Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features.

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.

Recurrent fibrous solitary tumor of the parotid gland with satellite location: imaging, clinical and histological findings of rare entity.

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.

Massive juvenile polyposis of the stomach in a family with SMAD4 gene mutation.

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.

Saliva of patients affected by salivary gland tumour: An NMR metabolomics analysis.

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.

Risk of colorectal polyps and of malignancies in asymptomatic carriers of mutations in the main DNA mismatch repair genes.

OBJECTIVE: 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. MATERIAL AND METHODS: 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. RESULTS: 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-. CONCLUSIONS: 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.

Attenuated polyposis of the large bowel: a morphologic and molecular approach.

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 implementation of a Community Health Centre-based primary care model in Italy. The experience of the Case della Salute in the Emilia-Romagna Region.

BACKGROUND: 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. METHODS: We present updated data on the implementation on the CHC Case della Salute primary care model in the Emilia-Romagna Region. RESULTS: 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. DISCUSSION: 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.

Attitudes Toward Collaboration Among Practitioners in Newly Established Medical Homes: A Survey of Nurses, General Practitioners, and Specialists.

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.

An unusual case of familial adenomatous polyposis with very early symptom occurrence.

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.

Primary care units in Emilia-Romagna, Italy: an assessment of organizational culture.

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.

The relationship between physician empathy and disease complications: an empirical study of primary care physicians and their diabetic patients in Parma, Italy.

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.

Long-term survey of patients with curable colorectal cancer with specific reference to the quality of life.

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.

Relative role of APC and MUTYH mutations in the pathogenesis of familial adenomatous polyposis.

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.

Brugada-like EKG pattern and myocardial effects in a chronic propofol abuser.

INTRODUCTION: Cases of death are reported due to medical use of propofol, whereas deaths due to recreational purpose are unusual. CASE REPORT: 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. DISCUSSION: 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. CONCLUSION: 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.

Effects of early inpatient rehabilitation after acute exacerbation of COPD.

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.

Survival, surgical management and perioperative mortality of colorectal cancer in the 21-year experience of a specialised registry.

BACKGROUND AND AIMS: 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 AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Attitude of the Italian general population towards prevention and screening of the most common tumors, with special emphasis on colorectal malignancies.

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.

A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea.

BACKGROUND: 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. METHODS: NKX2.1, PAX8, NKX2.5, and TAZ genes were sequenced. RESULTS: 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. CONCLUSIONS: 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.

Myeloperoxidase-positive cell infiltration in colorectal carcinogenesis as indicator of colorectal cancer risk.

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 x100 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.

Beta-tryptase and quantitative mast-cell increase in a sudden infant death following hexavalent immunization.

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.