ERG alterations and mTOR pathway activation in primary prostate carcinomas developing castration-resistance

Introduction

One of the most common sites of distant metastasization of prostate cancer is bone, but to date reliable biomarkers able to predict the risk and timing of bone metastasization are still lacking.

Low prevalence of anti-HCV antibody among Italian children

Summary The seroprevalence of anti-HCV antibody was studied among 2,749 children and teenagers (1,438 males and 1,311 females) living in Italy. Anti-HCV antibody testing was positive by both EIA and RIBA in ten (0.36%) subjects. The positivity rate increased with age, ranging from 0 among children less than 6 years of age to 0.8% among those aged 17–19 years x² linear regression=0.038). Anti-HCV prevalence ranged from 0.2% in northeastern regions and in Apulia to 0.6% in Sicily and Sardinia (p>0.005), and no difference was seen between males (0.35%, C.I. 95%: 0.04–0.66) and females (0.38%, C.I. 95%:0.04–0.66) (Fisher's exact test=0.565). From these data it appears that in Italy HCV infection is an uncommon event during childhood.

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Niedrige Prävalenz von Anti-HCV-Antikörpern bei italienischen Kindern

Zusammenfassung Bei 2.749 Kindern und Jugendlichen (1.438 Jungen und 1.311 Mädchen), die in Italien leben, wurde eine Studie zur Seroprävalenz der anti-HCV Antikörper durchgeführt. Bei zehn der Getesteten (0,36%) fand sich mit EIA und RIBA ein positiver Befund. Die Rate an positiven Fällen nahm mit dem Alter zu von 0 bei Kindern unter 6 Jahren auf 0,8% bei den 17–19jährigen (Chi² lineare Regression=0,038). In den nordöstlichen Regionen and Apulien lag die anti-HCV Seroprävalenz bei 0,2%, in Sizilien und Sardinien bei 0,6% (p>0,005). Zwischen Mädchen und Jungen fand sich kein Unterschied (0,35%, 95% CI: 0,04–0,66 bei Jungen und 0,38%, 95% CI: 0,04–0,66; Fisher's exakter Test 0,565). Aus diesen Daten läßt sich ableiten, daß die HCV-Infektion in der Kindheit in Italien ein seltenes Ereignis ist.

     

Pancreatic undifferentiated carcinoma with osteoclast‐like giant cells is genetically similar to,but clinically distinct from,conventional ductal adenocarcinoma

Undifferentiated carcinoma of the pancreas with osteoclast‐like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well‐defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

InVivo Loss of Function Screening Reveals Carbonic Anhydrase IX as a Key Modulator of Tumor Initiating Potential in Primary Pancreatic Tumors

Reprogramming of energy metabolism is one of the emerging hallmarks of cancer. Up-regulation of energy metabolism pathways fuels cell growth and division, a key characteristic of neoplastic disease, and can lead to dependency on specific metabolic pathways. Thus, targeting energy metabolism pathways might offer the opportunity for novel therapeutics. Here, we describe the application of a novel in vivo screening approach for the identification of genes involved in cancer metabolism using a patient-derived pancreatic xenograft model. Lentiviruses expressing short hairpin RNAs (shRNAs) targeting 12 different cell surface protein transporters were separately transduced into the primary pancreatic tumor cells. Transduced cells were pooled and implanted into mice. Tumors were harvested at different times, and the frequency of each shRNA was determined as a measure of which ones prevented tumor growth. Several targets including carbonic anhydrase IX (CAIX), monocarboxylate transporter 4, and anionic amino acid transporter light chain, xc- system (xCT) were identified in these studies and shown to be required for tumor initiation and growth. Interestingly, CAIX was overexpressed in the tumor initiating cell population. CAIX expression alone correlated with a highly tumorigenic subpopulation of cells. Furthermore, CAIX expression was essential for tumor initiation because shRNA knockdown eliminated the ability of cells to grow in vivo. To the best of our knowledge, this is the first parallel in vivo assessment of multiple novel oncology target genes using a patient-derived pancreatic tumor model.     

MicroRNA in pancreatic adenocarcinoma: predictive/prognostic biomarkers or therapeutic targets?

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, short overall survival and few chemotherapeutic choices. MicroRNAs (miRNAs) are non-coding, single-stranded RNAs of around 22 nucleotides involved in the pathogenic mechanisms of carcinogenesis and metastasis. They have been studied in many tumors in order to identify potential diagnostic, prognostic or therapeutic targets. In the current literature, many studies have analyzed the role of miRNAs in PDAC. In fact, the absence of appropriate biomarkers, the difficultly of early detection of this tumor, and the lack of effective chemotherapy in patients with unresectable disease have focused attention on miRNAs as new, interesting advance in this malignancy.In this review we analyzed the role of miRNAs in PDAC in order to understand the mechanisms of action and the difference between the onco-miRNA and the tumor suppressor miRNA. We also reviewed all the data related to the use of these molecules as predictive as well as prognostic biomarkers in the course of the disease.Finally, the possible therapeutic use of miRNAs or anti-miRNAs in PDAC is also discussed.In conclusion, although there is still no clinical application for these molecules in PDAC, it is our opinion that the preclinical evidence of the role of specific miRNAs in carcinogenesis, the possibility of using miRNAs as diagnostic or prognostic biomarkers, and their potential therapeutic role, warrant future studies in PDAC.     

Hyaluronan in the Treatment of Chronic Rhinosinusitis with Nasal Polyposis

Chronic rhinosinusitis (CRS) is a common condition and affects the quality of life of approximately 16 % of adults in US and 10.9 % in Europe. Hyaluronan (HA) is a nonsulphate glycosaminoglycan found in the extracellular matrix of connective tissues, and plays an important role in the healing process and repair of mucosal surfaces. We aim to evaluate the effect of HA on nasal symptoms and endoscopic appearance in patients with CRS and nasal polyps (NP) who have not undergone sinus surgery. Eighty patients older than 18 years old were randomized to receive either open-label nebulized saline solution (NS) or intranasal corticosteroid spray (ICS) 200 µg bid or nebulized sodium hyaluronate (NHA, YABRO^®) or both ICS and NHA. Results were collected at 1 month, 3 months and 3 months after treatment. Significant improvements in nasal symptoms scores, endoscopic appearance scores, radiologic scores, rhinomanometry and saccharine clearance test were observed in the NHA, ICS and ICS + NHA groups after 1 month and 3 months of treatment compared with baseline (all p ≤ 0.005). The use of oral steroids was significantly reduced after 3 months of therapy in the same groups versus baseline (all p < 0.05). The incidence of adverse events at 3 months was similar between the 4 groups (all p > 0.05). Throat irritation, nasal burning and drug-related epistaxis were not reported in the group NHA. HA, as a nebulized nasal douche preparation, improved nasal symptoms and endoscopic appearances in patients with CRS and NP who have not undergone sinus surgery.     

Monosomy of chromosome 17 in breast cancer during interpretation of HER2 gene amplification

Monosomy of chromosome 17 may affect the assessment of HER2 amplification. Notably, the prevalence ranges from 1% up to 49% due to lack of consensus in recognition. We sought to investigate the impact of monosomy of chromosome 17 to interpretation of HER2 gene status. 201 breast carcinoma were reviewed for HER2 gene amplification and chromosome 17 status. FISH analysis was performed by using double probes (LSI/CEP). Absolute gene copy number was also scored per each probe. HER2 FISH test was repeated on serial tissue sections, ranging in thickness from 3 to 20 µm. Ratio was scored and subsequently corrected by monosomy after gold control test using the aCGH method to overcome false interpretation due to artefactual nuclear truncation. HER2 immunotests was performed on all cases. 26/201 cases were amplified (13%). Single signals per CEP17 were revealed in 7/201 (3.5%) cases. Five out of 7 cases appeared monosomic with aCGH (overall, 5/201, 2.5%) and evidenced single signals in >60% of nuclei after second-look on FISH when matching both techniques. Among 5, one case showed amplification with a pattern 7/1 (HER2/CEP17>2) of copies (3+ at immunotest); three cases revealed single signals per both probes (LSI/CEP=1) and one case revealed a 3:1 ratio; all last 4 cases showed 0/1+ immunoscore. We concluded that: 1) monosomy of chromosome 17 may be observed in 2.5% of breast carcinoma; 2) monosomy of chromosome 17 due to biological reasons rather than nuclear truncation was observed when using the cut-off of 60% of nuclei harboring single signals; 3) the skewing of the ratio due to single centromeric 17 probe may lead to false positive evaluation; 4) breast carcinomas showing a 3:1 ratio (HER2/CEP17) usually show negative 0/1+ immunoscore and <6 gene copy number at FISH.