Novel cholesterol biosynthesis inhibitors targeting human lanosterol 14alpha-demethylase (CYP51)

Novel cholesterol biosynthesis inhibitors, a group of pyridylethanol(phenylethyl)amine derivatives, were synthesized. Sterol profiling assay in the human hepatoma HepG2 cells revealed that compounds target human lanosterol 14alpha-demethylase (CYP51). Structure-activity relationship study of the binding with the overexpressed human CYP51 indicates that the pyridine binds within the heme binding pocket in an analogy with the azoles.     

Fine needle aspiration cytology: a survey of current European practice

Fine needle aspiration cytology (FNAC) is practised widely throughout Europe. The majority of countries have dedicated cytopathologists as well as histopathologists practicing cytology. Despite this, FNAC is performed mostly by clinicians and radiologists except in the larger centres with dedicated staff with a special interest in cytopathology. The advent of One-Stop diagnostic services and image-guided procedures are prompting further development of FNAC clinics where cytopathologists take their own samples, issue reports in the same clinical session and take extra material for ancillary tests to complete the diagnosis. The volume of FNAC work varies accordingly; in dedicated centres FNAC represents up to 80% of the workload whilst, in the majority of countries, it represents one quarter or less. Hence, the rate of inadequate FNAC varies widely, depending on the local sampling policies and the organ, but does not exceed 25% in any of the countries. The most sampled organs are breast and thyroid, followed by lymph nodes. Most countries have dedicated training in cytopathology for pathology trainees, the duration varying between 6 months and 2 years of the total training time. This discussion, focusing on European practices, highlights the heterogeneity of FNAC activity but also its success in many centres where it is practiced to a high standard, particularly in breast, thyroid and lymph node pathology. The relatively high rate of inadequate material in some centres reflects local policies and calls for greater uniformity of FNAC practice, particularly specimen sampling. To achieve this, the future direction should concentrate on specialist training, to include performing as well as interpreting FNAC, as part of the curriculum. Current emphasis on web-based training may not provide first hand experience of the FNAC procedure and should be supplemented by attending FNAC clinics and developing the technique to its full potential.     

Endoscopic ultrasound-guided tissue sampling by combined fine needle aspiration and trucut needle biopsy: a prospective study

BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has a diagnostic accuracy of 70-90%, depending on the site under evaluation. In order to improve EUS-guided tissue sampling a novel 19-gauge trucut-type needle has been designed to obtain core biopsies during EUS. We prospectively evaluated the safety and accuracy of EUS-FNA alone versus combined EUS-FNA and trucut needle biopsy (TNB) in patients referred to our Unit over a 3-year period. PATIENTS AND METHODS: A total of 159 patients underwent EUS-FNA alone (lesions<2 cm) or the combination of both sampling modalities (lesions>or=2 cm). The adequacy of sampling, sensitivity, specificity and overall accuracies of EUS-FNA or EUS-TNB alone and combined EUS-FNA/TNB were determined. RESULTS: Adequate samples were obtained by EUS-FNA, EUS-TNB and EUS-FNA/TNB in 91%, 88% and 97% of patients, respectively. From the pancreas (n=83), adequate samples were obtained by FNA in 94% and by TNB in 81%, compared with 87% and 92% from non-pancreatic sites (n=76), respectively. The combination of both techniques resulted in more adequate samples from non-pancreatic cases than EUS-FNA alone (P=0.044). The specificity was 100%. Overall accuracy for EUS-FNA alone was 77%, for EUS-TNB alone 73% and for EUS-FNA/TNB 91% (P=0.008). For pancreatic sampling, the accuracy of EUS-FNA alone was 77%, for EUS-TNB alone 56% and for EUS-FNA/TNB 83%. For non-pancreatic sampling, the accuracy for EUS-FNA alone was 78%, for EUS-TNB alone 83% and for EUS-FNA/TNB 95% (P=0.006). The complication rate was 0.6%. CONCLUSIONS: Combined EUS-FNA/TNB for lesions>or=2 cm improves adequacy of sampling and diagnostic accuracy compared with either technique alone and is safe.     

O‐6RESPECTIVE ROLES OF FINE NEEDLE ASPIRATION CYTOLOGY AND CORE BIOPSY IN DIAGNOSIS OF SYMPTOMATIC BREAST LESIONS

Introduction: To evaluate and compare the respective roles of fine needle aspiration cytology and core biopsy for diagnosis of symptomatic breast lesions. Methods: Retrospective study on 589 breast fine needle aspiration cytology (FNAC) cases and 88 core biopsies (CB) with no associated FNAC, performed between January and December 2004. A computer database was searched for initial results, subsequent investigations and outcomes. Results: Of the cases that had FNAC performed as an initial investigation, the final diagnosis was reached by FNAC alone in 81.8% of cases. Of these, 59.2% were benign, 6.1% malignant and 2.4% remaining suspicious with 14.1% inadequate samples. There were 31 cases reported as suspicious (C3/C4) on FNAC, of these 14% of C3 and all of C4 were malignant on CB. Of the 86 cases that had both FNAC and CB, CB improved on the FNAC diagnosis of malignancy in 19.8% of cases, half of which were considered inadequate on FNAC. The positive predictive value of malignant cases was 100%, and the negative predictive value 98%. The absolute sensitivity of FNAC in this study was 65% and complete sensitivity 72%. The false negative rate was 8% and false positive rate 0%. The diagnosis of 88 CB without FNAC showed 37.5% to be malignant and 60.2% as benign, with 2.3% as inadequate biopsies. Discussion: FNAC remains the first line investigation in symptomatic breast lesions. Its best use is in the diagnosis of benign disease which constitutes over two thirds of patients in our practice. In suspicious and clinically malignant lesions, it is complemented by CB which may provide additional information relevant to management. In conclusion, the majority benign findings in our patients who had CB without prior FNAC, does not justify the use of CB as a first line investigation. CB is indicated in cases of inadequate or suboptimal FNAC. The continuous use of suspicious categories (C3/C4) in breast cytology is justified by the subsequent outcomes, both benign and malignant.     

Identification of a Novel Human Papillomavirus,Type HPV199, Isolated from a Nasopharynx and Anal Canal,and Complete Genomic Characterization of Papillomavirus Species Gamma-12

The novel human papillomavirus type 199 (HPV199) was initially identified in a nasopharyngeal swab sample obtained from a 25 year-old immunocompetent male. The complete genome of HPV199 is 7,184 bp in length with a GC content of 36.5%. Comparative genomic characterization of HPV199 and its closest relatives showed the classical genomic organization of Gammapapillomaviruses (Gamma-PVs). HPV199 has seven major open reading frames (ORFs), encoding five early (E1, E2, E4, E6, and E7) and two late (L1 and L2) proteins, while lacking the E5 ORF. The long control region (LCR) of 513 bp is located between the L1 and E6 ORFs. Phylogenetic analysis additionally confirmed that HPV-199 clusters into the Gamma-PV genus, species Gamma-12, additionally containing HPV127, HV132, HPV148, HPV165, and three putative HPV types: KC5, CG2 and CG3. HPV199 is most closely related to HPV127 (nucleotide identity 77%). The complete viral genome sequence of additional HPV199 isolate was determined from anal canal swab sample. Two HPV199 complete viral sequences exhibit 99.4% nucleotide identity. To the best of our knowledge, this is the first member of Gamma-PV with complete nucleotide sequences determined from two independent clinical samples. To evaluate the tissue tropism of the novel HPV type, 916 clinical samples were tested using HPV199 type-specific real-time PCR: HPV199 was detected in 2/76 tissue samples of histologically confirmed common warts, 2/108 samples of eyebrow hair follicles, 2/137 anal canal swabs obtained from individuals with clinically evident anal pathology, 4/184 nasopharyngeal swabs and 3/411 cervical swabs obtained from women with normal cervical cytology. Although HPV199 was found in 1.4% of cutaneous and mucosal samples only, it exhibits dual tissue tropism. According to the results of our study and literature data, dual tropism of all Gamma-12 members is highly possible.     

Serous fluid cytology of multicentric Castleman’s disease and other lymphoproliferative disorders associated with Kaposi sarcoma‐associated herpes virus: a review with case reports

C. Lobo, S. Amin, A. Ramsay, T. Diss and G. Kocjan Serous fluid cytology of multicentric Castleman’s disease and other lymphoproliferative disorders associated with Kaposi sarcoma‐associated herpes virus: a review with case reports Objective: The aim of this study is to describe and review the cytological features of Kaposi sarcoma‐associated herpes virus (KSHV) related entities, such as multicentric Castleman’s disease (MCD), plasmablastic‐lymphoma (PBL) and primary effusion lymphoma (PEL), which all may present as body cavity effusions. Serous fluid cytology of MCD and PBL has not, to our knowledge, thus far been described. Although different in nature, MCD, PBL and PEL are characterized by similar morphological features. Materials and methods: Body cavity effusions from four different patients with previously known or unknown KSHV‐related lymphoproliferations have been examined by routine cytology, immunocytochemistry (IC) and polymerase chain reaction (PCR). Results: MCD, PBL and PEL are all characterized by increased cellularity, comprising mainly lymphoid and plasmacytoid cells with variable proportions of immunoblasts. Immunocytochemistry and PCR results show the MCD to be CD138 and KSHV positive, CD30 negative, IgM, IgH and lambda restricted but IgH polyclonal. PBL was CD138 positive, kappa restricted, weakly positive with VS38 and over 80% positive with MIB 1. PEL was CD45, EMA, CD138, KSHV, p53 and CD3 positive, CD20, EBV, CD30, CD2, CD4, ALK1, epithelial and mesothelial markers negative, and PCR monoclonal B‐cell expanded (Ig‐kappa bands). Conclusion: Cytological examination of effusions in KSHV‐related lymphoproliferative disorders may show similar morphological features but clonality studies and immunocytochemistry are very helpful in distinguishing between these rare benign and malignant lymphoproliferative diseases.