Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.

BACKGROUND: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. PATIENTS AND METHODS: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. RESULTS: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. CONCLUSIONS: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.

Clinical characteristics and outcome of patients over 60 years with Hodgkin lymphoma treated in Switzerland.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

Cervical vertebrae maturation: a blinded trial study.

This blinded trial was conducted to analyze possible correlations between the cervical vertebrae maturation method (CVM) and the mineralization of mandibular teeth as described by Demirjian et al. (TMS). Panoramic and cephalometric radiographs of 500 orthodontic patients were analyzed by two blinded operators. TMS was utilized to analyze mineralization of second molar, second and first premolar and canine on the left side of the mandible; CVM stage was also evaluated. A blinded statistician performed statistical correlations and multiple regression analysis. Significant relations between CVM and TMS stages were identified for each tooth. Significant age differences resulted for CVM, second molar and second premolar (p<0.05). Significant correlations for second molar were observed between TMS D and CVM I-II, TMS G and CVM III, TMS H and CVM V-VI (p less than 0.01). Second molar stage G for both sexes indicates the ongoing of growth spurt. Stage G for boys and stage H for girls correlate significantly with the late part of PGS.

Is static friction affected by aging and amount of elastomeric ligatures in orthodontic sliding mechanics? An in-vitro investigation.

In straight-wire mechanics, friction can significantly influence the forces expressed by wires. The aim of this study is to assess whether the aging and the sum of elastomeric ligatures affect the static friction during orthodontic space closure. A 0.017x 0.025-in SS was drawn throughout a 3-bracket experimental model and engaged with elastomeric ligatures. Before performing the test, the ligatures were soaked in artificial saliva for 48 hours (Group 1), 2 weeks (Group 2) and 4 weeks (Group 3); brand-new ligatures were also tested as control group (Group 4). The resistance to sliding (RS) was recorded at 3 different numerical configurations of ligatures using a customized testing machine and tests were repeated for ten times. Data of RS were statistically analysed by using two way analysis of variance (ANOVA) and Tukey's multiple comparison tests. RS was found to increase systematically when more elastomeric ligatures were included in the wire engaging system. At two weeks of immersion in artificial saliva elastomeric ligatures showed the lowest values of RS while they became significantly more frictional after immersion for 4 weeks. The results of this study showed that in multi-bracket orthodontic therapy, the RS increases with the number of elastomeric ligatures involved for arch-wire engagement. Differently from the frictional behavior of elastomeric modules, the aging of these ligatures does not influence their incremental effect of frictional forces.

Glutathionyl-hemoglobin levels in carotid endarterectomy: a pilot study on 12 cases clinically uneventful.

Aim: Carotid endarterectomy is a widely accepted procedure for stroke prevention, and carotid clamping is a necessary surgical step. Glutathionylated haemoglobin (HbSSG) has been recently employed as a biomarker of oxidative stress, its level being increased under several conditions, including hypoxia. This study aims to evaluating whether HbSSG level in peripheral and/or jugular blood is affected during carotid surgery under normal routine operative conditions. Methods: This study enrolled 13 consecutive patients undergoing elective carotid endarterectomy under general anesthesia. At different times during surgery, blood was taken simultaneously from both a peripheral vein and the jugular vein ipsilateral to the clamped carotid. HbSSG was measured in RBC hemolysates by MALDI-ToF mass spectrometry in each sample. Results: Three patients showed a complex pattern of rise and fall of HbSSG levels in different time periods before, during and after surgery. They also showed statistically significant differences between peripheral and jugular blood, with mean HbSSG levels in jugular blood higher by approx. 30% than those of peripheral blood at the end of the period of carotid clamping. In all three patients HbSSG levels fell to pre-clamping values within 2 min from removal of carotid artery clamp. Conclusion: Although effective routine drug management allowed brain safety during carotid clamping time, a number of patients showed a fast modification over time of the HbSSG levels in jugular blood, suggesting that "resident" cerebral biochemical protection mechanisms could play some role to compensate clinically silent brain oxidative stress.

How to assess appearance distress and motivation in plastic surgery candidates: Italian validation of Derriford Appearance Scale 59 (DAS 59).

OBJECTIVE: The Derriford Appearance Scale (DAS) 59 was specifically designed to measure psychosocial adjustment in patients with appearance problems. Previous studies using the DAS59 have proven it to be a reliable method of assessing the appearance-related quality of life after plastic surgery procedures. The aim of this study was to develop a valid and reliable Italian version of the DAS59. PATIENTS AND METHODS: The first Italian translation of this questionnaire was conducted according to the DAS59 protocol that was designed by the original authors of the questionnaire. Eight hundred patients participated in this study and filled out three questionnaires (DAS59, General Health Questionnaire (GHQ)12 and Beck's Depression Inventory (BDI)-II). There were 400 adult patients with a history of previous plastic surgeries and 400 adult patients without any personal history of previous plastic surgery procedures. A total of 50 patients were selected randomly for test-retest analysis. RESULTS: The overall internal consistency was excellent (α = 0.95) and equal to that of the original article that first described the scale. There was a good correlation between all the items. Domains demonstrated good internal consistency (Cronbach's alpha) and correlation within themselves. The construct validity of the Italian DAS59 was assessed under convergent validity that confirmed the correlation with scales related to other psychological conditions. GHQ12 showed relevant correlation with DAS59, while BDI-II did not. CONCLUSIONS: A valid and reliable Italian DAS59 version was developed that can be used for research and clinical assessment of patients with appearance problems and concerns, especially before and after plastic surgery procedures.

Necessity of therapy for post-thyroidectomy hypocalcaemia: a multi-centre experience.

PURPOSE: Hypoparathyroidism is one of the most common and most feared complications of total thyroidectomy (TT). The aim of this study is to detect possible markers that may facilitate early tracing of hypocalcaemia-prone patients in order to reduce clinical cost by optimizing patient discharge and to avoid unnecessary treatment. METHODS: Over an 18-month period, 995 patients, 23 % male and 77 % female, aged 52.9 ± 13.4 years, underwent TT in ten Lombardy hospitals. The following parameters were analyzed: calcaemia before and 12-24 and 48 h after surgery, pre- and post-operative parathyroid hormone (PTH) at 24 h and pre-operative 25OH vitamin D. RESULTS: Mortality was nil and morbidity was 22.4 %. Mean 24-h calcaemia and PTH were 2.17 ± 0.15 mmol/l and 31.81 ± 20.35 pg/ml, respectively; mean 24-h PTH decay was 36.7 ± 34.12 %. Four hundred seventy-three (47.5 %) patients were hypocalcaemic at discharge; 142 of whom had transient hypoparathyroidism that became permanent in 27. Patients developing hypocalcaemia had significantly higher values of PTH and calcium decay. At multiple logistic regression, only 24-h calcium decay, PTH drop and the presence of symptoms and parathyroid auto-grafting were significantly related to hypoparathyroidism. The association of these factors had a 99.2 % negative predictive value (NPV) for the development of hypoparathyroidism. A 70 % PTH drop had a 93.75 NPV for transient hypoparathyroidism. A 12 % calcaemia decay had a 95.7 NPV for hypoparathyroidism. CONCLUSIONS: Hypocalcaemic asymptomatic patients with less than 70 % PTH and 12 % calcaemia decay may be safely discharged without treatment. Symptomatic patients and those with parathyroid grafting should receive calcium and vitamin D.

[Aware and cooperative reduction]. / Riduzione consapevole e cooperante.

The aim of this work is to address the question of reduction in the scientific method, to evaluate its legitimacy as well as its pro and contra from an epistemological point of view. In the first paragraph we classify some kinds of reductionism, analysing their presuppositions and epistemological status and showing some examples of scientific reduction. The presentation includes a classificatory table that shows some of the different forms of biological reductionism. In the second paragraph we study the epistemology of science starting from its modern beginning: the Vienna Circle, focusing on the meaning of methodological reductionism. What did it mean for science to define itself mainly as method, which effects did this new concept of science have on methodology and what kind of problems did this movement bring about. In the third paragraph we examine the reactions triggered by methodological reductionism, we analyze the theoretical consistency of these answers, trying to offer a balanced view. We show how complexity can be seen as a paradigm of the anti-reductionism effort, and we study its epistemological basis. In the fourth paragraph we outline our operative proposal: the reduction that is both aware and cooperative. We point out the main reasons why science cannot avoid being reductive in some way, and therefore how we need to deal with this feature in order to prevent it to degenerate into reductionism. We show some examples of this new proposal taken from the practical realm and from literature, where it is possible to discern the spirit of this alternative methodology.

Acute thrombosis of abdominal aorta and hypercoagulable disorders.

Acute abdominal aortic occlusion (AAAO) is a rare, life threatening condition, which usually occurs in elderly patients, causing challenging management issues. In patients who have no cardiac or vascular disease this catastrophic event is very rare and is due to hypercoagulable disorders. This study reviews the literature on AAAO in hypercoagulable states in the light of our experience on a case of an acute thrombosis of nonaneurysmal, nonatherosclerotic abdominal aorta in a female patient with protein S deficiency and Sjögren's syndrome and her younger brother, which was found to have atherosclerotic involvement of distal aorta and elevation in homocysteine levels. Because of a misleading clinical presentation, the diagnosis was delayed and conservative treatment failed. Both were successfully treated with emergency aorto-bifemoral grafting. Other cases of arterial thrombosis and hypercoagulable disorders were found in first-degree relatives. Our experience and the review of the literature suggest that the interaction between host and environment factors can lead to acute thrombosis of the non-pathologic abdominal aorta; not only classic hypercoagulability disorders, but also immunologic, metabolic, toxicological cofactors can be involved. Delay in diagnosis is frequent and may not influence the prognosis, but does not allow conservative therapy. Prognosis depends mainly on pathologic cofactors that require detection and appropriate treatment in order to prevent complications and recurrences.

Common carotid artery pseudoaneurysm after neck dissection: colour Doppler ultrasound and multidetector computed tomography findings.

Common carotid artery pseudoaneurysm is a rare disease, which has been previously unreported in association with neck dissection. We describe the Doppler ultrasound and multidetector computed tomography (CT) findings of a case of carotid pseudoaneurysm, one month after pharyngolaryngectomy with bilateral neck dissection. Multidetector CT confirmed the diagnosis made on the basis of Doppler ultrasound; the high image quality of axial and three-dimensional reconstructions avoided the need for pre-operative conventional angiography. In the presence of a pulsatile cervical mass after neck surgery, pseudoaneurysm of the carotid artery should be included in the differential diagnosis, and multidetector CT can be the sole pre-operative diagnostic imaging modality.

Hypercholesterolaemia is not associated with early atherosclerotic lesions in primary biliary cirrhosis.

BACKGROUND: Hypercholesterolaemia often occurs in primary biliary cirrhosis (PBC) as a result of chronic cholestasis, but whether these patients are exposed to greater cardiovascular risk is unknown. AIM: To establish whether hypercholesterolaemia is associated with subclinical atherosclerosis in PBC. PATIENTS: 103 consecutive patients with PBC (37 with total cholesterol > or =6.21 mmol/l) and 37 controls with hypercholesterolaemia, and 141 matched controls with normocholesterolaemia. METHODS: Ultrasound imaging of carotid artery to determine intima-media thickness (IMT) and stenosis. RESULTS: Controls with hypercholesterolaemia had higher IMT and prevalence of carotid stenosis compared with patients with hypercholesterolaemic PBC (mean (SD) 0.850 (0.292) mm v 0.616 (0.137) mm, p(c)<0.001; 43% v 19%, p(c) = 0.129) who, in turn, were similar to the 66 patients with normocholesterolaemic PBC (0.600 (0.136) mm; 5%). Compared with subjects with normocholesterolaemia, controls with hypercholesterolaemia, but not patients with hypercholesterolaemic PBC, had an increased risk of raised IMT (odds ratio (OR) 5.4, 95% confidence interval (CI) 2.5 to 11.9, p<0.001; and 0.7, 0.3 to 2.0, p = 0.543) or carotid stenosis (8.2, 3.4 to 20, p<0.001; and 2.5, 0.9 to 6.9, p = 0.075). In PBC, compared with younger patients without hypertension, the risk of increased IMT was OR (CI) 3.1 (0.6 to 17; p = 0.192) in patients with hypertension or old age, but not hypercholesterolaemia, and 4.6 (0.8 to 27; p = 0.096) in patients who also had hypercholesterolaemia. The corresponding figures for risk of stenosis were 3.6 (0.4 to 36; p = 0.277) and 15.8 (1.8 to 141; p = 0.014). CONCLUSIONS: Hypercholesterolaemia is not consistently associated with subclinical atherosclerosis in PBC, but should be treated if other risk factors for cardiovascular disease are also present. The search for factors that may protect patients with hypercholesterolaemic PBC against atherosclerosis should be encouraged.

Ser128Arg gene polymorphism for E-selectin and severity of atherosclerotic arterial disease.

AIM: Genetic factors appear to be important in the pathogenesis of cardiovascular and cerebrovascular disease. Adhesion molecules like the members of the selectin family participate in the interaction between leukocytes and the endothelium. They are also involved in the pathogenesis of the atherosclerotic process. In E-selectin, exchange from serine to arginine (position 128, S128R) is correlated with early atherosclerosis. The aim of this study was to assess E-selectin Ser128Arg polymorphism in subjects with clinical and instrumental evidence of atherosclerosis and to analyze the correlations with clinical severity. METHODS: A total of 144 subjects (100 men and 44 women, mean age 72 years, range 48-78) with atherosclerotic disease in different vascular sites documented by angiography were studied; 138 volunteers were recruited as a control group. Whole blood was collected; DNA was extracted with a commercial kit and amplified with 2 primers. The PCR was performed by standard procedure. To assess the disease severity all patients were classified by an arbitrary clinical and angiographic score scale. RESULTS: The genotype distribution between patients and controls was different, although statistical significance was not achieved (p=0.06). In patients a significant difference in Arg allele frequency was observed between mild and severe atherosclerotic disease (OR 2.28; 95% CI 1.15-4.52; p=0.017). Four ho-mozygous cases for S128R were found in patients, none in controls. All these 4 patients had the highest severity score, that means a more severe atherosclerotic disease. CONCLUSION: Our study suggests that the E-selectin polymorphism may be associated with severity of atherosclerotic disease, but does not allow us to conclude that it is actually a risk factor for atherosclerosis.

Multidetector helical angio CT oblique reconstructions orthogonal to internal carotid artery for preoperative evaluation of stenosis. A prospective study of comparison with color Doppler US, digital subtraction angiography and intraoperative data.

AIM: The recent introduction to clinical practice of multidetector helical angio CT (MHACT) has generated a new interest in the diagnosis of carotid artery atherosclerosis. In recent years there has been a redefinition of the indications to carotid artery endarterectomy; there is a tendency to appraise plaque morphology and composition, and not only stenosis degree. The aim of this prospective study is to analyze the validity of MHACT in the diagnosis of atheromasic stenosis of the carotid bifurcation, in comparison with US color Doppler (USCD), digital subtraction angiography (DSA) and intraoperative evidence (OP). Special emphasis is given to the analysis of plaque composition and to precise evaluation of the stenosis percentage computed as an area rate on oblique reconstructions performed exactly orthogonal to the axis of the vessel at the point of maximal stenosis. METHODS: Twenty-seven carotid stenosis (in 24 patients) were preoperatively evaluated by USCD, MHACT, DSA. We calculated the stenosis degree with USCD, by the ECST method, both as a diameter rate and as a bidimensional value. By MHACT we computed the percentage of stenosis as an area rate, in an MPR oblique plane orthogonal to the vessel axis, at the point of maximal stenosis; by DSA we used NASCET and the common carotid artery method (CC). DSA measurements have been mathematically converted as area rate (NASCET2 and CC2). All the patients were operated on with the eversion technique (EEA); it was always possible to obtain an intact cylindrical specimen of the plaque and to perform a reliable and accurate evaluation of the degree of stenosis by sectioning and measuring it on the desk. We gave a score to the presence and amount of lipid and calcium components, and these data were compared to those obtained with the different diagnostic instruments. RESULTS: Statistical analysis of the 7 data sets showed an important underestimate of the angiographical method (DSA), even if the measurements were carried on by a precision caliper. The mathematical conversion of a linear stenosis rate into an area rate gives these values more reliability, indicating, as for NASCET2, non statistically significant differences when compared to surgical evidence, notwithstanding a high standard deviation. The rates obtained by USCD (area rate) and MHACT proved to be very accurate with respect to surgical evidence. In this study there was no significant difference in the detection of various components (lipid and calcium) of the atheromasic lesion, by MHACT and surgical evidence (OP). CONCLUSION: MHACT promises to be a very accurate instrument in the detection of plaque components and identification of the stenosis degree. It shows some limits in very calcific lesions and occasionally, in relevant cardiac failure, may be useless. Hence one feels the need to reassess the role of DSA, once considered the "gold standard", with more extensive prospective studies, including comparison with MHACT and USCD.

Combined surgical approach for carotid and coronary stenosis. Sixty-four patients and review of literature.

BACKGROUND: The proper role of combined carotid endarterectomy (CEA) and coronary bypass (CABG) is still controversial. We contribute to the discussion through the critical evaluation of 64 consecutive patients, whose data have been collected in a prospective way. METHODS: Between 1990 and 1999, 64 patients presenting a critical coronary disease (unemendable by PTA) associated with severe carotid stenosis (= or >70% if symptomatic, = or >80% if asymptomatic), underwent combined CEA-CABG. Cardiological symptoms were evident in 90.6% of cases. Thirty-five patients (54.7%) had a three-vessel coronaropathy, 18 (28.1%) a two-vessel disease and 11 (17.2%) severe stenosis of the common trunk; furthermore 7 patients (10.9%) had a low ejection fraction (<50%). A positive neurologic history was present in 22 (44%) patients. Thirty-four patients (55%) had a carotid stenosis >90%; a significant disease of the contralateral carotid axis was observed in 53% of cases: stenosis >50% in 30 patients and thrombosis in 4. CEA was performed with somato-sensorial evoked potential monitoring. RESULTS: The hospital mortality rate was 6.2% (4 patients). The cause of death was cardiac in 2 cases (1 early bypass thrombosis and 1 irreversible coronary spasm) and related to a multiorgan failure in 2. The neurologic morbidity rate was 0%. CONCLUSIONS: Our data highlight that in these high-risk patients the combined approach dramatically reduces the stroke risk although the mortality rate is still higher than that observed after CEA or CABG.

Temporary spinal cord stimulation for peripheral cholesterol embolism.

Cholesterol embolism is often an unrecognized complication of some cardiac and vascular procedures (i.e. coronarography, angioplasty, aortocoronary bypass, abdominal aortic aneurysmectomy) and of therapies affecting coagulation (thrombolysis, anticoagulation). The degree of pain associated with ischaemic and necrotic lesions secondary to cholesterol embolism involving the lower limbs is disproportionate to the extension of tissue involvement. Spinal cord stimulation (SCS) has been recognized as effective in relief of pain of ischaemic and neuropathic nature, although its mechanism of action is still not completely clear. The authors are unaware of previous reports of peripheral cholesterol embolism treated by SCS. Two case reports of inferior limb ischaemia secondary to cholesterol embolism in patients who had undergone cardiac invasive procedures. Temporary surgical implantation of SCS devices, which were removed after 4 to 6 weeks. Pain relief was achieved within 1 to 4 hours of surgical procedure. Any analgesic medications could be immediately discontinued. Pain control was effective and normal daily activities were rapidly regained. Ischaemic lesions healed within 4 to 6 weeks of SCS. Pain control is the most critical aspect of the management of peripheral cholesterol embolism without visceral organ involvement. SCS provided effective pain relief in the reported cases and its established ability to improve peripheral microcirculation allowed rapid resolution of necrotic lesions. Temporary SCS should be considered in the management of painful necrotic skin lesions secondary to iatrogenic cholesterol embolism.

Multigenerational familial medullary thyroid cancer (FMTC): evidence for FMTC phenocopies and association with papillary thyroid cancer.

BACKGROUND: Occurrence in a familial setting is well established for medullary thyroid carcinoma (MTC) and has been more recently reported for papillary thyroid cancer (PTC). Germline mutations or rearrangements of the RET proto-oncogene are the genetic background of the majority of hereditary MTCs and of about 25-40% of PTCs. PATIENTS: A large multigenerational familial medullary thyroid cancer (FMTC) family, comprised of four generations and a total of 60 subjects, has been fully evaluated. Studies on germline RET mutations and polymorphisms, on somatic RET activation and on haplotyping with RET-linked markers, were performed. RESULTS: RET mutational analysis revealed a rare missense point mutation in exon 15 of RET (A891S), associated with FMTC. Haplotype analysis showed a co-segregation between the allelic variant 5 of D10S578 marker (which is tightly linked to the RET locus) and the RET mutation. Two patients, from different branches of the family, did not harbour the point mutation A891S despite histological confirmation of MTC. In these cases, haplotype analysis excluded the involvement of the RET gene itself in the pathogenesis of the MTC. In three patients, the coexistence, in different foci, of medullary and papillary thyroid cancer was documented. The genetic studies did not show ret/PTC rearrangements. The microsatellite analysis excluded co-segregation of RET locus with the MTC/PTC phenotype. CONCLUSIONS: We report a full clinical and molecular analysis of a large FMTC kindred with an uncommon RET mutation. In two family members, phenotype and genotype were not concordant, representing the first evidence of FMTC phenocopies. Furthermore, the association of familial forms of medullary and papillary thyroid cancers has been found in 30% of patients undergoing thyroidectomy for MTC. In these situations, genetic analyses excluded the possible germline involvement of RET. Though FMTC phenocopies are likely to represent an exceptional finding, such a possibility should be taken into account in the genetic counselling for MEN 2 syndromes.

Loss of heterozygosity of the NOS3 dinucleotide repeat marker in atherosclerotic plaques of human carotid arteries.

We have investigated 28 atherosclerotic plaques of human carotid arteries with a panel of 39 microsatellite markers for the presence of LOH. The objective of this research was to verify if LOH, described in association with tumorigenic process, could be involved also in benign fibroproliferative disease. Seventy percent of samples demonstrated allelic imbalance: 50% of cases showed LOH at a minimum of one locus, 3.5% at a minimum of two loci and 14.3% at three or more loci. The percentages of LOH ranged between 3.8 and 14.3% and the highest involved polymorphic marker is the NOS3 internal dinucleotide repeat. Our results indicate that, like tumorigenesis, the atherogenic process could also involve LOH mechanism. Furthermore, the finding regarding the NOS3 internal polymorphism suggests a possible role of the gene as cofactor in formation of the atheromas.

Matrix metalloproteinase-1 promoter polymorphism 1G/2G is correlated with colorectal cancer invasiveness.

PURPOSE: Matrix metalloproteinase-1 (MMP-1) is likely to be involved in invasion and metastasis of several tumors by degrading the extracellular matrix. A single guanine insertion polymorphism (2G) in the MMP-1 promoter region creates an Ets binding site causing the elevation of transcriptional level and local expression of MMP-1. The aim of this study was to evaluate the impact of this 2G insertion type polymorphism on invasion and metastasis of colorectal cancer (CRC). EXPERIMENTAL DESIGN: We genotyped for this 1G/2G polymorphism 60 patients, who were operated on for CRC and followed for 6-30 months (median: 21). A control population of 164 age- and sex-matched tumor-free subjects was also genotyped for the same polymorphism. RESULTS: The proportion of 2G homozygotes was higher in the CRC group than in the controls (P = 0.014; odds ratio, 2.21; 95% confidence interval, 1.17-4.16). The CRC group was divided in a group without metastasis (M-) and a group that had developed metastasis (M+). At the time of diagnosis, 2G homozygotes were more represented in the M+ group than in M- (P = 0.0082; odds ratio, 4.73; 95% confidence interval, 1.46-15.26). The difference between M- patients and controls did not achieve statistical significance (P = 0.52). CONCLUSIONS: Our results suggest that the presence of 2G polymorphism at the MMP-1 promoter region may favor the growth and the metastatic process in CRC patients and could be looked at as a risk factor for a worse prognosis.