the first case. Together with evidence for specific somatic chromosomal events leading to loss of 11p15 alleles in familial cases of ADCC, it can be hypothesized that a gene involved in predisposition to ADCC maps to region 11p15.5.