Uveal melanoma is the most frequent primary tumour of the eye. It is molecularly clearly distinct from cutaneous melanoma and shows a different pattern of driver mutations. The influence of sunlight ...ultraviolet (UV) exposure on the aetiology of uveal melanoma is a matter of debate. The recent identification of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene with UV-induced cytidine-to-thymidine transitions in cutaneous melanoma prompted us to investigate whether these mutations also occur in uveal melanoma.
We analysed 50 cases of uveal melanoma obtained from enucleation surgery for mutations in the genes GNAQ, GNA11, BAP1, SF3B1, EIFAX1 and TERT, measured gene expression using microarrays and analysed gene copy numbers by SNP arrays.
We detected a TERT mutation in only one case of a 57-year-old white male patient with clinical and histopathological features typical for uveal melanoma. The tumour showed mutations in GNA11 and EIF1AX that are typical for uveal melanoma and absent from cutaneous melanoma. No mutations were detected in GNAQ, BAP1 and SF3B1 that are frequently mutated in uveal melanoma. Both copies of chromosome 3 were retained. Several tumours among which the one carrying the TERT promoter mutation showed elevated TERT expression. Consistent with previous reports, GNAQ is inversely associated with chromosome 3 monosomy and metastasis. BAP1 mutations are significantly associated with chromosome 3 monosomy but not with relapse.
These data indicate that TERT mutations are rare in uveal melanoma. No conclusion can be drawn on their potential influence on tumour progression.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective response to dacarbazine, the intravenous form of temozolomide (TMZ), in metastatic colorectal cancer (mCRC) is confined to tumors harboring O(6)-methylguanine-DNA-methyltransferase (MGMT) ...promoter hypermethylation. We conducted a phase II study of TMZ enriched by MGMT hypermethylation in archival tumor (AT), exploring dynamic of this biomarker in baseline tumor (BT) biopsy and plasma (liquid biopsy).
We screened 150 mCRC patients for MGMT hypermethylation with methylation-specific PCR on AT from FFPE specimens. Eligible patients (n = 29) underwent BT biopsy and then received TMZ 200 mg/m2 days 1–5 q28 until progression. A Fleming single-stage design was used to determine whether progression-free survival (PFS) rate at 12 weeks would be ≥35% H0 ≤ 15%, type I error = 0.059 (one-sided), power = 0.849. Exploratory analyses included comparison between MGMT hypermethylation in AT and BT, and MGMT methylation testing by MethylBEAMing in solid (AT, BT) and LB with regard to tumor response.
The PFS rate at 12 weeks was 10.3% 90% confidence interval (CI) 2.9–24.6. Objective response rate was 3.4% (90% CI 0.2–15.3), disease control rate 48.3% (90% CI 32.0–64.8), median OS 6.2 months (95% CI 3.8–7.6), and median PFS 2.6 months (95% CI 1.4–2.7). We observed the absence of MGMT hypermethylation in BT in 62.7% of tumors.
Treatment of mCRC with TMZ driven by MGMT promoter hypermethylation in AT samples did not provide meaningful PFS rate at 12 weeks. This biomarker changed from AT to BT, indicating that testing BT biopsy or plasma is needed for refined target selection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated ...the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Using proteomic analysis of the nuclear matrix (NM), we found that heterogeneous nuclear ribonucleoprotein K (hnRNP K), a member of the hnRNP family with pleiotropic functions, was differentially ...expressed in prostate cancer (PCa) tissues. This study aimed to characterise the expression of hnRNP K and its subcellular localisation in PCa, utilising immunohistochemical and quantitative western blot techniques. Furthermore, the hnRNP K expression was studied in human PCa cell lines in order to determine its modulation by bicalutamide, the anti-androgen widely used in PCa therapy. Immunohistochemical staining of paraffin-embedded tissues showed that hnRNP K was overexpressed in PCa, where it was localised both in the cytoplasm and in the nucleus. Staining of non-tumour tissues showed exclusively nuclear localisation and a less intense or absent signal. Immunoblot analysis demonstrated that the hnRNP K level within the NM was higher in PCa compared with non-tumour tissues and closely correlated with Gleason score (P=0.008). Higher expression within the NM was significantly (P=0.032) associated with poor prognosis. In two-dimensional western blot analysis hnRNP K presented several isoforms; the one with pI 5.1 was the most differently expressed between non-tumour and PCa tissues. Preliminary results indicate that hnRNP K can be modulated in vitro by a non-steroidal anti-androgen. Taken together, our findings suggest that hnRNP K has potential implications at the diagnostic, prognostic and therapeutic levels in PCa.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To obtain a picture of the work done in Italian anatomical pathology centres in 2014, and evaluate differences between the various centres in terms of the workloads of medical and non-medical staff.
...A self-administered questionnaire designed by a SIAPEC working group was e-mailed to 256 centres and subsequently collected by the Anatomical Pathology Service of Bolzano. QlikView software was used to prepare the final database and check the quality of the data, which were processed using version 18.0 of SPSS for Windows statistical software.
The questionnaire was completed by 120 of the centres (46.9%), which were staffed by a mean number of 6.6 physicians (range 1-24), 1.6 biologists (range 0-7), 10.8 laboratory technicians (range 2-47) and 2.2 administrative personnel (range 0-9). During 2014, the centres carried out a mean of 15,000 histology examinations (range 3,215-50,680), almost 11,700 immunohistochemistry examinations (range 0-54,359), and a mean of 1,471 molecular biology examinations (range 0-31,322) relating to a mean of 704 patients (range 0-9,434), and a mean of 16,509 cytology examinations (range 0-150,000) relating to 13,383 patients (range 0-120,000). Each centre physician issued a mean of 2,444 histology examinations reports (range 613-11,000); the ratio between the number of immunohistochemistry examinations and the number of histology examinations was 0.8 (range 0-2.7); and each laboratory technician had a mean overall annual workload of 3,072 histology, molecular biology and cytology examinations (range 793-9,882/year). These values varied widely among the participating centres. The mean ratio between the number of histology examinations carried out and the number of physicians was 1,982.77:1 a year in the small centres (< 10,000 histology cases/year), 2,627:1 a year in the medium-sized centres (10-24,999 histology cases/year), and 2,881.34:1 in the large centres (> 25,000 histology cases/year). There were significant differences between the small and medium-sized centres (p = 0.004) and between the small and large centres (p = 0.001), but not between the medium-sized and large centres.
The ratio between the total number of histology, molecular biology and cytology examinations and the number of laboratory technicians was 1,963.34 in the small centres (< 10,000 examinations/year), 2,717.11 in the medium-sized centres (10,000-24,999 examinations/year), and 3,531.56 in the large centres (≥ 25,000 examinations/year). There were significant differences between the small and large centres (p = 0.001) and between the medium-sized and large centres (p = 0.004), but not between the small and medium-sized centres.
The data collected by means of this survey provide an important, albeit partial, point of reference concerning the status of Italian anatomical pathology centres and their recent, everyday working situation.
Mencoboni M1, Bergaglio M2, Truini M3, Varaldo M4 1Medical Oncology Unit, "Villa Scassi" Hospital, Genova, Italy. 2Medical Oncology Unit, "Villa Scassi" Hospital, Genova, Italy. 3Pathology Unit, ..."National Cancer Institute", Genova, Italy. 4Urology Unit, "Villa Scassi" Hospital, Genova, Italy. Abstract The case presented here illustrates a 75 year old female patient who underwent surgical resection of a right adrenal mass of uncertain nature. The ï¬nal histological diagnosis was consistent with leiomyosarcoma arising from the adrenal anatomic site. Primary leiomyosarcoma of the adrenal gland is a very rare malignant mesenchymal neoplasm: to our knowledge, this is only the twelfth case reported in literature. We describe the clinical course and a brief review of clinical and histological features, biologic behaviour, diagnostic approaches and therapeutic strategies.
The development of malignant lymphomas, generally of the non-Hodgkin type (NHL), and with a preference to diffuse large cell B lymphomas (DLCBL), in systemic lupus erythematosus (SLE), has been ...analysed in an exhaustive recent literature. The combination of germline and somatic mutations, persistent immune overstimulation and the impairment of immune surveillance facilitated by immunosuppressive drugs, is thought to be at the origin of the increased lymphoma genesis. However the treatment and course of such affected patients is less known, and prognosis is generally estimated as poor. Out of 258 patients with complete/incomplete lupus and secondary antiphospholipid syndrome (APS) seen and treated at the institutional Day Hospital between 1982 and 2009, 6 developed lymphomas (4 DLCBL, 1 Hodgkin's and 1 indolent lymphocytic lymphoma). The first 5 patients were treated with high dose chemotherapy (HDCT) and achieved complete remissions (CR) with a follow-up comprised between 13 and 172 months. One patient relapsed of lymphoma and died 15 months following CR, with persistent lupus serology. One patient achieved complete remission (CR) of both diseases. In the other 3 lupus serology, Antinuclear and antiphospholipid antibodies (ANA, aPL) persisted, with occasional lupus flares and vascular complications. While eradication of the last cancer stem cell is tantamount to cure in neoplastic disease, persistent autoantigenic overstimulation may contribute to the refractoriness of autoimmunity. The implications of these results for the increasing utilisation of haematopoietic stem cell transplantation for severe autoimmune diseases (SADS), with lupus as a paradigm, are discussed.
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