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Fibrous Solitary Tumors are infrequent neoplasms originating from mesenchymal tissues, most commonly arising from the visceral pleura and frequently exhibiting a benign behavior. Extra-pleural localization is unusual and the site of origin of these tumors from the parenchyma of the parotid gland is considered extremely rare. We report the case of a 66-years old woman with non-painful slow-growing left latero-cervical mass, who underwent a gadolinium-enhanced Magnetic Resonance Imaging showing a mass originating from the deep lobe of the parotid gland extending into the retro-pharyngeal space. After a total parotidectomy with tumor excision, a diagnosis of histologically proven fibrous solitary tumor of the parotid gland was made. Two years later, CT scan showed post-operative recurrence and further satellite localization in the neck, distant from the initial mass. We performed a literature review of the published similar cases, in order to clinicopathological and imaging features of this rare entity.

We describe a patient with constitutional mismatch repair-deficiency (CMMR-D) in whom the syndrome started at age 10 with the development of multiple adenomas in the large bowel. In the successive 25 years, four malignancies developed in different organs (rectum, ileum, duodenum, and lymphoid tissue). The patient had biallelic constitutional pathogenic variants in the PMS2 gene. We speculate that besides the PMS2 genotype, alterations of other genes might have contributed to the development of the complex phenotype. In the nuclear family, both parents carried different PMS2 germline mutations. They appeared in good clinical condition and did not develop polyps or cancer. The index case had a brother who died at age three of lymphoblastic leukemia, and a sister who was affected by sarcoidosis. Tumor tissue showed diffuse DNA microsatellite instability. A complete absence of immunoreactivity was observed for the PMS2 protein both in the tumors and normal tissues. Next-generation sequencing and multiple ligation-dependent probe amplification analyses revealed biallelic PMS2 germline pathogenic variants in the proband (genotype c.[137G>T];[(2174+1_2175-1)_(*160_?)del]), and one of the two variants was present in both parents—c.137G>T in the father and c.(2174+1-2175-1)_(*160_?)del in the mother—as well as c.137G>T in the sister. Moreover, Class 3 variants of MSH2 (c.1787A>G), APC (c.1589T>C), and CHEK2 (c.331G>T) genes were also detected in the proband. In conclusion, the recognition of CMMR-D may sometimes be difficult; however, the possible role of constitutional alterations of other genes in the development of the full-blown phenotype should be investigated in more detail.

Cancers affecting the salivary glands have been an increasing incidence. Salivary gland cancer is not detected until it reaches an advanced stage, which would generally result in a poor prognosis and survival rate. Therefore, early detection as well as the screening of high risk populations with precancerous lesions remains an unmet medical need. In the present work, we present a NMR-based metabolomic study of the saliva of patients suffering from salivary gland tumours. Analysis of data was done using a combined approach based on PRICONA quantitative analysis and statistical multivariate analysis. Interestingly, both the analytical methods indicate that individuals affected by parotid tumour have a characteristic metabolomic profile characterized by abnormalities in the concentration of several aminoacids. Among these the most significant are those relative to Alanine and Leucine suggestive of an alteration in the metabolic pathways of glycogenic aminoacids and ketone bodies. Our data, describing the preliminary metabolomics fingerprint of parotid tumour, are consistent with the recent view that oncogenic signalling corresponds to alteration in the metabolism of nutrient pull (Vander Heiden et al., 2009), rather than to a single metabolite.

Mutation carriers (Mut+) in DNA mismatch repair genes are predisposed to cancer of various organs and to adenomatous polyps; however, they may remain asymptomatic and cancer or polyp-free for several years. We purposed to analyse the clinical follow-up of individuals carrying constitutional mutations in the MLH1, MSH2 or MSH6 genes who were unaffected by benign polyps or malignant tumours at diagnosis.Mut + subjects (n.81) were members of Lynch syndromes in whom mutations were detected between 1993 and 2015; all were asymptomatic at diagnosis. They were informed of the cancer risk and surveillance was suggested. As controls, 113 nongene carriers (Mut-) in the same Lynch families were identified.About one-fourth of the mutation carriers developed polyps, mostly adenomas; polyps were less (12%, p .05) in Mut - subjects, and hyperplastic lesions were the prevalent histology. More polyps were detected in MLH1 vs. MSH2 mutation carriers. In Mut+, 21 malignant tumours developed in 14 carriers vs. 4 tumours in 3 patients among Mut- (p .001). Tumours were mostly of the Lynch spectrum; however, three glioblastomas were developed, together with neoplasms of various organs (duodenum, thyroid, skin, lung and cervix). Mean age of tumour occurrence was 43.0 years in Mut + vs. 53.0 among Mut-.Cancer developed more often in Mut+, with no consistent difference between MLH1 and MSH2 carriers. More polyps (mostly adenomas) were detected in MLH1 carriers. The majority (13 of 21) of malignant tumours occurred in organs for which there is no recommended surveillance, and were lethal in three patients.

Body fatness is a risk factor for colorectal cancer, and promotes an inflammatory environment. Indeed, inflammation in normal colorectal mucosa may be a factor linking body fatness to colorectal carcinogenesis. In this study, we evaluated myeloperoxidase (MPO)-positive cells infiltration of normal colorectal mucosa as a marker of cancer-promoting inflammation in overweight and obese subjects. One hundred and three subjects with normal colonoscopy entered the study. Waist circumference (WC) and body mass index (BMI) were measured, and MPO-positive cells on histological sections of biopsies of normal colorectal mucosa were counted under a light microscope. The occurrence of adenomas was then evaluated on follow-up colonoscopies. Mean MPO-positive cell count (±s.e.m.) was higher in subject with a WC equal or above the obesity cutoff values according to gender (2.63±0.20 vs 2.06±0.18, P=0.03), and in subjects with BMI equal or above 25 kg m-2 (2.54±0.18 vs 1.97±0.20, P=0.03). A Cox proportional hazard model showed that mean MPO-positive cell count in normal colorectal mucosa was the only factor independently related to occurrence of adenomas in follow-up colonoscopies. Though preliminary, these results show that MPO-positive cell infiltration in normal colorectal mucosa is related with body fatness, as evaluated by WC and BMI, and it may be considered a useful and simple marker to estimate adenoma occurrence risk.

The objective was to evaluate the attitudes toward collaboration of nurses, general practitioners (GPs), and specialists practicing in newly established Medical Homes (MHs) in Parma Local Health Authority (LHA), Emilia-Romagna region, Italy. The 15-item Jefferson Scale of Attitudes Toward Physician-Nurse Collaboration was administered electronically to 172 physicians (66 GPs, 106 specialists) and 113 nurses practicing in 12 MHs. In all, 191 surveys (45 GPs, 59 specialists, 87 nurses) were completed (67% response rate). The mean total score among nurses (51.5, standard deviation [SD] = 3.7) reflected a significantly (P < .01) more positive attitude toward collaboration compared with GPs (47.8, SD = 4.6) and specialists (45.3, SD = 7.7). Discrepancies in attitudes are concerning because conflicting perceptions of professional roles may impede a successful transition to integrated care within MHs in Parma LHA. Internationally, further research into understanding interprofessional relationships within MHs is needed to inform policy and build a necessary culture of team-based care.

Relatively little is known on the genotype-phenotype correlations between SMAD4 gene mutations, juvenile polyposis of the intestine and Hereditary Hemorrhagic Teleangectasia. We describe a family in which the proband (a 46-year old woman) had massive polyposis of the stomach-leading to surgery-with high-grade dysplasia at histology. Molecular analysis was carried out using Next Generation sequencing techniques with Miseq Illumina Platforms and a minimal coverage of 40 reads. In the proband, the analysis showed the presence of a truncating mutation in the SMAD4 gene (c.1213dupC, a variant previously associated with juvenile polyposis and Hereditary Hemorrhagic Teleangectasia). The same mutation was detected in two other members of the family (father and brother of the proband), who showed massive polypoid involvement of the stomach at gastroscopy. By taking the family history, subtle evidence of Hereditary Teleangectasia was found (nasal bleeding and arterovenous malformations) in the three gene carriers. Colonoscopy showed polyp occurrence in all three affected members with SMAD4 mutation, with prevalence of adenomatous lesions in one (father), of hamartomas in the brother, and of a mix of histological types in the proband. The main features of the family can be summarized as follows: (A) In hereditary juvenile polyposis, lesions of different histology can be detected at colonoscopy; (B) In the gene carriers of SMAD4 mutations, lesions of the stomach require careful surveillance and, when necessary, surgical interventions; (C) Signs and symptoms of Hereditary Hemorrhagic Teleangectasia should be suspected (and searched) in individuals with SMAD4 constitutional mutations.

Dit artikel geeft een overzicht van enkele van de meest recente beleidsmaatregelen ten behoeve van jeugdwerkloosheid, die de sterke en zwakke punten van het Italiaanse jeugdbeleid duidelijk laten zien. Door de belangrijkste historische mijlpalen te beschrijven wordt gereflecteerd op de oorzaken van de noodzaak tot diep structurele hervormingen. Een belangrijk gegeven in de analyse is dat jeugdbeleid in Italie vooral op lokaal niveau wordt ontwikkeld, waar het zijn ideale omvang heeft gevonden, terwijl tegelijkertijd al vele jaren een algemene strategie op nationaal niveau ontbreekt. Dit verklaart de rijke diversiteit van benaderingen die we kunnen vinden in Italie en de belangrijke aanwezigheid van vrijwilligerswerk naast de overheid. Ten slotte beschrijft het artikel de inzichten over de nieuwe innovatieve diensten en programma’s en laat het de best practices zien op het gebied van jongerencreativiteit en jongerenzelfbestuur.

Objective. Familial adenomatous polyposis (FAP) is an interesting model for the study of colorectal tumour. Two genes contribute to the FAP phenotype - APC and MUTYH - but their relative role is still undefined. The objective of this study was to evaluate the contribution of the two genes to the pathogenesis of FAP by means of a series of FAP families. Material and methods. Sixty-one unrelated families with a diagnosis of FAP and a total of 187 affected individuals were evaluated. After extracting DNA, APC and MUTYH genes were sequenced. Results. In the whole series of patients, colectomy with ileorectal anastomosis was the most frequent surgery, although the number of patients treated by total proctocolectomy and ileoanal anastomosis was increasing. Duodenal and jejunal-ileal adenomas were present in more than half of the patients. Constitutional mutations were detected in 37 of the 45 families (82.2%); there were 33 families with APC and 4 with MUTYH alterations. Age at onset of polyposis and age at surgery were 10-15 years delayed for carriers of MUTYH mutations; cancer at diagnosis was frequent, and extracolonic manifestations were diagnosed in the majority of MUTYH-positive families. MUTYH-associated polyposis showed the horizontal transmission expected for recessive inheritance (at variance with the dominant pattern seen with APC mutations). Conclusions. At least two genes are associated with the FAP phenotype. APC mutations account for the majority of cases, while MUTYH mutations can be observed in 10% of patients. There are few but definite differences between APC-and MUTYH-associated FAP, such as age at diagnosis and pattern of transmission.

This study investigates the organizational culture and associated characteristics of the newly established primary care units (PCUs)-collaborative teams of general practitioners (GPs) who provide patients with integrated health care services-in the Emilia-Romagna Region (RER), Italy. A survey instrument covering 6 cultural dimensions was administered to all 301 GPs in 21 PCUs in the Local Health Authority (LHA) of Parma, RER; the response rate was 79.1%. Management style, organizational trust, and collegiality proved to be more important aspects of PCU organizational culture than information sharing, quality, and cohesiveness. Cultural dimension scores were positively associated with certain characteristics of the PCUs including larger PCU size and greater proportion of older GPs. The presence of female GPs in the PCUs had a negative impact on collegiality, organizational trust, and quality. Feedback collected through this assessment will be useful to the RER and LHAs for evaluating and guiding improvements in the PCUs.

Attenuated polyposis could be defined as a variant of familial adenomatous polyposis (FAP) in which synchronous polyps of the large bowel range between 10 and 99. We analysed all cases of attenuated polyposis observed over the last 30 years with the objectives: (A) to classify the disease according to different type and proportion of polyps; (B) To ascertain the contribution of APC and MutYH genes; (C) to discover features which could arise the suspicion of mutations; (D) To obtain indications for management and follow-up. 84 individuals in 82 families were studied. Polyps were classified into four groups as adenoma, hyperplastic, other serrated lesions or others; APC and MutYH mutations were assessed. Mean age at diagnosis was 54 ± 14 years in men and 48 ± 13 in women (P = 0.005). Polyps were more numerous in women (37 ± 26 vs 29 ± 22). Sixty % of patients underwent bowel resection, mainly for cancer; the remaining were managed through endoscopy. A total of 2586 polyps were detected at diagnostic endoscopy: 2026 (80 %) were removed and analysed. Adenomas were diagnosed in 1445 (70 %), hyperplastic polyps in 541 (26 %), other serrated lesions in 61 (2.9 %). Adenomas and hyperplastic lesions were detected in the majority of patients. In 68 patients (81 %) in whom studies were executed, APC mutations were found in 8 and MutYH mutations in 10. Genetic variants were more frequent in women (12 vs 6, P = 0.039). Taking into consideration the prevalent (>50 %) histology and presence of mutations, patients could be subdivided into four groups: (1) APC mutated polyposis (AFAP), when adenomas were >50 % and APC mutations detected (no. 8, 10 %); (2) MutYH mutated polyposis (MAP), adenomas >50 % and biallelic MutYH mutations (no. 10, 12 %); (1) attenuated polyposis without detectable mutations, prevalence of adenomas, 48 cases (57 %); (1) hyperplastic-serrated polyposis, with prevalence (>50 %) of hyperplastic/other serrated lesions and no constitutional mutation (no. 18, 21 %). Aggregation of tumors, cancer in probands, distribution of polyps and other clinical characteristics showed no difference among the four groups. In conclusions, AFAP and MAP, the polyposis labeled by constitutional mutations, represented about 25 % of all attenuated polyposis. Mutation-associated cases showed an earlier age of onset of polyps and were more frequent in the female sex.

The Comunity Health Centre (CHC) primary care model is a team-based health care delivery model intended to provide comprehensive and continuous medical care to patients within a defined community. The CHC, Case della Salute in Italian, model was introduced in the Emilia-Romagna Region in 2010.We present updated data on the implementation on the CHC Case della Salute primary care model in the Emilia-Romagna Region.There are 67 operating CHCs in Emilia-Romagna (update March 2015); 26 small (39%), 24 medium (36%) and 17 large (25%). Since 2011 the number of operating CHCs has increased by 60%, reaching 55% of the target planned CHCs (n. = 122). There is, on average, one running CHC per 66.524 inhabitants. 16% of total general practitioners (GPs) and 8.4% of total family paediatricians working in Emilia-Romagna have their practice in CHCs. CHCs offer primary and specialist integrated care, prevention services, health education and social care.Although preliminary results suggest CHCs have fostered primary care's quality and efficiency, more research is needed to assess their impact on improving clinical, social and economic outcomes.

Colorectal mucosa is targeted by toxic agents, which can initiate or promote colon cancer. The mechanism of damage might be a focal irritation with loss of normal epithelial cell barrier function. Genetic alterations in tumors may also affect host inflammatory response. The aim of this study was to define the extent of inflammation in colorectal mucosa, along colorectal carcinogenesis, and in microsatellite stable and unstable colorectal carcinomas. We collected 103 samples of normal colorectal mucosa from 65 patients (35 with colorectal cancer or adenoma, 8 with inflammatory bowel diseases, and 22 controls with normal colonoscopy). We also examined 24 aberrant crypt foci, 14 hyperplastic polyps, 16 adenomas, and 67 samples of colorectal carcinoma. Immunohistochemistry was used to count myeloperoxidase (MPO)-positive cells (neutrophils and monocytes) in ×100 optical fields under a light microscope. Patients with colorectal tumors had a higher mean number of MPO-positive cells in normal mucosa than controls (mean ± SD, 2.7 ± 2.0 versus 1.4 ± 1.4; P = 0.017). MPO-positive cell number was tightly linked to dysplasia in aberrant crypt foci and adenomas, and it was higher in carcinomas microsatellite unstable than those microsatellite stable (21.6 ± 15.5 versus 11.9 ± 8.0; P < 0.01). MPO immunohistochemistry is a simple and reliable technique for the quantification of inflammation in colorectal mucosa., and it may be a potential marker of colorectal cancer risk. Microsatellite instability seems to influence host immune responses to colorectal carcinoma. These observations strongly support a key role of inflammation in colorectal carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2291–7)

A unique mutation of the MLH1 gene was recently reported in six families living in a small area of Northern Italy. The mutation consists in the insertion of a T base between nucleotides 2269 and 2270 (2269-2270insT), causing the synthesis of an unstable polypeptide. The mutation was not reported by other investigators or outside this small geographic area, thus suggesting a possible founder effect. The main purpose of this investigation was to investigate whether patients (and families) with the 2260-2270insT mutation show relevant clinical differences when compared with individuals with other MLH1 or MSH2 gene alterations.We identified hereditary non-polyposis colorectal cancer (HNPCC) families through the specialized colorectal cancer registry following a previously described multistep approach. In all, 58 HNPCC families were identified; of these, 38 were detected through the registry, and 20 were referred from other areas in Italy.Small differences were found in the main clinical and pathologic features; however, tumour burden per family tended to be higher in kindred sharing the founder mutation; in addition, multiple primaries (four or five different tumours in some subjects) were significantly more frequent in patients with the 2269-2270insT than in individuals with MSH2, MLH1 gene mutations or sporadic colorectal neoplasms. No significant difference in prognosis was found between patients with the founder mutation and those with other MLH1 or MSH2 mutations. Regardless of the type of mutation, neoplasms of the colon-rectum, stomach and endometrium represented nearly 80% of the tumour burden in families with HNPCC.A proclivity to multiple tumours arising in the same subject and a higher tumour burden per family were the most relevant findings observed in affected patients with the founder mutation compared with other MLH1 or MSH2 mutations. In general, the results of the study underline the difficulty in discriminating between Lynch I and Lynch II syndromes on the basis of specific molecular changes.

Introduction: Multiple sclerosis (MS) is a chronic and progressive disease characterised by central nervous system lesions and subsequent neural damage. Patients have increasingly severe disability and there are no therapies for healing. Since the onset, usually between 20 and 40 years old, MS dramatically affects the quality of life (QoL) of patients and their families. Whereas literature suggests the importance of integration in MS management, evidences show many difficulties to achieve integration and seamless integrated clinical pathways (ICPs) for this target of patients. Hitherto there are limited experiences around comprehensive interventions for the MS management, exploiting a life-course approach and broader scales and scopes towards special group commissioning strategies – with only one relevant exemption in the U.S. Veterans Integrated Service Network (VISN) supporting MS Regional Program. The paper presents the undergoing experience at the LHA of Parma, located in northern Italy, in Emilia Romagna Region, which accounts for 443.770 habitants, covering a surface of 3.448 kilometres, including a mountain area, with 46 municipalities. Of interest, in the context of a broad regional programme oriented to reorganise primary health care through the development of medical homes model, the LHA in mid-2014 started a project for setting up a MS managed care network. Moving from a systematic analysis yet of the demand of MS patients yet of the local supply chain, the project has sought for establishing a managed care network based on the newly primary health care system and for identifying special commissioning strategies for this targeted group through ICPs. Objectives and methods: The project pursues two main objectives: developing a managed care network for MS patients from the commissioners’ perspective and therefore identifying a system International Journal of Integrated Care – Volume 15, 27 May – URN:NBN:NL:UI:10-1-117030 – http://www.ijic.org/ 15th International Conference on Integrated Care, Edinburgh, UK, March 25-27, 2015 2 for programme planning resources needed for MS management and procuring services within the LHA. The project is broken down into three major phases exploiting different methods and stakeholders’ engagement. The first phase focused on the demand analysis. On one hand, the MS patients’ population was identified and stratified using LHA administrative databases. An algorithm based on the individual fiscal code and patient exemption extrapolated the targeted population. To stratify the targeted group and analyse their current pattern of resources’ utilization two further actions were performed. Firstly, neurologists’ team from MS centres fulfilled a Joint Need Assessment (JNA) through clinical vignette for their patients. Health needs were assessed through the Expended Disability Status Scale (EDSS) that measures the rate of MS progression. The scale was aggregated in three clusters relying on the disease staging and use of disease modifying drugs (DMDs): little disability (EDSS 0 2); severe (x≥2). Cross-tabulating the level of disability and fragility, the group of MS patients was stratified in 9 classes. Secondly, the pattern of resources utilisation for each class was analysed to create care-profiles based on the types of care (PCTC) provided. To this extent through the unique patient record different data sources were consulted: patients discharge reports, A&E reports, specialty and diagnostic outpatients services, pharmaceutical prescriptions (hospital and community databases), home care services, care home and intermediate care services, hospice, social care services and personal budget/disability allowance dataset and finally prosthetics. On the other hand, the first phase included also the analysis of the supply chain, to identify current MS centres and their resources as well as the broad range of services accessed by the MS patients. The second phase is going set up nine ICPs, one for each care-profile, to design seamless and integrated processes through different settings (MS centre, medical homes, rehab services etc.). Moreover, this phase includes the estimation of the total cost of care for each ICP based on the resources’ utilisation pattern associated with each PCTC. Finally, the third phase is going to set up the managed care network for SM patients, based on the nine ICPs as standard base-line of the care packages guaranteed and integrated processes of care delivery. To fulfil this phase a consensus building process with professionals and providers will support the implementation of ICPs and the set-up of a dashboard of process and outcome indicators, directly monitored by the LHA commissioners. Timeline: The project started in June 2014 and is expected to end up in February 2015 with the outline of the MS managed care network. The demand analysis and stratification across the nine care-profiles as well as the supply chain review were completed in November 2014. Current work is focused on the ICPs’ design for the nine care-profiles and their cost-assessment. Highlights and conclusions: The project holds a paradigmatic and innovative value from two perspectives. Firstly, the methods used for the MS patients group identification and segmentation is remarkable for further exploitation and transferrable yet to different contexts yet to different care groups, providing a reliable tools for strategic commissioning for complex care needs. In fact, the method applied to the LHA of Parma, was previously tested in other contexts and gradually improved through adjustments and due to the maturity of data management systems. Secondly, this methodology hinges on the set-up of ICPs, thus it allows to directly establish a routinely system relating the patient-centred perspective and the commissioners objectives, focused on the programme planning and procuring in a given local health economy. Therefore, the efforts to standardise a set of ICPs through a process-based set of PCTC paved the way for interesting practice achievements in the management of complex chronic conditions. Finally, the project delivers an innovative experience towards understanding how to implement a managed care network through the integrative function of primary care and ICPs. One of the major question the project ought to reply, in fact, is whether the MS centre, the hub of the care network, could be placed in the future in a medical home, out of hospital, if it will have to coordinate spokes centres at the community level through ICPs. International Journal of Integrated Care – Volume 15, 27 May – URN:NBN:NL:UI:10-1-117030 – http://www.ijic.org/ 15th International Conference on Integrated Care, Edinburgh, UK, March 25-27, 2015 3

Colorectal cancer (CRC) occurs rarely in young individuals (45 yr) and represents one of the criteria for suspecting hereditary cancer families. In this study we evaluated clinical features and molecular pathways (chromosomal instability [CIN] and microsatellite instability [MSI]) in early-onset CRC of 71 patients.Detailed family and personal history were obtained for each patient. Expression of APC, beta-catenin, p53, MLH1, MSH2, and MSH6 genes was evaluated by immunohistochemistry. MSI analysis was performed and constitutional main mutations of the mismatch repair (MMR) genes were searched by gene sequencing.Fourteen (19.7%) out of the 71 cases showed both MSI and altered expression of MMR proteins. In the 57 MSI-negative (MSI-) lesions altered expression of APC, beta-catenin, and p53 genes were found more frequently than in MSI-positive(MSI+) tumors. Seven (50%) out of the 14 patients with MSI+ tumors presented clinical features of Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]) and in all but one, constitutional mutations in MLH1 or MSH2 genes could be detected. The same mutations were also found in other family members.Our study demonstrates the involvement of CIN in a majority of early-onset colorectal tumors. Furthermore, we identified Lynch syndromes in seven cases (50%) of early-onset colorectal carcinomas with impairment of the MMR system. These results suggest that patients with early-onset CRC should be screened for hereditary cancer syndrome through clinical and molecular characterizations.

This review focuses on the role of estrogen in men, mainly in male reproduction. The continuing increase in data obtained, and recent discoveries in this area will enable a better understanding of male physiology; these, in turn, will have important clinical implications.

We report the clinical case of a patient who showed an “accelerated” form of polyposis, with development of major lesions within the first decade of life. The patient belongs to a familial adenomatous polyposis family—already described in 2001—featured by profuse polyposis at an early age of onset and desmoid tumors in the majority of affected individuals (of both sexes). The family was characterized by an uncommon mutation of the APC gene (c.4391_4700del310insCACCTACTGCTGAAA, previously defined as c.4394ins15del310) consisting in a large deletion of 310 bp at codon 1,464 with duplication of the breakpoint leading to a stop codon at position 1,575. The proband was affected by desmoids tumors at the age of 3 years. In the same year (2004) numerous polyps in the large bowel and a hepatoblastoma developed. After several months new desmoids appeared in the surgical scar. In 2010, at age 9, the patient was operated of total colectomy and endorectal pull-through of the small intestine owing to profuse colorectal adenomatosis. New desmoids developed in 2011 and 2012, and required chemotherapy. Further analysis of the APC gene in the proband revealed several polymorphisms. One of these (c.398A>G) had not been previously reported, nor was present in two other affected members of the family. The clinical case, and the practical implications for therapy, are discussed according to the most recent theories of colorectal cancer development. Long-term treatment with Cox-2 inhibitors might represent a good option for this patient.

Purpose To test the hypothesis that scores of a validated measure of physician empathy are associated with clinical outcomes for patients with diabetes mellitus. Method This retrospective correlational study included 20,961 patients with type 1 or type 2 diabetes mellitus from a population of 284,298 adult patients in the Local Health Authority, Parma, Italy, enrolled with one of 242 primary care physicians for the entire year of 2009. Participating physicians’ Jefferson Scale of Empathy scores were compared with occurrence of acute metabolic complications (hyperosmolar state, diabetic ketoacidosis, coma) in diabetes patients hospitalized in 2009. Results Patients of physicians with high empathy scores, compared with patients of physicians with moderate and low empathy scores, had a significantly lower rate of acute metabolic complications (4.0, 7.1, and 6.5 per 1,000 patients, respectively, P < .05). Logistic regression analysis showed physicians’ empathy scores were associated with acute metabolic complications: odds ratio (OR) = 0.59 (95% confidence interval [CI], 0.37–0.95, contrasting physicians with high and low empathy scores). Patients’ age (≥69 years) also contributed to the prediction of acute metabolic complications: OR = 1.7 (95% CI, 1.2–1.4). Physicians’ gender and age, patients’ gender, type of practice (solo, association), geographical location of practice (mountain, hills, plain), and length of time the patient had been enrolled with the physician were not associated with acute metabolic complications. Conclusions These results suggest that physician empathy is significantly associated with clinical outcome for patients with diabetes mellitus and should be considered an important component of clinical competence.

Colorectal cancer can be a painful event, generally associated with changes in lifestyle for many patients. We studied the quality of life of the patients operated for colorectal malignancies 5 years after the diagnosis. Using detailed questionnaires, we investigated 220 patients of both sexes (mean age 66.5 years) 5 years (or more) after a curative operation for cancer of the large bowel. The short form 36 (SF-36) questionnaire took into consideration several aspects concerning work activity, physical activity, psychological attitude, alimentation, familial relationships, and other relevant components of lifestyle. Moreover, we compared the perception of the so-called SF-36 score between our patients and a comparison group in the general population. Both univariate and multivariate analysis were used. The obtained results revealed that familial and social relations were equally unchanged or tended to improve. Sexual activity declined in only 61(31.3%) subjects. Rather surprisingly (because of the average age at diagnosis), work activity remained unchanged in about half of the patients. Using the SF-36 questionnaire, the main differences from the general Italian population were seen in bodily pain (especially in the few individuals in whom a permanent stoma was necessary), social functioning and general physical health. In conclusion the results seem to suggest that the majority of patients who survive for more than 5 years after an operation for colorectal malignancy return to an almost normal life. The awareness among individuals about their disease, the improvements in surgical techniques and medical treatments are among the factors responsible for these positive results.

INTRODUZIONE: L’otite media secretiva (OMS) è una patologia di frequente riscontro in età pediatrica. Oltre l’80% dei bambini presenta almeno un episodio di otite nei primi 3 anni di vita e in circa un terzo dei soggetti si evidenzia una significativa ricorrenza degli episodi. L’ipoacusia trasmissiva che ne deriva può alterare lo sviluppo della produzione del linguaggio, dal momento che la maggior parte delle regole linguistiche vengono acquisite dal bambino entro i primi 4/5 anni di vita. MATERIALE E METODI: Sono stati esaminati 30 bambini di età compresa tra 3 e 6 anni giunti alla nostra osservazione, da Settembre 2010 a Giugno 2011, per OMS e ipertrofia adenoidea sottoposti ad intervento di adenoidectomia con apposizione di drenaggio transtimpanico (DTT) bilaterale. Prima e dopo l’intervento chirurgico, sono stati praticati esame audiometrico tonale, esame impedenzometrico e visita logopedica (controlli a uno, due e tre mesi dall’intervento), analizzando l’eventuale miglioramento del linguaggio secondo i livelli fonetico-fonologico, lessicale-semantico, morfo-sintattico e pragmatico. RISULTATI: Abbiamo osservato un miglioramento medio della soglia uditiva di 28,5 dB (range 20-35 dB). A livello fonetico-fonologico sono stati evidenziati: in input, normalizzazione dell’abilità di discriminazione uditiva di parole nel 40% dei casi e della discriminazione uditiva di non parole nel 33%; in output, eliminazione della nasalizzazione diffusa sui foni occlusivi e riduzione delle semplificazioni di sistema e di struttura nel 75% dei pazienti; riduzione delle interdentalizzazioni e lateralizzazioni a carico delle fricative e affricate nel 37,5%; stabilizzazione dei foni nel 25% dei bambini. A livello morfo-sintattico: aumento significativo di 4,1 della lunghezza media dell’enunciato. Ai livelli lessicale-semantico e pragmatico non si sono registrate differenze significative tra il pre e il post-operatorio. CONCLUSIONI: Considerando il periodo relativamente breve di osservazione (3 mesi), i miglioramenti linguistici apprezzati possono essere considerati indicatori di uno sviluppo psicolinguistico connesso ed incentivato dalla normalizzazione dell’udito derivante dall’apposizione del DTT piuttosto che legato alla normale crescita ed evoluzione del bambino

This paper concerns the modeling and numerical simulation of pulse combustion. As the title highlights, focus is on self-sustained acoustic vibrations, the cause of self-excitation being an unstable feedback loop closed by the combustion process. A Helmholtz-type mechanical-valve pulsating combustor was considered. Numerical models were two-dimensional axis-symmetrical, and efforts were made to model the elementary steps of the unstable feedback loop (valve opening, injection of reactants, turbulent mixing and combustion, etc.) as well as possible, to provide a realistic description of the self-excitation mechanism as a whole. Simulations were carried out the analyse the effects of several design and operation parameters on the feedback loop (from injection of reactants to turbulent combustion rate to history of heat release) and ultimately on the growth rate and frequency of vibrations. Results of simulations were post-processed to extract the time evolution of the total mechanical enery (sum of pressure and kinetic energy) of vibrations. Finite-amplitude self-sustained periodic oscillations in the combustor are completely reproduced and the limit cycle (at which dissipated energy per cycle is equal to amount of mechanical energy furnished by the combustion process) found. The software used was ‘Fluent,” a commerical CFD (Computational Fluid Dynamics) code [13] incorporating a reaction rate model accounting for turbulent mixing. A general purpose CFD code instead of classical linearized models was chosen to preserve the nonlinearity of the original equations, thus allowing us to carry out non-linear instability analysis (not only initial growth rate) and to find the limit cycle of the system.

Cases of death are reported due to medical use of propofol, whereas deaths due to recreational purpose are unusual.A 26-year-old Caucasian man, physician trainee in anesthesiology, was referred to an intensive care unit. The man was found unconscious in his bed with a butterfly-needle canalized into the vein of the left forearm and connected to an empty syringe. Transferred to the local hospital, the patient was monitored, and EKG showed typical Brugada features in V1-V3. Profound hypotension and metabolic acidosis were registered. Half an hour after admission, the patient developed prolonged QT interval, idioventricular rhythm, and ventricular fibrillation. Strong positive reaction for tumor necrosis factor alpha in cardiac myocytes and a diffuse apoptotic process in the heart specimens were observed. The multiple needle marks on the hands and forearms, and the propofol concentration in the hair examined (0.73 microg/g), led us to believe that the young man was a long-term propofol abuser.Development of the EKG pattern of ST-segment elevation in leads V1-V3 may be the first indicator of electrical instability and high risk for imminent sudden death. Whether this finding applies to other patients poisoned with propofol is unclear, but the association of sudden death and the acquired EKG pattern has been observed in other disease states.This article describes a fatal propofol-related death case because of recreational purpose; the EKG pattern, the cardiac morphology, and the expression of tumor necrosis factor alpha and apoptosis in cardiac tissue specimens are discussed to elucidate the mechanism of death.

A general improvement of colorectal cancer prognosis has been observed. Reasons of this more favourable trend are diffusion of screening, advancements in molecular biology, new developments in chemotherapy and surgical techniques. Through the data of a colorectal cancer registry, we purposed to evaluate changes in surgical procedures for colorectal neoplasms and to analyse trends of perioperative mortality. Patients with colorectal cancer were registered from 1984 to 2004. The main surgical procedures were recorded and classified. Perioperative mortality was defined as death of patients within 1 month since the operation. Regression analysis showed an increase over time of right and left hemicolectomy. Both colectomy and endoscopic polypectomy showed significant rise over time. In contrast, abdominoperineal operations dropped during the study period. A similar decrease was observed for palliative surgery. Perioperative mortality declined from 7–11% to 3–6% of all operations; main factors associated with perioperative mortality were presence of comorbidities, increasing age and advanced stage. The better prognosis of patients with colorectal cancer was associated with changes of surgical techniques, with a tendency to prefer large operations over limited resections. Perioperative mortality showed a gradual decrease and is at present in the order of 3% to 6% of all operations.

Screening and early diagnosis of cancer represent relatively recent tools in the long-lasting battle against tumors. If the American public opinion manifests its enthusiasm towards screening, the attitude of European is less well known. The purpose of the present study was to assess the level of knowledge and awareness of cancer screening (with particular emphasis on colorectal neoplasms) among middle-aged individuals. The study group consisted of 945 healthy individuals (489 men, 456 women, average age 57 +/- 12.4 years) who were asked to answer a series of questions about cancer screening and surveillance through a questionnaire presented by trained residents. Each interview lasted 20-30 min. Middle-aged Italians of both sexes seem to be aware of the fact that cancer is a frequent disease; moreover, many of the interviewed subjects believe almost all neoplasms are incurable. Diet, style of life, other environmental factors and familial factors are fully appreciated as relevant risk factors. The exact meaning of prevention was clear to less than half of the subjects. When various cancer sites were analyzed, the existence of preventive measures was well known for breast, cervical and prostate tumors, but their role was less clear for colorectal cancer. Only a fraction of the interviewed individuals were willing to undergo screening; the main reasons for refusal were lack of usefulness and fear of results. Among various tests, ultrasound and endoscopy were usually carried out in the presence of symptoms. Finally, multivariate analysis showed that the two factors significantly associated with the decision to undergo screening procedures were increasing age and level of education. The results of the study suggest that middle-aged Italian individuals, predominantly from Northern regions, have a correct perception of some aspects (frequency, risk factors) of cancer biology, whereas the knowledge of other aspects (outcome, prevention) remains poor or approximate. It follows that one of the main objectives of the Political Class should be to obtain a better education of overage individuals about cancer and the many problems related to this common disease.

We studied a boy with congenital hypothyroidism, benign hereditary chorea, and respiratory distress. His mother and his grandfather were affected by hypothyroidism with a late onset and benign hereditary chorea. The aim of this study was to establish the genetic defects that cause that phenotype and study the molecular mechanisms of the pathology.NKX2.1, PAX8, NKX2.5, and TAZ genes were sequenced.Direct sequencing of the NKX2.1 gene showed, in all the affected, a new heterozygous mutation from cytosine to adenine in the second base of the triplet encoding for the amino acid at position 145. The mutation (C609A) is responsible for a change from serine to a stop codon (S145X). We also demonstrated that the mutant protein is predominantly in the cytoplasm and unable to translocate into the nucleus. Of note, the S145X mutation produces variable phenotypes in the affected members of the family. No mutations have been identified in the NKX2.5, PAX8, and TAZ genes.Our study extends the knowledge of the functional effect of NKX2.1 mutations and further highlights the complexities of genotype-phenotype correlation in the NKX2.1 deficiency syndromes.

The association between sudden infant death syndrome and immunization is frequently discussed. Serious adverse events following vaccination have generally been defined as those adverse events that result in permanent disability, hospitalization or prolongation of hospitalization, life threatening illness, congenital anomaly or death. They are generally referred to the inherent properties of the vaccine (vaccine reaction) or some error in the immunization process (programme error). The event could also be totally unrelated but only temporally linked to immunization (coincidental event). A fatal case of a 3-month-old female infant, who died within 24 h of vaccination with hexavalent vaccine is presented. Clinical data, post-mortem findings (acute pulmonary oedema, acute pulmonary emphysema), quali-quantitative data collected from immunohistochemical staining (degranulating mast cells) and laboratory analysis with a high level of beta-tryptase in serum, 43.3 microg/l, allows us to conclude that acute respiratory failure likely due to post hexavalent immunization-related shock was the cause of death.

Symptoms of cardiac contusion are very greatly and sometimes are non recognized or are masked by associated injury in severe chest trauma. Cardiac contusion clinically presents as a spectrum of signs and symptoms of varying severity, ranging from precordial pain, dyspnoea, and non specific ECG changes to increased serum activity of several enzymes, early severe rhythm abnormalities, severe conduction defects and death. We present a fatal case in which the definitive diagnosis of myocardial contusion has proved complex. All clinical data were suggestive of acute myocardial infarction, but the history of chest wall injury and gross and histological examination of the heart and coronary vessels led us to conclude for a cardiac contusion without myocardial infarction. In case of chest blunt trauma, the ECG should be interpreted within the context of the clinical situation, on history of chest wall injury, since a fatal myocardial contusion may occur after apparently mild injury.

The first recorded death caused by electrical current from an external source was reported in 1879, when a carpenter in Lyon, France, inadvertently contacted a 250 V alternating current generator [1]. Electrical injuries (excluding lightning) are responsible for >500 deaths per year in the USA. A little more than half of them occur in the workplace and constitute the fourth leading cause of work-related traumatic death (5–6% of all worker’s deaths) [2]. Medical literature typically categorizes electrocution according to the level of applied voltage: low voltage (less than 1000 V) and high voltage (greater than 1000 V); as reported from medical-legal practice, 14–40% of mortal electrocution are caused by high-voltage injuries [3,4]. It is well known that an electrical shock may cause death or any degree of damage to various organs and systems; the severity of electric shock injury is dependent upon many variables: type of current, level of applied voltage, duration of shock, body contact surface area, resistance of tissue involved, contact with water or metal conductor and current pathway through the body [5]. The electrical shock may strike the victim’s central nervous system, the cardiovascular apparatus, the skeletal muscular tissue, the lungs, the skin and other internal organs [6]. Severe abdominal visceral injuries by electricity are a rare entity; in particular, we rarely come across cases of hepatic lesions. In

The Authors describe a rare case of suicide in a 31-year-old woman, due to oral ingestion of lidocaine; the histological and toxicological findings are discussed to provide useful information to the present experience with this particular modality of death. Histological examination revealed generalized stasis. In the myocardium we observed segmentation of the myocardial cells and/or widening of intercalated discs and associated group of hypercontracted myocardial cells with "square" nuclei in line with hyperdistended ones. Non-eosinophilic bands of hypercontracted sarcomeres alternating with stretched, often apparently separated sarcomeres, small foci of paradiscal contraction band necrosis, and perivascular fibrosis were observed too. Lidocaine was detected in the subject's urine through immunoenzymatic screening. Toxicological analysis by solid-liquid extraction and gas chromatography-mass spectrometry (GC-MS) analysis, was carried out to identify and quantify the individual substances present in the biological fluids and organs. Lidocaine concentrations were as follows: blood 31 microg/mL, gastric content 2.5 g, liver 10 microg/g, kidney 12 microg/g, brain 9 microg/g, spleen 24 microg/g, lung 84 microg/g, heart 9 microg/g, urine 9 microg/mL, and bile 6 microg/mL. No other drugs or alcohol were detected. When blood lidocaine reaches toxic levels, serious toxic symptoms associated with the central nervous system and cardiac system are noted. The overdose of lidocaine produces death from ventricular fibrillation or cardiac arrest. In this case, according to macroscopic and microscopic findings, the cause of death was most likely cardiac and possibly related to ventricular fibrillation.

Patients with stage I colorectal cancer have a good prognosis, however, a small fraction of them die of local or distant recurrence after curative resection. The aggressive behavior reflects some biological properties of these tumors. In this study, we evaluated the prognostic role of some histopathological and biological parameters in stage I colorectal carcinomas. From the Colorectal Cancer Registry of Modena, we selected two series of patients; the first included all patients who had died of disease progression, the second included patients with a favorable outcome. The histopathological parameters assessed were grade of differentiation, growth pattern at the invasive tumor front, peritumoral lymphocytic infiltration, tumor budding and vascular invasion. The biological variables were proliferative activity (using Ki-67 nuclear antigen), overexpression of p53 protein and altered expression of the mismatch repair proteins (MLH1 and MSH2). The results showed that an infiltrating growth pattern, absent or sparse peritumoral lymphocytic infiltration, the presence of tumor budding and vascular invasion are significantly related to the risk of recurrence. Among the biological parameters, p53 overexpression was significantly correlated with a poor clinical outcome. Our study showed that the histopathologial features are relevant prognostic indicators and might be used as markers for an appropriate treatment strategy in patients with stage I carcinomas.

Study objective To assess the clinical effectiveness of pulmonary rehabilitation (PR) after 10 or 20 consecutive sessions in outpatients with chronic airway obstruction (CAO). Design Observational prospective cohort trial. Setting Outpatient clinic of a rehabilitation center. Patients and interventions Twenty-five outpatients (mean age, 65 ± 9 years [± SD]; FEV 1 , 64 ± 12% predicted) admitted to a comprehensive PR program, including exercise training. Measurements and results The load reached on a cycloergometer (maximal achieved load [W-max]), the maximal and isoload dyspnea and leg fatigue on a Borg scale, 6-min walk distance (6MWD), and the health-related quality of life as assessed using the St. George's Respiratory Questionnaire (SGRQ) [total and components score] have been recorded as outcome measures at baseline, after 10 sessions (T10), and after 20 sessions (T20). The predefined criteria of the clinically significant improvement were as follows: + 15% W-max, + 54 m at 6MWD, − 1 point at isoload dyspnea and leg fatigue, and − 4% at SGRQ scores. There was a mean significant difference between changes at T20 and T10 for 6MWD (− 42.96 m; 95% confidence interval [CI], − 57.79 to − 28.12 m; p = 0.001), total SGRQ (4.80; 95% CI, 2.29 to 7.31; p = 0.001), activity SGRQ (3.60; 95% CI, 0.48 to 6.71; p = 0.025), and symptoms SGRQ (5.96; 95% CI, 2.72 to 9.2; p = 0.001). The percentage of patients who improved was different at T20 as compared with T10 for W-max (68% and 48%, respectively; p = 0.025), 6MWD (76% and 20%, p = 0.001), and total SGRQ (64% and 36%, p = 0.008). Conclusions A 10-session course of PR provides only limited clinically significant changes of outcome measures when compared with a 20-session course in outpatients with CAO of mild-to-moderate severity.

Purpose: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC); however, the results are not conclusive. The aim of this study was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy. Experimental Design: In three different institutions, 1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables. Results: Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of 5-year–specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non–polyposis colorectal cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared. Conclusions: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients. The survival benefit for patients with hereditary non–polyposis colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.

BACKGROUND The Muir–Torre syndrome (MTS) is an autosomal-dominant genodermatosis characterized by the presence of sebaceous gland tumors, with or without keratoacanthomas, associated with visceral malignancies. A subset of patients with MTS is considered a variant of the hereditary nonpolyposis colorectal carcinoma, which is caused by mutations in mismatch-repair genes. The objective of the current study was to evaluate whether a combined clinical, immunohistochemical, and biomolecular approach could be useful for the identification of Muir–Torre syndrome among patients with a diagnosis of sebaceous tumors and keratoacanthomas. METHODS The authors collected sebaceous skin lesions and keratoacanthomas recorded in the files of the Pathology Department of the University of Modena during the period 1986–2000. Through interviews and examination of clinical charts, family trees were drawn for 120 patients who were affected by these skin lesions. RESULTS Seven patients also were affected by gastrointestinal tumors, thus meeting the clinical criteria for the diagnosis of MTS. In the MTS families, a wide phenotypic variability was evident, both in the spectrum of visceral tumors and in the type of skin lesions. Microsatellite instability was found in five MTS patients: These patients showed concordance with immunohistochemical analysis; moreover, a constitutional mutation in the MSH2 gene was found in 1 patient. Lack of expression of MSH2/MSH6 or MLH1 proteins was evident in the skin lesions and in the associated internal malignancies of 3 patients and 2 patients with MTS, respectively. CONCLUSIONS The clinical, biomolecular, and immunohistochemical characterization of sebaceous skin lesions and keratoacanthomas may be used as screening for the identification of families at risk of MTS, a disease that is difficult to recognize and diagnose. Cancer 2005. © 2005 American Cancer Society.

Patients with stage I (Dukes' A) colorectal carcinoma tend to show a good prognosis; however, recurrences can be observed in some patients. Through a specialized colorectal cancer Registry, we attempted to investigate the epidemiological and clinical features of individuals with Dukes' A neoplasms.From 1984 to 1998, 295 individuals were diagnosed with Stage I /Dukes' A tumors; 150 of these had lesions infiltrating the muscular wall (T2), while 145 had neoplasms limited to the submucosa (T1).Dukes' A tumors represented 13.8% of all registered neoplasms; the percentage doubled over the study period (8.1% in the first year vs. 16.8% in the final year). In each year of observation, the preferential locations were the rectum and sigmoid colon (75% of all lesions). Most patients required surgery, but only 21.3% could be managed by endoscopic polypectomy. Overall 5-year survival was 81.0% (82.1% in T1, 80.0% in T2). Recurrences were seen in 6.8% (2.8% in T1, 10.7% in T2), while 36 patients (12.2%) died of causes unrelated to colorectal cancer. In 17 out of 20 patients who died of cancer, the lesions were localized in the rectosigmoid region. Survival analysis showed a significantly better prognosis (P0.007) for patients with T1 tumors.The proportion of stage I colorectal tumors tended to increase over time. Although the overall prognosis is good in four-fifths of the cases, approximately one-fifth of these patients die of recurrent disease or of other causes. As expected, the prognosis was significantly more favorable for patients with T1 lesions. For patients with T2 tumors, radical surgery is the most appropriate approach.

The main purpose of this study was to examine the expression of mucins and mismatch repair proteins in colorectal carcinomas. The immunohistochemical distribution of apomucins MUC2, MUC5AC, and the expression of MLH1 and MSH2 proteins were examined in 76 mucinous and 60 non-mucinous colorectal carcinomas. MUC2 was noted in all mucinous carcinomas, whereas MUC5AC was present in 41 cases only (54%). In non-mucinous carcinomas, MUC2 was expressed in 61.7% of the tumors; by contrast, MUC5AC was present in 20% of the cases. The expression level of apomucins was significantly different in mucinous and non-mucinous lesions (p0.001). Twenty-seven (35.5%) of the mucinous carcinomas showed no MLH1 expression, whereas 11 (18.3%) of the non-mucinous tumors did. This difference was statistically significant (p0.005). Altered expression of MSH2 protein was never observed. The lack of MLH1 expression was considerably more frequent in carcinomas with secretion of MUC5AC (p0.005). Our study has demonstrated this close relationship by immunohistochemical methods. In summary, our data show: (1) differences in the expression of mucins between mucinous and non-mucinous tumors; (2) a high frequency of altered MLH1 protein expression (35.5%) in mucinous carcinomas; (3) a significant relationship between the presence of MUC5AC and the altered expression of MLH1 protein in colorectal carcinomas.

Background and aims: Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors. Patients and methods: Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2 , hMLH1 , and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing. Results: Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected. Conclusions: The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the main genes involved in HNPCC can be detected in only 20% of cases.

Evidence-based guidelines on treatment of patients with Chronic Obstructive Pulmonary Disease (COPD) have recently been developed. Non-pharmacological therapy of COPD has been receiving more interest and has been evolving rapidly in the last decade as an essential part of COPD treatment. In fact, non-pharmacological treatment is a complementary approach mainly in the advanced stages of COPD. Most of these care options appear to benefit patients in terms of quality of life and cost-effectiveness. The aim of the present review is to survey the most important non-pharmacological treatments for COPD (smoking cessation, rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation, and surgery) and their usefulness based on the currently available evidence. This review is based on an evaluation of the literature using a multimethod approach. A computerized MEDLINE search from 1966 through June 2003 was undertaken using the search terms pulmonary rehabilitation, surgery, smoking cessation, respiratory insufficiency/failure, and lung disease/obstructive. Non pharmacological treatment of COPD is a real option to successfully treat these patients and prevent further deterioration. All the included therapies are based on actual scientific evidence for patient benefits. To date, smoking cessation, comprehensive rehabilitation and long-term oxygen therapy are widely accepted as therapies which may positively impact the long-term management of COPD patients.

In order to evaluate the factors associated with change in exercise capacity after comprehensive inpatient Pulmonary Rehabilitation (IPR) we studied 132 consecutive adults with Chronic Obstructive Pulmonary Disease (COPD) recovering from an acute exacerbation.Lung function, arterial blood gases, and respiratory muscle strength were measured at baseline. Perceived breathlessness (B), 6-minute walk distance (6MWD), dyspnea at rest and post-exertion (D), hospital anxiety and depression (HAD), and health-related quality of life were assessed before (T0) and after (T1) IPR. The patients were divided into two groups depending on the change in 6MWD: Improvers (IM at least +54 meters after IPR, n=81) or Non-Improvers (NIM, less than 54 meters or no change, n=51).At T1 61% of the patients showed improvement as here defined. The IM group showed lower 6MWD and higher B and resting-D at T0 than NIM (p0.05). A stepwise multiple regression analysis was performed using 6MWD change as the dependent variable. and anthropometric and physiological measures at T0 as the independent variables. This regression model explained 26% of the 6MWD-change; 6MWD and PaO2 significantly contributed to this model.In COPD patients recovering from an acute exacerbation, the predicted change in exercise capacity using anthropometric, demographic, clinical, and physiological variables after 2 weeks of comprehensive IPR is likely to be low. The baseline level of exercise performance and arterial oxygenation show the most consistent correlation with change in walking ability in these patients.

MMR gene mutations and MSI are not found in all clinically diagnosed HNPCC families. We evaluated whether MMR genotyping and tumor MSI analysis could identify distinct clinical subgroups among HNPCC families. Twenty-nine clinical HNPCC families were divided into 3 groups: A, families with hMLH1 or hMSH2 gene mutations; B, MMR gene mutations not present but MSI present in at least 50% of tumors tested; C, mutational and MSI analyses negative. We evaluated tumor spectrum, age at onset, risk of cancer in the follow-up and survival for CRC in the 3 groups. Tumors of the target organs in HNPCC (colon and rectum, endometrium, ovary, small bowel, stomach, renal pelvis and ureter) were more frequent in the first 2 groups than in the latter. Colon cancer was more frequently located in the proximal colon and showed an earlier age at onset in families with MMR gene mutation or with MSI than in families with stable tumors. Comparing the occurrence of tumors in the follow-up, in the first 2 groups patients younger than 50 years had a higher RR, which was particularly marked for CRC (RR = 18.6 for group A vs. group C, RR = 16.7 for group B vs. group C). CRC patients in the first 2 groups had a better clinical prognosis. The results of molecular analysis could distinguish, within clinically defined HNPCC families, different subgroups to which specific programs of surveillance could be addressed.

The transducer comprises a support structure carrying piezoresistive sensors, particularly of the thick-film type, which are intended to be resiliently deformed by the fluid pressure to be measured and to provide an electrical signal indicative of the value of the pressure. The support structure comprises a substantially mushroom-shaped metal body with a head and a shank. An axial blind hole is formed in the shank and is intended to contain the fluid whose pressure is to be measured. The hole also extends into the head and, with the end surface of the head, defines a wall which is resiliently deformable by the pressure to be measured. The piezoresistive sensors are connected to the end surface of the head of the mushroom-shaped body in correspondence with or adjacent the deformable wall so that they can in turn be deformed as a result of the deformation of the wall. The piezoresistive sensors are deposited on a thin plate fixed to the upper surface of the head of the mushroom-shaped body. The plate also carries the components of the circuits for amplifying and processing the signals generated by the sensors. A metal structure is also connected to the mushroom-shaped body to screen it from radio-frequency interference.

We have undertaken an observational retrospective cohort study to assess feasibility and clinical effectiveness of early rehabilitation in patients recovering from acute exacerbation of COPD (AECOPD). A cohort of 1826 inpatients (73% male, age 70+/-8 yrs, FEV(1) 50+/-16% pred.) admitted to a pulmonary rehabilitation (PR) program and completing at least 15 sessions were divided into categories according to their dyspnoea grade (Medical Research Council--MRC scores 2-5) as assessed before AECOPD. The pre-post changes in 6-minute walking distance (6MWD) test, perceived end-effort dyspnoea (Borg scale), and self-reported quality of life (St. George's respiratory Questionnaire: SGRQ) were measured throughout. Absolute change in 6MWD (52 [95%CI 45-59], 65 [95%CI 60-70], 63 [95%CI 59-66], and 70 [95%CI 67-74] meters in MRC 2-5 respectively) and the percentage of patients achieving the minimal clinically important difference (MCID) of +54 m (40, 55, 57, and 61%, respectively, p=0.001) differed across MRC grades. Proportion of patients able to reach > or = 350 m at the 6MWD after PR was higher in MRC 4 and 5 (18 and 22%) as compared to MRC 2 and 3 (6 and 15%). Early PR in a cohort of AECOPD patients is feasible and it is associated to clinically meaningful improvement in exercise tolerance independent on the severity of dyspnoea. The proportion of patients reaching the limit of > or = 350 m after this intervention is higher in the most severe patients.

PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer. PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P < .01), high mucinous component (P < .01), and poor differentiation (P = .002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations. CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.