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Abstract: Electrochemotherapy (ECT) is an effective locoregional therapy for cutaneous melanoma metastases and has been safely combined with immune checkpoint inhibitors in preliminary experiences. Since ECT is known to induce immunogenic cell death, its combination with immune checkpoint inhibitors might be beneficial. In this study, we aimed to investigate the effectiveness of ECT on cutaneous melanoma metastases in combination with pembrolizumab. We undertook a retrospective matched cohort analysis of stage IIIC%IV melanoma patients, included in the International Network for sharing practices of ECT (InspECT) and the Slovenian Cancer Registry. We compared the outcome of patients who received the following treatments: (a) pembrolizumab alone, (b) pembrolizumab plus ECT, and (c) ECT. The groups were matched for age, sex, performance status, and size of skin metastases. The local objective response rate (ORR) was higher in the pembrolizumab-ECT group than in the pembrolizumab group (78% and 39%, p < 0.001). The 1 year local progression-free survival (LPFS) rates were 86% and 51% (p < 0.001), and the 1 year systemic PFS rates were 64% and 39%, respectively (p = 0.034). The 1 year overall survival (OS) rates were 88% and 64%, respectively (p = 0.006). Our results suggest that skin-directed therapy with ECT improves superficial tumor control in melanoma patients treated with pembrolizumab. Interestingly, we observed longer PFS and OS in the pembrolizumab-ECT group than in the pembrolizumab group. These findings warrant prospective confirmation.
Keywords: electrochemotherapy, metastatic melanoma, skin metastases
Published in DiRROS: 10.10.2022; Views: 465; Downloads: 233
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Abstract: BAP1 cancer syndrome is a rare and highly penetrant hereditary cancer predisposition. Uveal melanoma, mesothelioma, renal cell carcinoma (RCC) and cutaneous melanoma are considered BAP1 cancer syndrome core cancers, whereas association with breast cancer has previously been suggested but not confirmed so far. In view of BAP1 immunomodulatory functions, BAP1 alterations could prove useful as possible biomarkers of response to immunotherapy in patients with BAP1-associated cancers. We present a case of a patient with BAP1 cancer syndrome who developed a metastatic breast cancer with loss of BAP1 demonstrated on immunohistochemistry. She carried a germline BAP1 likely pathogenic variant (c.898_899delAG p.(Arg300Glyfs*6)). In addition, tumor tissue sequencing identified a concurrent somatic variant in BAP1 (partial deletion of exon 12) and a low tumor mutational burden. As her triple negative tumor was shown to be PD-L1 positive, the patient was treated with combination of atezolizumab and nab-paclitaxel. She had a complete and sustained response to immunotherapy even after discontinuation of nab-paclitaxel. This case strengthens the evidence for including breast cancer in the BAP1 cancer syndrome tumor spectrum with implications for future cancer prevention programs. It also indicates immune checkpoint inhibitors might prove to be an effective treatment for BAP1-deficient breast cancer.
Keywords: BAP1, breast cancer, hereditary cancer syndromes, immunotherapy
Published in DiRROS: 19.09.2022; Views: 449; Downloads: 181
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Abstract: Pathogenic/likely pathogenic variants in susceptibility genes that interrupt RNA splicing are a well-documented mechanism of hereditary cancer syndromes development. However, if RNA studies are not performed, most of the variants beyond the canonical GT-AG splice site are characterized as variants of uncertain significance (VUS). To decrease the VUS burden, we have bioinformatically evaluated all novel VUS detected in 732 consecutive patients tested in the routine genetic counseling process. Twelve VUS that were predicted to cause splicing defects were selected for mRNA analysis. Here, we report a functional characterization of 12 variants located beyond the first two intronic nucleotides using RNAseq in APC, ATM, FH, LZTR1, MSH6, PALB2, RAD51C, and TP53 genes. Based on the analysis of mRNA, we have successfully reclassified 50% of investigated variants. 25% of variants were downgraded to likely benign, whereas 25% were upgraded to likely pathogenic leading to improved clinical management of the patient and the family members.
Keywords: hereditary cancer, RNA sequencing, spliceogenic
Published in DiRROS: 07.09.2022; Views: 467; Downloads: 240
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Abstract: Objectives. To evaluate the access to comprehensive diagnostics and novel anti-tuberculosis medicines in European countries. Methods. We investigated access to genotypic and phenotypic M. tuberculosis drug susceptibility testing, availability of anti-tuberculosis drugs and calculated cost of drugs and treatment regimens at major tuberculosis treatment centers in countries of the World Health Organization (WHO) European region where rates of drug-resistant tuberculosis are highest among all WHO regions. Results are stratified by middle-income and high-income countries. Results. Overall, 43 treatment centers in 43 countries participated in the study. For WHO Group A drugs, the frequency of countries with availability of phenotypic drug susceptibility testing was as follows: 30/40 (75%) for levofloxacin, 33/40 (82%) for moxifloxacin, 19/40 (48%) for bedaquiline and 29/40 (72%) for linezolid, respectively. Overall, 36/43 (84%) and 24/43 (56%) of countries had access to bedaquiline and delamanid, while only 6/43 (14%) had access to rifapentine. Treatment of patients with extensively drug-resistant tuberculosis with a regimen including a carbapenem was only available in 17/43 (40%) of the countries. Median cost of regimens for drug-susceptible tuberculosis, multidrug-resistant/rifampicin-resistant tuberculosis (shorter regimen, including bedaquiline for six months) and extensively drug-resistant tuberculosis (including bedaquiline, delamanid and a carbapenem) were € 44 (min-max € 15-152), € 764 (min-max € 542-15152) and € 8709 (min-max € 7965-11759) in middle-income countries (n=12), and € 280 (min-max-€78-1084), € 29765 (min-max 11116-40584), € 217591 (min-max € 82827-320146) in high-income countries (n=29). Conclusion. In countries of the WHO Europe Region there is a widespread lack of drug susceptibility testing capacity to new and re-purposed anti-tuberculosis drugs, lack of access to essential medications in several countries and high treatment cost for drug-resistant tuberculosis.
Keywords: tuberculosis - drug therapy, Mycobacterium tuberculosis - drug therapy, health care costs - drug therapy, Europe
Published in DiRROS: 31.08.2022; Views: 698; Downloads: 144
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Keywords: non-native tree species, Alps, invasive alien species, forest management, urbanspace, climate changes
Published in DiRROS: 12.08.2022; Views: 539; Downloads: 201
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