Pharmacoeconomic management of patient with severe asthma in the Emergency Department: retrospective multicentric and cost of illness study.

OBJECTIVE: The aim of the study was to develop a cost-of-illness model that would investigate the costs associated with the management of patients suffering from asthma and severe asthma in the context of acute episodes managed in the emergency room. PATIENTS AND METHODS: A total of 795 records were collected between adults and paediatric patients. The data collection form reported an identification code for each patient included, gender, age, main discharge diagnosis, medical examinations carried out in the emergency room, the hospitalizations, and, if required by the patient condition, an outpatient visit performed by a pneumologist after the acute event that led the patient to the emergency room. In addition, the data collection form included information related to the pharmacological therapy taken by the patient. RESULTS: Among adult patients who had an admission with an asthma diagnosis, the average cost for the management of an adult patient in a green code in the emergency room is €330.39. As for the yellow code and the red code, the cost rises respectively to €444.04 and €808.25. The paediatric population has a slightly higher cost. As for the green code, the average cost stands at €355.87, for the yellow code €562.34 and €1,041.96 for the red code. CONCLUSIONS: Asthma and severe asthma impose a high burden on patients and society due to its chronicity, losses of productivity, and an increase in use of healthcare resources. We carried out the present observational retrospective analysis on asthma and severe asthma patients with the aim of assessing the economic impact from the Italian NHS perspective focusing also on the prescribed pharmacological therapies in the target conditions.

The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition.

The transcription factor Snail is a master regulator of cellular identity and epithelial-to-mesenchymal transition (EMT) directly repressing a broad repertoire of epithelial genes. How chromatin modifiers instrumental to its activity are recruited to Snail-specific binding sites is unclear. Here we report that the long non-coding RNA (lncRNA) HOTAIR (for HOX Transcript Antisense Intergenic RNA) mediates a physical interaction between Snail and enhancer of zeste homolog 2 (EZH2), an enzymatic subunit of the polycomb-repressive complex 2 and the main writer of chromatin-repressive marks. The Snail-repressive activity, here monitored on genes with a pivotal function in epithelial and hepatic morphogenesis, differentiation and cell-type identity, depends on the formation of a tripartite Snail/HOTAIR/EZH2 complex. These results demonstrate an lncRNA-mediated mechanism by which a transcriptional factor conveys a general chromatin modifier to specific genes, thereby allowing the execution of hepatocyte transdifferentiation; moreover, they highlight HOTAIR as a crucial player in the Snail-mediated EMT.

Evidence for a common progenitor of epithelial and mesenchymal components of the liver.

Tissues of the adult organism maintain the homeostasis and respond to injury by means of progenitor/stem cell compartments capable to give rise to appropriate progeny. In organs composed by histotypes of different embryological origins (e.g. the liver), the tissue turnover may in theory involve different stem/precursor cells able to respond coordinately to physiological or pathological stimuli. In the liver, a progenitor cell compartment, giving rise to hepatocytes and cholangiocytes, can be activated by chronic injury inhibiting hepatocyte proliferation. The precursor compartment guaranteeing turnover of hepatic stellate cells (HSCs) (perisinusoidal cells implicated with the origin of the liver fibrosis) in adult organ is yet unveiled. We show here that epithelial and mesenchymal liver cells (hepatocytes and HSCs) may arise from a common progenitor. Sca+ murine progenitor cells were found to coexpress markers of epithelial and mesenchymal lineages and to give rise, within few generations, to cells that segregate the lineage-specific markers into two distinct subpopulations. Notably, these progenitor cells, clonally derived, when transplanted in healthy livers, were found to generate epithelial and mesenchymal liver-specific derivatives (i.e. hepatocytes and HSCs) properly integrated in the liver architecture. These evidences suggest the existence of a 'bona fide' organ-specific meso-endodermal precursor cell, thus profoundly modifying current models of adult progenitor commitment believed, so far, to be lineage-restricted. Heterotopic transplantations, which confirm the dual differentiation potentiality of those cells, indicates as tissue local cues are necessary to drive a full hepatic differentiation. These data provide first evidences for an adult stem/precursor cell capable to differentiate in both parenchymal and non-parenchymal organ-specific components and candidate the liver as the instructive site for the reservoir compartment of HSC precursors as yet non-localized in the adult.

An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs.

Preservation of the epithelial state involves the stable repression of epithelial-to-mesenchymal transition program, whereas maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular mini-circuitry between master elements of these biological processes might provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4α, directly represses the expression of the epithelial microRNAs (miRs)-200c and -34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4α, previously identified as a transcriptional repressor of Snail, induces the miRs-34a and -200a, b, c that, when silenced, causes epithelial dedifferentiation and reacquisition of stem traits. Altogether these data unveiled Snail, HNF4α and miRs-200a, b, c and -34a as epistatic elements controlling hepatic stem cell maintenance/differentiation.

Isolation and characterization of a murine resident liver stem cell.

Increasing evidence provides support that mammalian liver contains stem/progenitor cells, but their molecular phenotype, embryological derivation, biology and their role in liver cell turnover and regeneration remain to be further clarified. In this study, we report the isolation, characterization and reproducible establishment in line of a resident liver stem cell (RLSC) with immunophenotype and differentiative potentiality distinct from other previously described liver precursor/stem cells. RLSCs, derived from fetal and neonatal murine livers as well as from immortalized hepatocytic MMH lines and established in lines, are Sca+, CD34-, CD45-, alpha-fetoprotein+ and albumin-. This molecular phenotype suggests a non-hematopoietic origin. RLSC transcriptional profile, defined by microArray technology, highlighted the expression of a broad spectrum of 'plasticity-related genes' and 'developmental genes' suggesting a multi-differentiative potentiality. Indeed, RLSCs spontaneously differentiate into hepatocytes and cholangiocytes and, when cultured in appropriate conditions, into mesenchymal and neuro-ectodermal cell lineages such as osteoblasts/osteocytes, chondrocytes, astrocytes and neural cells. RLSC capability to spontaneously differentiate into hepatocytes, the lack of albumin expression and the broad differentiative potentiality locate them in a pre-hepatoblast/liver precursor cells hierarchical position. In conclusion, RLSCs may provide a useful tool to improve liver stem cell knowledge and to assess new therapeutic approaches for liver diseases.

Angiolymphoid hyperplasia with eosinophilia: a rare artery lesion.

BACKGROUND: Angiolymphoid hyperplasia with eosinophilia (AHE) is a rare skin condition of unknown aetiology. The lesion seems neoplastic in nature, or at least an abnormal vasoproliferative reaction. CASE REPORT: A 40-year-old man presented with an 18-month history of erythematous papula over the right temporal area without a history of trauma. The patient reported a history of Hodgkin lymphoma at the age of 20, treated by radiochemotherapy. A subcutaneous nodule was found on the superior branch of the right temporal artery. An echocolordoppler revealed a normal temporal artery flow with pariental thickness. An excisional biopsy was performed and the patient remained asymptomatic at 24 months. The histological diagnosis was angiolymphoid hyperplasia with eosinophilia of the temporal artery. CONCLUSION: More appropriate studies are necessary to assess whether AHE is a manifestation of an unknown immunological disorder. If a correlation could be found between an altered immunological system and AHE, an intensive follow-up could be applied to patients. We report this case to encourage further studies to highlight potential challenges in the diagnosis and management of variants of vascular processes, such as AHE.

Two twins with teratoma of the ovary. An unusual association: case report.

Teratomas are neoplasms composed of tissue foreign to the area in which it is found. They are considered to be an acquired neoplastic disease and familial incidence has not been reported. Only one occurrence of teratoma between monozygotic twins has been found in the literature. Here we report the case of two heterozygotic twins with benign cystic teratomas of the ovary as a base for future research for efficacy of an accurate familial follow-up in order to diagnose this neoplasm in early stage and for the molecular understanding of pathogenesis of teratoma.

Monodermal highly specialized teratoma of the ovary: a sebaceous gland tumor.

Teratomas are neoplasms that originate in pluripotential cells and contain representations of all three germ layers in a rather mature state. Specialized forms of teratoma with unilateral development of certain tissues, such as struma ovarii, argentaffin tumors, cholesteatoma, primary choriocarcinoma of the ovary, pseudomucinous cystoma and neurogenic cysts are known. In this paper we describe an ovarian teratoma consisting entirely of sebaceous glands.

Synchronous and metachronous retroperitoneal sarcomas: two case reports.

BACKGROUND: Retroperitoneal sarcomas represent less than 1% of all diagnosed human neoplasias. They are generally malignant and can infiltrate retroperitoneal structures. The value of chemotherapy and radiotherapy are difficult to evaluate and the dominating factor in the outcome is the ability to resect the tumor. A few patients develop distant metastases. Recurrence of sarcoma at the operative site and on peritoneal surfaces is a prominent cause of morbidity and mortality. CASE REPORTS: Here we report two patients who underwent surgery for retroperitoneal sarcoma. In each of them at least two primary retroperitoneal tumors were diagnosed. The neoplasms were histologically different, thus they cannot be considered local recurrence but rather primary tumors. CONCLUSION: This is the first report underlying the synchronous or metachronous presence of different histological subtypes in this neoplastic pathology. In explanation of the occurrence of satellite tumors and multiple primary tumors, a virus-associated etiology or polyclonality of the tumor or pluripotentiality of tumor stem cells should be considered.

Prognostic impact of CD31 antigen expression in anal canal carcinoma.

BACKGROUND/AIMS: CD31 is a platelet endothelial cell adhesion molecule. Thus CD31 immunostaining of vascular endothelial cells can be used to measure degree of angiogenesis. As angiogenesis is necessary for tumor growth and metastasis, microvessels density could be a predictor of prognosis. The purpose of this study was to examine the relationship between CD31 value and standard pathologic parameters and prognosis of anal canal carcinoma. METHODOLOGY: Twenty-four patients with anal canal carcinoma were evaluated. Five-micron sections of formalin-fixed, paraffin-embedded tissue were tested with monoclonal anti-CD31 antibody. CD31 value is considered positive if more than 185 vessels/mm2 were counted. Pearson's chi 2 test was employed to test for association between CD31 value and clinicopathological variables. RESULTS: We found no correlation between CD31 value and histologic type, lymph node involvement, patients age and neoplastic relapse. Significant correlation was found between CD31 score and depth of parietal invasion. CONCLUSIONS: The relapse type could strengthen the hypothesis that increased vascularity promotes neoplastic dissemination. As angiogenesis could be used as prognostic indicator to determine patients who may be at higher risk for relapse, our results warrant further confirmation. Development of markers of angiogenic activity in anal canal carcinoma must be an integral part of proper clinical trials.

Plasma and tissue prolactin detection in colon carcinoma.

Serum concentrations of prolactin, a trophic hormone produced by the pituitary gland, have been shown to be raised in certain group of patients with cancer. Prolactin was detected in 0-20% of the colon cancer by immunohistochemistry and in plasma in 6-53% of the patients. These conflicting results do not support the hypothesis of an ectopic prolactin production by colon carcinoma. The aim of this study was to confirm the reported incidence of hyper-prolactinemia in colorectal cancer and to find further evidence for an ectopic prolactin production by the tumor. Thirty consecutive patients with colon carcinoma were studied. Before surgery all the patients underwent blood sample collection to assay plasma prolactin levels. All patients underwent colectomy. All the neoplastic specimens were tested with antiprolactin antibody. In none of the patients were significantly high preoperative levels of plasma prolactin found. Prolactin immunostaining was not identified in any of the tumor specimens. We could not confirm previous reports of frequent hyperprolactinemia in patients with cancer. This is the first report in which the incidence of both hyperprolactinemia and prolactin positive immunostaining was 0%. Our study was unable to demonstrate the synthesis of prolactin by colorectal cancers. The tumor is unlikely to be the source of hormone production. Our results suggest that circulating prolactin levels cannot be used as prognostic marker in patients with colon cancer.

Analysis of a follow-up program for anal canal carcinoma.

The ideal follow-up program for anal canal cancer remains unclear and controversial. We hereby describe an extensive follow-up program for anal canal carcinoma in order to evaluate which examinations and which diagnostic techniques really had impact on survival and management. We evaluated 25 patients with anal canal carcinoma. Local excision (LE) was performed in 5 patients, radiochemotherapy (RCT) in 13, radiochemotherapy and local excision (RCTE) in 7. Mean follow-up time was 6.3 years (range 20 months-11 years). The follow-up program included clinical examination, serum tumor markers evaluation, transrectal ultrasonography (TRUS), anoscopy with either mucosal or by Tru-cut needle multiple biopsies, standard chest X-ray and hepatic-inguinal ultrasonography, endoanal magnetic resonance imaging and in some cases total-body skeletal scintigraphy. A large multicentered randomized and prospective trial is surely lacking and should be undertaken as soon as possible. Our results suggest that an effective local control, rather than a higher survival is the reachable goal at present for anal canal carcinomas. However, further steps should be made to achieve better results. After this experience we propose a more semplified follow-up protocol which consists in performing only rectal examination, endoscopy, Tru-cut needle biopsies and TRUS for local control and inguinal ultrasound and TC to evidence distant metastases.

Hemangioma of the breast: an unusual lesion without univocal diagnostic findings.

Hemangiomas of the breast, either capillary or cavernous, are thin-walled, blood-filled vascular spaces, separated by fibrous septa, with extensive fibrosis and sometimes phleboliths. Clinical diagnosis is rather difficult. Generally they are coincidental microscopic findings. We report herein a case of breast hemangioma misdiagnosed at ultrasound and mammography. A 63-year-old woman described intermittent sharp pain in the right breast. Physical examination, mammography and ultrasonography were not sufficient for the diagnosis. Surgical excision of the lesion was performed. At histology it was found to be a cavernous hemangioma without cellular atypia. The patient is now 9 months post surgery and is well. The role of the single diagnostic examination is limited. The Authors believe the complementary role of all available techniques in the evaluation of a breast lesion.

Duodenal pancreatic heterotopy diagnosed by magnetic resonance cholangiopancreatography: report of a case.

We describe herein the case of a heterotopic pancreas that caused stenosis in the second portion of the duodenum. A 46-year-old man presented with upper abdominal pain and a 12-month history of intermittent vomiting. There was no history of melena, hematochezia, hematemesis, clay-colored stools, jaundice, or hepatitis and he did not describe any food dyscrasias, although fatty foods and alcohol seemed to make the symptoms worse. No specific medication or change in position relieved the pain. An initial diagnosis of chronic pancreatitis with multiple pseudocysts was made on the basis of elevated serum amylase and lipase levels, and abdominal ultrasonography and computed tomography (CT) findings. Medical treatment with octreotide was given for 8 weeks, but without any marked effect. Double-contrast barium examination and esophagogastroduodenoscopy were not diagnostic. Magnetic resonance (MR) cholangiopancreatography revealed findings indicative of cystic dystrophy of a heterotopic pancreas (CDHP), and an endoscopy supported this diagnosis. A pancreatoduodenectomy was performed and pathological examination confirmed a diagnosis of CDHP. In our opinion, MR cholangiopancreatography is the diagnostic tool of choice when CDHP is suspected.

Does extended lymphadenectomy influence prognosis of gastric carcinoma after curative resection?

BACKGROUND/AIMS: It is unclear whether gastric cancer prognosis is improved by extended lymph node dissection more than by lymph node dissection limited to the contiguous N1 perigastric lymph nodes. METHODOLOGY: Four hundred and thirty-eight patients treated by curative gastrectomy were evaluated. Outcomes of D1/D1.5 lymphadenectomy, limited lymph node dissection and of D2/D2.5 lymphadenectomy, extended lymph node dissection and histopathological prognostic factors as in the 1993 TNM staging classification supplement were analyzed. RESULTS: Estimated overall 5-year survival was 54.9%. Five-year survival was 58.4% in the limited lymph node dissection group and 54% in the extended lymph node dissection (P n.s.). Stage I 5-year survival was 59% after D2.5 lymph node dissection, 58% after D1.5 and 50% after D2 dissection (P n.s.). Stage II 5-year survival was 86% in D2.5 group and 56% in D1.5 group (P = 0.041). Stage IIIa survival was 61% in the D2.5 group and 22% in the D1.5 group (P = 0.001). Stage IIIb 5-year survival was 42% after D2.5 resection and 0% in D1.5 group (P = 0.001). In the pT3 group 5-year survival was 72% after D2.5 dissection and 33% after D2 dissection (P = 0.001). In the positive N1 lymph nodes group 5-year survival was better after extended lymph node dissection than after limited lymph node dissection. In pN2a patients 5-year survival was 57% after D2.5 resection and 0% after D2 resection (P < 0.001). In pN2b and pN2c patients extended lymph node dissection did not statistically improve survival. CONCLUSIONS: Even if no statistical differences were found in overall survival, prognosis was improved by extended lymph node dissection in stage II and III, particularly in T2 and T3 subgroups and in N1 and N2a subgroups. When large numbers of positive nodes were found, improved survival was dependent upon resection of extragastric nodes distal to the uppermost echelon of positive nodes.

Magnetic resonance imaging using endoanal coil in anal canal tumors after radiochemotherapy or local excision.

The ideal method for evaluation of anal canal tumors after radiochemotherapy and/or local excision remains controversial. Endoanal magnetic resonance imaging (EMRI) is a new, promising technique. The effectiveness of EMRI is reported in a study of 24 patients. Axial SET1-weighted and TSET2-weighted, sagittal and coronal T2-weighted sequences using Fat-suppression were acquired. In 4 cases, the low signal/noise ratio did not allow a diagnosis. In 6 cases, the lesion was not detected. Parietal hypo-intense thickening was detected in 14 patients, but it was not diagnostic for disease recurrence. In this study, EMRI showed 58.3% sensitivity and 41.6% specificity, thus it was not useful in the follow-up of anal tumors.

Inhibition of MMH (Met murine hepatocyte) cell differentiation by TGF(beta) is abrogated by pre-treatment with the heritable differentiation effector FGF1.

MMH (Met murine hepatocyte) liver cells derived from transgenic mice expressing a truncated constitutively active form of human c-Met are non-transformed immortalized cell lines. We have previously shown that they harbor: (1) epithelial cells that express the liver-enriched transcription factors HNF4 and HNF1(alpha), and that can be stably induced by FGF1 to express liver functions, and (2) fibroblast-like bi-potential palmate cells that can differentiate into bile duct-like structures in Matrigel cultures, or into epithelial cells competent to express hepatic functions. Low concentrations of TGF(beta) have been found to inhibit growth and differentiation of MMH cells. The factor stabilized the palmate cell phenotype, and it provoked epithelial cells to acquire palmate-like morphological characteristics, in parallel with down-regulation of expression of HNF4 and HNF1(alpha) and activation of Snail transcripts. The effects of TGF(beta) were dominant if it was added with FGF1, but the effects on differentiation were abrogated if cells had been pre-treated with FGF1. This work identifies TGF(beta) as a factor that could be implicated in maintaining bi-potential precursor cells in the liver, FGF1 as one that could over-ride the TGF(beta) effects and Snail as a candidate for mediation of the signal.

nm23-H1 protein expression in anal canal carcinoma: does it correlate with prognosis?

BACKGROUND AND OBJECTIVES: Anatomic extent is not the sole axis of classification of tumors and of tumor patients relevant to treatment planning and estimation of prognosis. This results in the need to demonstrate an improvement in prognostic assessment and choice of therapy achieved by consideration of factors other than TNM. nm23 protein does prevent tumor from metastasizing and may also play a role in the control of growth and development. The purpose of this study was to elucidate the clinical significance of nm23 expression in human anal canal carcinoma and to evaluate its influence on the outcome of patients after surgery or radiochemotherapy. METHODS: Twenty-two patients affected by anal canal carcinoma were evaluated. Each section was incubated with monoclonal antibody nm23 NDPK-A. Immunostaining was considered positive when at least 10% of the tumor cells were immunostained. RESULTS: nm23 immunoreactivity was detected in 6/22 (27.3%) tumors. No significant association was found between nm23 expression and prognosis. CONCLUSIONS: The mechanisms causing enhanced nm23-H1 expression in anal canal carcinoma are unknown. Although the level and expression were not correlated with prognosis, activation of nm23-H1 gene might be a prerequisite for oncogenesis in this type of tumor, while an alternate possibility is the modification of cellular characteristics in relation to proliferation and/or differentiation as a consequence of oncogenesis.

An unusual late radiotherapy-related complication requiring surgery in anal canal carcinoma.

We herein describe an unusual late radiation-related complication requiring surgery in a 60-year-old male affected by anal epidermoid carcinoma. The patient presented with obstructed defecation and ulcerated perianal lesions. The perianal biopsies were positive for anal squamous carcinoma. Transanal diagnostic investigations could not be performed because of anal stenosis. Computed tomography detected left inguinal lymphadenopathy and a nonhomogeneous presacral mass, infiltrating the rectal wall, the coccyx, and the sacrum. The patient underwent a colostomy, infusion of cisplatin and 5-fluorouracil, and irradiation of the pelvis, perianal region, and inguinal lymph nodes. In June 1997 the patient complained of the onset of continuous pain at the genitalia, and for penis necrosis he underwent penis amputation. The histologic examination was conclusive for postradiotherapy thrombosis. This complication could strengthen the hypothesis of vasculoconnective damage as the origin of long-term effects of radiotherapy. Probably the minimal dose in transit volume could not be achieved. Careful evaluation in choosing the treatment scheme is necessary if different options are available.

[Annular pancreas in adults: diagnostic considerations on a case]. / Il pancreas anulare nell'adulto: considerazioni diagnostiche su di un caso.

Annular Pancreas (AP) is a rare congenital anomaly that usually presents in childhood with symptoms referable to duodenal obstruction; nonetheless, this condition can manifest in adulthood with abdominal pain, pancreatitis, duodenal ulcer, pancreatic head mass. The Authors hereby discuss a case of AP observed in a 63 year-old patient in which EUS played a decisive role in achieving a certain diagnosis.