Modificazioni morfo-strutturali placentari nel ritardo di crescita asimmetrico idiopatico

Obiettivo: valutare le alterazioni dello sviluppo e della struttura dei villi coriali di placente di gravidanze con ritardo di crescita fetale asimmetrico idiopatico (IUGR) tardivo. Pazienti e metodi: sono state esaminate 45 placente di pazienti con IUGR idiopatico con parto, per via vaginale o addominale, espletato dal gennaio 2001 al dicembre 2007 . L'esame istologico è stato condotto secondo le linee guida del Gruppo Italiano di Anatomia Patologica. La diagnosi di IUGR è stata posta sulla base dell'evidenza clinica ed ultrasonica di ridotta crescita fetale e basso peso neonatale in associazione a riduzione del liquido amniotico e a placenta “matura” all'esame USG. Risultati: l'esame istologico ha evidenziato lesioni dello sviluppo e della struttura dei villi tipici della ipoperfusione cronica placentare così definite: maturazione accelerata dei villi (ipermaturità villare), villite ischemica (equivalente a microinfarti) ed infarti. In 10 casi, insieme a tali lesioni, ne è stata identificata un'altra , definita “ipercapillarizzazione dei villi”, che si associa ad una condizione di ipossia relativa del sangue materno che circola tra i villi. Conclusioni: il ritardo di crescita intrauterino asimmetrico idiopatico può essere ricondotto ad alterazioni dell'angiogenesi e vasculogenesi che avvengono nelle fasi iniziali della gravidanza. Ciò determina una condizione di ipossia placentare con alterazioni dello sviluppo dei villi tipici della ipoperfusione cronica placentare

Zebrafish caudal fin as a model to investigate the role of probiotics in bone regeneration

: Probiotics are live microorganisms that confer several beneficial effects to the host, including enhancement of bone mineralization. However, probiotic action on bone regeneration is not well studied and therefore we analysed various effects of probiotic treatment on the caudal fin regeneration of zebrafish. Morphological analysis revealed an increased regenerated area with shorter and thicker lepidotrichia segments after probiotic treatment. Fourier transform infrared spectroscopy imaging analysis highlighted the distribution of phosphate groups in the regenerated fins and probiotic group showed higher amounts of well-crystallized hydroxyapatite. At the midpoint (5 days post amputation) of regeneration, probiotics were able to modulate various stages of osteoblast differentiation as confirmed by the upregulation of some key marker genes such as runx2b, sp7, col10a1a, spp1 and bglap, besides suppressing osteoclast activity as evidenced from the downregulation of ctsk. Probiotics also caused an enhanced cell cycle by regulating the expression of genes involved in Retinoic acid (rarga, cyp26b1) and Wnt/β-catenin (ctnnb1, ccnd1, axin2, sost) signaling pathways, and also modulated phosphate homeostasis by increasing the entpd5a levels. These findings provide new outlooks for the use of probiotics as a prophylactic treatment in accelerating bone regeneration and improving skeletal health in both aquaculture and biomedical fields

"Pure" large cell neuroendocrine carcinoma of the gallbladder. Report of a case and review of the literature

Primary Neuroendocrine Tumours (NETs) of the gallbladder are rare. Among all NETs of the gallbladder, large cell neuroendocrine carcinoma (LCNEC) is exceedingly rare. In most of the cases LCNECs are combined with other histological components. We reviewed clinical presentation and management of all patients with "pure" LCNEC from published literature since the first case was published in 2000, as well as one patient from our experience. Only 7 cases of "pure" LCNEC has been described in the last 15 years, our case is the eighth. The diagnosis of gallbladder NETs is rarely made preoperatively since the presentation generally consists of non-specific symptoms including upper abdominal pain, discomfort, jaundice, weight loss. The majority of patients are identified incidentally at the time of cholecystectomy for cholelithiasis. It is not possible to differentiate preoperatively between gallbladder adenocarcinoma and gallbladder neuroendocrine carcinoma (NEC) with imaging techniques. The only curative therapeutic modality for LCNECs is a complete en bloc surgical resection, including regional lymph node clearances and hepatic lobectomy, but only in patients without multiple metastasis. LCNECs benefit from an aggressive surgical resection in combination with chemotherapy, if resectability is possible. If the tumour is non-resectable, the primary management is therefore medical and not surgical. All patients with LCNEC presented a poor prognosis with a median survival of 10 months after the initial diagnosis. Only in five patients (62.5%) a wide surgical excision was performed, while in the other cases the tumour was non-resectable or multiple liver metastases were present at diagnosis

Notiziario

Museo dell’educazione di Mara Orlando e Fabio Targhetta;ANEP – Associazione Nazionale Educatori Professionali di Paola Scarpa e Luca Sambugaro;Summer school SIREF 2010, Trento 15-18 settembre 2010 “Nuovi scenari, nuovi sistemi, nuove rappresentazioni. Dove va la pedagogia? di Elisabetta Madriz e Luca Agostinetto.

topoisomerase iiα gene status and prediction of pathological complete remission after anthracycline based neoadjuvant chemotherapy in endocrine non responsive her2 neu positive breast cancer

Abstract Purpose Topoisomerase IIα (Topo II) is a potential marker of responsiveness to anthracycline-based therapy. We analyzed the role of Topo II gene status in the prediction of pathological complete remission (pCR) after primary anthracycline-based chemotherapy in non- endocrine responsive breast cancers overexpressing Her2/neu. Methods Twenty-three patients, with T2–T4, ER and PgR absent, overexpressing Her2/neu breast cancers treated with anthracycline-based chemotherapy were evaluated. Topo II gene status was assessed by FISH in pre-treatment tumor specimens and the results were correlated to pathological and clinical responses. Results Overall, six patients had a pCR (26%). Topo II was amplified in 5 (22%) of the tumors. In all patients with Topo II amplification, Her2/neu gene amplification was also detected. Among patients without amplification, one had polysomia of chromosome (Cr) 17 and four patients had deletion of the Topo II gene. A higher probability of pCR was observed when Topo II amplification and Cr 17 polysomy were present: pCR was reported in 3 of 5 amplified tumors (60%), in the polysomic tumor (amplified plus polysomic 67%) and in only 2 out of 13 tumors without alteration of Topo II status (15%). If we compare the frequency of pCR in tumors with amplification or polysomy versus the frequency of tumors with not amplification (deletion or no modification), a significant difference was detected ( p =0.02). One progressive disease (PD) was reported in one tumor with Topo II deletion (1/4, 25%) and one in tumor without any modification of Topo II gene status (1/13, 8%). Conclusions In patients with endocrine unresponsive and Her2 overexpressing tumors, Topo II amplification or the presence of chromosome 17 polysomy correlate with a significantly high probability of achieving pCR after neoadjuvant, anthracycline-based chemotherapy. Further prospective studies in order to more clearly define the predictive role of Topo II status in this subgroup of patients are warranted

HER2-Displaying M13 Bacteriophages induce Therapeutic Immunity against Breast Cancer

The advent of trastuzumab has significantly improved the prognosis of HER2-positive (HER2+) breast cancer patients; nevertheless, drug resistance limits its clinical benefit. Anti-HER2 active immunotherapy represents an attractive alternative strategy, but effective immunization needs to overcome the patient's immune tolerance against the self-HER2. Phage display technology, taking advantage of phage intrinsic immunogenicity, permits one to generate effective cancer vaccines able to break immune tolerance to self-antigens. In this study, we demonstrate that both preventive and therapeutic vaccination with M13 bacteriophages, displaying the extracellular (EC) and transmembrane (TM) domains of human HER2 or its Δ16HER2 splice variant on their surface (ECTM and Δ16ECTM phages), delayed mammary tumor onset and reduced tumor growth rate and multiplicity in ∆16HER2 transgenic mice, which are tolerant to human ∆16HER2. This antitumor protection correlated with anti-HER2 antibody production. The molecular mechanisms underlying the anticancer effect of vaccine-elicited anti-HER2 antibodies were analyzed in vitro against BT-474 human breast cancer cells, sensitive or resistant to trastuzumab. Immunoglobulins (IgG) purified from immune sera reduced cell viability mainly by impairing ERK phosphorylation and reactivating retinoblastoma protein function in both trastuzumab-sensitive and -resistant BT-474 cells. In conclusion, we demonstrated that phage-based HER2 vaccines impair mammary cancer onset and progression, opening new perspectives for HER2+ breast cancer treatment

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873

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