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News Article | May 24, 2017
Site: www.eurekalert.org

"We expect our results to have a major influence on the future of autopsy practice in the UK, and across the world" - Professors Guy Rutty and Bruno Morgan A ground-breaking study by University of Leicester pathologists and radiologists could represent a breakthrough in how autopsy practice is conducted in the United Kingdom and around the world. The research was led by Professors Guy Rutty and Bruno Morgan from the University of Leicester. It was funded by the National Institute for Health Research (NIHR) and is published in the Lancet. Professor Rutty explained: "Over the years there have been several attempts to develop alternative approaches to the invasive autopsy to limit the extent to which the cadaver is dissected. Although these techniques have been published, the invasive examination remains the standard adopted approach." A previous study of PMCT published in the Lancet in 2012 showed promise for using medical imaging to investigate the cause of natural death, but with a major weakness: the inability to diagnose coronary artery disease, the most common cause of natural death. Professor Morgan explained: "In clinical CT scanning, a contrast agent is injected into a vein and circulation delivers it around the body. This allows the CT scan to show the state of blood vessels anywhere in the body. However, the lack of circulation in cadavers means these techniques cannot be used." This has been overcome by developing a novel minimally invasive coronary artery angiography technique. A variety of these techniques have been developed around the world over the last few years, but this is the first large-scale fully autopsy-controlled trial to demonstrate their efficacy in adult natural death. Professor Rutty explained: "Here at the University of Leicester we developed a quick and minimally invasive approach to improve diagnostic accuracy. This uniquely uses a combination of standard contrast agent (positive) and air (negative) to show the coronary artery lumens and ventricular cavities." Professor Morgan explained: "By 'minimally invasive' we mean that we use a catheter inserted into an artery to perform the angiography. The insertion techniques are like those we use on patients every day in our clinics, with just the use of local anaesthetic to numb the skin." The Leicester team applied their PMCTA technique to a cohort of 240 deaths investigated by the HM coroner. They show that a cause of death could be given in 92% of cases, based on "the balance of probabilities", the burden of proof required by the HM Coroner. Comparison with independently generated autopsy results showed that PMCTA had a similar accuracy to autopsy, did not miss autopsy-identifiable unnatural or "reportable" causes of death, and would also not significantly change population "cause of death" statistics. Professor Morgan added: "We have shown that PMCT enhanced by targeted coronary angiography can diagnose the cause of death in up to 90% of HM Coronial investigations for suspected natural death. This is the most successful application of PMCT and PMCTA to-date in natural death, and shows that a significant number of deaths could be investigated without the need for an invasive autopsy." PMCTA was found to be superior at identifying trauma and haemorrhage, whereas autopsy was superior at identifying pulmonary thromboembolism. Both tests had different strengths and weaknesses in heart and lung disease. Professor Rutty cautioned: "Both autopsy and PMCTA have different strengths and weaknesses as investigative approaches. When a higher burden of proof is required the 'gold standard' of death investigation should include both PMCT and invasive autopsy." The findings of the study are unique from an international perspective as it focuses on natural death. In the study a small number of unnatural deaths were also examined, showing PMCTA was also useful in these cases. Professor Rutty concludes: "There is already great interest in providing PMCTA as an alternative to autopsy in the UK with several centres, including Leicester, recently initiating services. These data now provide strong evidence to validate these services, especially where they use angiography techniques. We therefore expect these results to have a major influence on the future of autopsy practice in the UK, and across the world." Professors Rutty and Morgan are internationally recognised as pioneers, researchers and practitioners within the field of post mortem computed tomography. They are the authors of the largest body of scientific publications in this field within the United Kingdom, including research studies and educational papers and book chapters. They both state "we dedicate the success of our research to the families of Leicestershire, who have consented for their loved ones to be involved in these studies, despite being in a period of bereavement." They have pioneered other investigative adjuncts to augment PMCT studies, developed a 'patent-pending' PMCT catheter, and they have launched the first educational postgraduate teaching programs for PMCT at the University of Leicester, which started in 2016. The team believes adopting PMCTA as the standard first-line test in natural death would have a positive and profound effect on the public and religious groups within the UK and potentially beyond. The research was authored by Professor Guy Rutty (East Midlands forensic Pathology Unit, CSMM) and Professor Bruno Morgan (University Radiology Unit, CSMM), in collaboration with other University of Leicester, and University Hospitals of Leicester employees past and present. The paper 'Diagnostic accuracy of post-mortem Computed Tomography with targeted Coronary Angiography (PMCTA) when used as the first-line investigation for HM Coroner post-mortem investigations: prospective, blind comparison to a gold standard study' is published in The Lancet. More information about the postgraduate teaching programs in PMCT at the University of Leicester is available below: A video highlighting the new research is available here: https:/ Images are available here: https:/


Marech I.,Interventional Radiology Unit with Integrated Section of Translational Medical Oncology | Zizzo N.,University of Bari | Gadaleta C.,University of Bari | Introna M.,University of Bari | And 3 more authors.
Critical Reviews in Oncology/Hematology | Year: 2014

Masitinib mesylate (AB1010) is a novel potent and selective tyrosine kinase inhibitor, targeting mainly wild-type and mutated c-Kit receptor (c-KitR), Platelet Derived Growth Factor Receptor-alfa/beta (PDGFRa/ß), Lymphocyte-specific kinase (Lck), Lck/Yes-related protein (LYn), Fibroblast Growth Factor Receptor 3 (FGFR3) and Focal Adhesion Kinase (FAK). It is the first anticancer therapy approved in veterinary medicine for the treatment of unresectable canine mast cell tumors (CMCTs), harboring activating c-KitR mutations, at dose of 12.5. mg/kg once daily. Considering its anti-proliferative action, principally given by inhibiting the MCs c-KitR anti-angiogenic pathway that leads cancer progression, and its role as chemosensitizer, masitinib is under clinical investigation in several human malignancies (Gastro-Intestinal Stromal Tumors, acute myeloid leukemia, systemic mastocytosis, pancreatic cancer, multiple myeloma, non-small cell lung cancer, melanoma, ovarian and prostate cancer), which are characterized by similar canine c-KIT proto-oncogene mutations. Here, we analyze masitinib structure activity, its pharmacokinetics compared to imatinib, the c-KitR pathway referring to the most frequent c-KIT mutations sensitive or resistant to this novel drug compared to imatinib, and masitinib safety profile. We, also, explore preclinical and clinical (completed and ongoing) trials with the aim to emphasize as this recent anti-angiogenic therapy, at first approved in CMCTs and, currently in development for the treatment of several human neoplasms, could be represent a milestone in translational oncology, in which the murine experimental model of cancer research could be integrated by canine spontaneous tumor model. © 2013 Elsevier Ireland Ltd.


Caresana G.,Dermatology Unit | Giardini R.,Pathology Unit
Journal of the European Academy of Dermatology and Venereology | Year: 2010

Background: In basal cell carcinoma (BCC), excision margins between 3 and 10 mm, according to site, size, borders, previous treatment and histology, can allow for radical excision in at least 95% of cases. Objective: The objective was to ascertain whether dermoscopy can detect more accurately the lateral borders in BCCs than clinical examination alone, and allow us to obtain radical excision in more than 95% of cases with only 2-mm excision margins. Methods: A prospective study was performed of 200 consecutive BCCs of the head and neck removed with 2-mm dermoscopically detected excision margins. Morpheaform BCC, deeply recurrent BCC, BCC in Gorlin-Goltz syndrome, BCC located in sites not accessible through dermoscopy and superficial multifocal BCC were excluded. All cases of excised BCC were submitted to a uniform method of histological examination of the whole specimen with serial parallel sections at 2-mm intervals. Results: In only three cases did surgical excision with 2-mm margins prove to be inadequate; in the remaining 197 cases, the excision margins were tumour-free. The comparison of clinical and dermoscopic extension measurement showed concordance in 131 cases (65.5%). In 69 cases (34.5%), dermoscopic evaluation showed a larger peripheral extension. Conclusions: These results indicate that 2-mm dermoscopically detected excision margins can achieve histologically confirmed complete excisions in 98.5% of cases. © 2010 European Academy of Dermatology and Venereology.


Damm-Welk C.,Justus Liebig University | Mussolin L.,University of Padua | Mussolin L.,Instituto Of Ricerca Pediatrico Fondazione Citta | Zimmermann M.,Justus Liebig University | And 8 more authors.
Blood | Year: 2014

Detection of minimal disseminated disease (MDD) at diagnosis correlates with relapse risk in children with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL). We investigated whether minimal residual disease (MRD) positivity by qualitative reverse-transcriptase polymerase chain reaction (RT-PCR) for Nucleo-phosmin (NPM)-ALK during treatment identifies patients at the highest relapse risk. Blood and/or bone marrow of 180 patients with NPM-ALK-positive ALCL treated with Berlin-Frankfurt-Münster-type protocols were screened for NPM-ALK transcripts at diagnosis; 103 were found to be MDD-positive. MRD before the second therapy course could be evaluated in 52 MDD-positive patients. MRD positivity correlated with uncommon histology. The cumulative incidence of relapses (CIR) of 26 MDD-positive/MRD-positive patients (81% ± 8%) was significantly higher than the CIR of 26 MDD-positive/MRD-negative (31% ± 9%) and 77 MDD-negative patients (15% ± 5%) (P <.001). Five-year survival of MDD-negative and MDD-positive/MRD-negative patients was 91% ± 3% and 92% ± 5%, respectively, compared with 65% ± 9% of MDD-positive/MRD-positive patients (P >.001). Early evaluation of MRD in NPM-ALK-positive ALCL identifies patients with a very high relapse risk and inferior survival. © 2014 by The American Society of Hematology.


Donato M.F.,University of Milan | Monico S.,University of Milan | Malinverno F.,University of Milan | Aghemo A.,University of Milan | And 3 more authors.
Liver International | Year: 2015

Background & Aims: Recurrence of hepatitis C is a major cause of graft loss and shortened survival in patients receiving a liver transplant (LT) for end-stage hepatitis C virus (HCV) infection. The only way to improve graft and patient outcomes is a successful eradication of HCV infection by antiviral therapy either before or after transplant. This was achievable in a small proportion of recipients by IFN-based regimens, but could be obtained in the majority of them by using DAA IFN-free regimens before/after transplant. Methods: We describe a patient with decompensated cirrhosis because of severe recurrent hepatitis C, who had a retransplant following treatment with a combination of sofosbuvir and riba virin that started during the waiting time and was carried over during both the transplant and post-transplant phases for an overall period of 24 weeks. The patient gave a written consent to receive Sofosbuvir plus Rbv therapy pre and post-transplant. Results: Post-transplant serum HCV-RNA remains undetectable 24 weeks after discontinuing sofosbuvir and ribavirin (SVR24). Conclusions: Waiting for direct antiviral agents combinations, our findings not only support the use of sofosbuvir plus ribavirin as the first-line treatment in all patients on the LT waiting list, but also suggest to bridge treatment to the post-transplant period in case HCV RNA undetectability for at least 30 days has not been achieved at the time of LT. © 2014 John Wiley & Sons A/S.


Ovarian clear cell carcinoma is a unique type of ovarian cancer, often derived from endometriosis, and advanced-stage disease has a dismal prognosis primarily due to the resistance to conventional chemotherapy. Previous studies have shown frequent somatic mutations in ARID1A, PIK3CA, hTERT promoter, and amplification of ZNF217; however, the molecular alterations that are associated with its aggressiveness remain largely unknown. This study examined and compared cyclin E1 expression in endometriosis-related ovarian tumors, with the aim of determining the relationship between hTERT mutations and ARID1A expression and evaluating the effects of these molecular alterations on patient survival. We performed immunohistochemistry on 207 tumors [clear cell carcinoma (n=120), endometrioid carcinoma (n=49), and seromucinous tumors (n=38)], followed by two-color fluorescence in situ hybridization (n=88) and compared with ARID1A expression and hTERT promoter mutations in the same samples. Cyclin E1 overexpression and CCNE1 copy-number gain occurred in 23.3% and 14.8% of ovarian clear cell carcinomas, respectively, but they were not detected in any of the other endometriosis-related tumors. All cases with CCNE1 copy-number gain demonstrated an intense cyclin E1 immunoreactivity (P<0.001). Cyclin E1 overexpression was positively correlated with hTERT promoter mutations (P=0.01), but not with the loss of ARID1A expression. A multivariate analysis revealed that CCNE1 overexpression predicts poor overall survival, even after adjusting for stage and age. Specifically, CCNE1 overexpression and copy-number gain were both correlated with a poor outcome in patients with stage I disease. Moreover, the subset with CCNE1 overexpression and ARID1A retention demonstrated the worst outcome. Our findings suggest that gene copy-number gain and upregulation of CCNE1 occur in ovarian clear cell carcinoma and are associated with a worse clinical outcome, dictating the survival of early-stage patients, and that these molecular alterations are unique to clear cell carcinoma among different types of endometriosis-related ovarian neoplasms.Modern Pathology advance online publication, 21 October 2016; doi:10.1038/modpathol.2016.160. © 2016 United States & Canadian Academy of Pathology


Gandolfi G.,Instituto Of Ricovero E Cura A Carattere Scientifico | Sancisi V.,Instituto Of Ricovero E Cura A Carattere Scientifico | Torricelli F.,Instituto Of Ricovero E Cura A Carattere Scientifico | Ragazzi M.,Pathology Unit | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: The relevance of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) as a negative prognostic factor is a subject of intense debate. This mutation has been associated with several clinicopathological features, but the lack of consistency among data does not support its usefulness as marker of tumor aggressiveness and poorer outcome. Due to the genetic heterogeneity of the tumor, both the occurrence and the allele percentage of the BRAF mutation should be considered to unravel this controversy. Objective: We aimed to evaluate the impact of the BRAF V600E mutation occurrence and the allele percentage on the metastatic process in PTCs. Study Design: The presence and allele percentage of the BRAF mutation were determined by pyrosequencing in 132 cases of well-differentiated PTCs with (n = 37) or without lymph node metastases (LNMs) (n = 95) and in 40 LNMs matched with 35 PTCs. Results: No significant differences were observed in either the occurrence or the allele percentage of V600E mutation between the 2 groups of PTCs with or without LNMs. The LNMs were heterogeneous for the V600E mutation as the primary lesions. Conclusions: In this study, the occurrence and percentage of the BRAF V600E mutated allele was not preferentially associated with the development of metastases and the average mutated allele percentage decreased as the tumor progresses from the primary site to the lymph node metastatic sites. These observations support the need to reevaluate the role of the BRAF V600E mutation as a negative prognostic marker in PTCs. Copyright © 2013 by The Endocrine Society.


Betta P.-G.,Pathology Unit | Magnani C.,University of Eastern Piedmont and Azienda Ospedaliera Maggiore della Carita | Bensi T.,Pathology Unit | Trincheri N.F.,Pathology Unit | Orecchia S.,Pathology Unit
Archives of Pathology and Laboratory Medicine | Year: 2012

Context.-The pathologic approach to pleural-based lesions is stepwise and uses morphologic assessment, correlated with clinical and imaging data supplemented by immunohistochemistry (IHC), and more recently, molecular tests, as an aid for 2 main diagnostic problems: malignant mesothelioma (MM) versus other malignant tumors and malignant versus reactive mesothelial proliferations. Objective.-To present the current knowledge regarding IHC and molecular tests with respect to MM diagnosis, and in particular, the differentiation of the epithelioid type of MM from carcinoma metastatic to the pleural cavity. Data Sources.-A review of immunohistochemical features of 286 consecutive MMs from 459 cases of pleural pathology, diagnosed during routine practice from 2003 to 2009. A survey of biomedical journal literature from MedLine/PubMed (US National Library of Medicine) focused on MM and associated tissue-based diagnostic IHC markers and molecular tests. Conclusions.-The search for a single diagnostic marker of MM has so far been discouraging, given the biologic and phenotypic tumor heterogeneity of MM. The use of antibody panels has gained unanimous acceptance especially in the differential diagnosis between MM and metastatic carcinoma, whereas the usefulness of IHC is more limited when dealing with spindle cell malignancies or distinguishing malignant from reactive mesothelium. A great degree of interlaboratory variability in antibody combinations and clone selection within diagnostic panels still exists. Current investigations aim at selecting the most suitable and cost-effective combination of antibodies by using novel statistical approaches for assessing diagnostic performance beyond the traditional measures of sensitivity and specificity.


Cavazza A.,Pathology Unit | Muratore F.,Instituto Of Ricovero E Cura A Carattere Scientifico | Boiardi L.,Instituto Of Ricovero E Cura A Carattere Scientifico | Restuccia G.,Instituto Of Ricovero E Cura A Carattere Scientifico | And 6 more authors.
American Journal of Surgical Pathology | Year: 2014

We reviewed 888 temporal artery biopsies (TAB) performed in 871 patients in a single institution from January 1986 to December 2013. Forty-four biopsies (4.9%) were inadequate, 490 (55.2%) were devoid of inflammation and were considered negative, and 354 (39.9%) showed inflammation and were considered positive. On the basis of the localization of the inflammation, positive TABs were further classified into 4 categories: small vessel vasculitis (SVV), in which inflammation was limited to small periadventitial vessels devoid of muscular coat, with sparing of the temporal artery (32 cases, 9% of the positive biopsies); vasa vasorum vasculitis (VVV), in which inflammation was limited to the adventitial vasa vasorum (23 cases, 6.5% of the positive biopsies); inflammation limited to adventitia (ILA), in which inflammation extended from a strictly perivascular localization to the surrounding adventitia, without medial involvement (25 cases, 7% of the positive biopsies); and transmural inflammation (TMI), in which inflammation crossed the external elastic lamina and extended to the media (274 cases, 77.5% of the positive biopsies). In TMI, inflammation was generally more prominent between media and adventitia and mostly consisted of T lymphocytes and macrophages, with occasionally a significant number of plasma cells. Numerous eosinophils or neutrophils (with or without leucocytoclasia and suppurative necrosis), fibrinoid necrosis (limited to small branches of the temporal artery), and acute thrombosis were unusual, being present in 8%, 1.8%, 0.7%, and 9.5% of our biopsies with TMI, respectively. Giant cells, laminar necrosis, and calcifications prevailed along the internal elastic lamina and were present in 74.8%, 25.2%, and 20% of the biopsies with TMI, respectively. Among the 322 patients with positive TAB on whom we obtained clinical information, 317 had giant cell arteritis and 5 had a different disease: 3 (with SVV at histology) had ANCA-associated vasculitis, 1 (with SVV with amyloid deposits) had primary systemic amyloidosis, and 1 (with TMI limited to a small branch) had polyarteritis nodosa. In none of these cases the biopsy showed fibrinoid necrosis or significant numbers of eosinophils or neutrophils. Considering the 317 patients with giant cell arteritis, those with SVV and VVV compared with those with TMI had a significantly lower frequency of cranial manifestation (including headache, jaw claudication, and abnormalities of temporal arteries), lower serum levels of acute-phase reactants, and a reduced frequency of prednisone therapy at the time of TAB, of the "halo sign" at color duplex sonography of temporal arteries, and of systemic symptoms (for VVV). Polymyalgia rheumatica and blindness were equally represented in all patients groups, whereas there was a higher frequency of male sex and peripheral arthritis in patients with SVV. Patients with ILA were more similar to those with TMI, having a lower frequency of headache, of abnormalities of temporal arteries, and of a positive "halo sign" at color duplex sonography of temporal arteries. In conclusion, the histologic spectrum of inflammatory lesions that can be found in TAB is broad, and the differences have clinical implications. Copyright © 2014 by Lippincott Williams and Wilkins.


Piana S.,Pathology Unit | Ragazzi M.,Pathology Unit | Tallini G.,University of Bologna | De Biase D.,University of Bologna | And 3 more authors.
Human Pathology | Year: 2013

Papillary thyroid microcarcinoma generally carries an excellent prognosis, and fatal cases are becoming increasingly rare. Their pathologic and molecular features, however, remain largely unknown. We describe 3 cases of papillary thyroid microcarcinoma that, despite surgical and radioiodine treatment, recurred, metastasized, and eventually caused the death of the patients. In addition to morphology, immunohistochemical (cyclin D1 and p53) and molecular analyses (BRAF [v-raf Murine sarcoma viral oncogene homolog B1], KRAS [V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog], HRAS [v-Ha-ras Harvey rat sarcoma viral oncogene homolog], NRAS [neuroblastoma RAS viral oncogene homolog], and PIK3CA [phosphoinositide-3-kinase, catalytic, alpha polypeptide]) were performed. Interestingly, all 3 cases presented with massive lymph node metastases that showed morphological evidence of "tumor progression" (tall cell features, poorly differentiated areas, and high-grade cytologic features). Cyclin D1 was consistently immunoreactive in both primary and metastatic site, whereas p53 was negative. BRAF V600E was absent in both sites, and KRAS, HRAS, NRAS, and PIK3CA were consistently wild type. These data suggest that, in cases of metastatic papillary thyroid microcarcinoma, an accurate morphologic analysis of the metastatic deposits could contribute to a more accurate prediction of tumor behavior. © 2013 Elsevier Inc.

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