Hepatic Ultrasonography Compared with Computed Tomography and Magnetic Resonance Imaging at Diagnosis of Metastatic Uveal Melanoma

Purpose To evaluate the consistency of hepatic ultrasonography (US) with staging computed tomography (CT) and magnetic resonance imaging (MRI), to analyze why US was inconsistent with CT/MRI, and to compare CT/MRI. DESIGN Reliability analysis. METHODS Two hundred fifteen patients whose primary uveal melanoma was managed in the Helsinki University Hospital and who were diagnosed with hepatic metastases by US within 60 days of staging CT/MRI from January 1999 to December 2016, were included. Patients attended a real-life follow-up schedule including hepatic US, liver function tests (LFT), and a confirmatory CT/MRI. We evaluated the consistency of US with staging CT/MRI regarding the presence and number of metastases. RESULTS The enrolled patients underwent 215 US, 167 CT, and 69 MRI examinations, and 67% of them had biopsy-confirmed metastases. Screening was regular for 98% of the patients, and 66% were asymptomatic. US was fully consistent with CT/MRI in detecting metastases in 113 (53%) patients, in 63 (29%) CT/MRI showed more metastases, and in 16 (7%) less metastases than US. CT/MRI was inconsistent with US in 23 (11%) patients. The sensitivity of US in detecting metastases was 96% (95% confidence interval, 92-98). US failed to suggest metastases in 10 patients. LFT were abnormal in six of them, and a newly-detected hepatic lesion was present by US in four. CONCLUSIONS Hepatic US is a sensitive screening modality in detecting metastases in patients with primary uveal melanoma, if combined with LFT and in case of any new detected lesion, a confirmatory MRI.Peer reviewe

Metastatic uveal melanoma managed with best supportive care

Non peer reviewe

Induction of adenocarcinoma from hamster pancreatic islet cells treated with N-nitrosobis(2-oxopropyl)amine in vitro

Our previous studies in the hamster pancreatic cancer model have indicated that pancreatic ductal adenocarcinomas derive not only from ductal/ductular cells but also from islets. To verify the presence of carcinogen-responsive cells within islets, we tested the effect of the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) on recently established continuous hamster pancreatic islet culture. Isolated pure pancreatic islets of hamsters were treated in vitro with BOP at a concentration of 0.25 mM three times a week for 19 weeks. Each treatment week was designed as a stage. The growth of these cells, designated KL5B, was compared with untreated cultured islets, designated KL5N. As in our previous study, between 14 and 21 days of culture, exocrine and intermediary cells developed within both KL5N and KL5B islets, which were then replaced by undifferentiated cells. No differences were found in the growth patterns of KL5N and KL5B until stage 4, when KL5B cells showed accelerated cell growth and cell pleomorphism, which increased gradually at later stages of treatment. Anchorage-independent and in vivo growth did not appear until stage 19. Mutation of c-Ki-ras at codon 12 (GGT→GAT) was detected in KL5B cells but not in KL5N cells. In vivo KL5B cells formed anaplastic invasive cancer with areas of glandular formation, overexpressed TGF-α and EGFR, expressed cytokeratin, vimentin, laminin and α-1 antitrypsin and reacted strongly with L-phytohemagglutinin and tomato lectin. Some cells within islets are responsive to the carcinogenic effects of BOP. Whether these cells represent islet cell precursors (stem cells) or malignant transdifferentiated islet cells remains to be see

Determinants of Long-Term Survival in Metastatic Choroidal and Ciliary Body Melanoma

Peer reviewe

Metastatic uveal melanoma : The final frontier

Publisher Copyright: © 2022Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10–13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95–100% and 83–100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.Peer reviewe

Silmämelanooma

English summaryPeer reviewe

Levinneen suonikalvoston melanooman hoito on kautta Suomen kansainvälistä tasoa

Lähtökohdat : Silmän suonikalvoston levinneen melanooman (uveamelanooma) hoitosuositukset vaihtelevat. Keräsimme väestöpohjaisen aineiston, jonka avulla selvitimme, onko yliopistopiirien välillä eroa elossaoloajassa tai hoitolinjoissa. Menetelmät : Aineistona oli 338 potilasta, joiden emokasvain oli hoidettu keskitetysti Hyksissä ja joiden levinnyt tauti todettiin 1999–2016 ja hoidettiin hajautetusti eri sairaanhoitopiireissä. Potilaat jaoteltiin Suomessa kehitetyn levinneisyysluokituksen, ensilinjan hoidon ja yliopistosairaalapiirin mukaan. Tulokset : Oireenmukaista hoitoa sai 33 % potilasta ja aktiivista 67 %, yliopistosairaalapiireittäin 21–40 % ja 60–79 %. Vastaavat elossaoloajan mediaanit olivat 1,6 kk ja 12 kk ja koko kohortissa 9,0 kk. Aktiivisesti hoidetusta leikattiin 9 %. Hoitotutkimuksiin osallistui 4 % potilaista. ­Suotuisimmassa levinneisyysluokassa IVa (ennuste ≥ 12 kk) oireenmukaisesti ja aktiivisesti ­hoidettujen elossaoloajat olivat 12 kk ja 18 kk. Levinneisyysluokissa IVa ja IVb (6–12 kk) ­elossaoloajat yliopistopiireittäin olivat toisiinsa verrattavat (p = 0,90 ja 0,91). Luokassa IVc (< 6 kk) oli eroa, mutta se hävisi tarkemmassa analyysissä (p = 0,33). Päätelmät : Yliopistosairaalapiirien tulokset vastaavat toisiaan ja kansainvälistä tasoa.Peer reviewe

Continuous-Time Classical and Quantum Random Walk on Direct Product of Cayley Graphs

In this paper we define direct product of graphs and give a recipe for obtained probability of observing particle on vertices in the continuous-time classical and quantum random walk. In the recipe, the probability of observing particle on direct product of graph obtain by multiplication of probability on the corresponding to sub-graphs, where this method is useful to determine probability of walk on complicated graphs. Using this method, we calculate the probability of continuous-time classical and quantum random walks on many of finite direct product cayley graphs (complete cycle, complete $K_n$, charter and $n$-cube). Also, we inquire that the classical state the stationary uniform distribution is reached as $t\longrightarrow \infty$ but for quantum state is not always satisfy.Comment: 21, page. Accepted for publication on CT

Toksični učinci olova u profesionalno izložene indijske obitelji

This article describes an entire family manufacturing lead acid batteries who all suffered from lead poisoning. The family of five lived in a house, part of which had been used for various stages of battery production for 14 years. Open space was used for drying batteries. They all drank water from a well located on the premises. Evaluation of biomarkers of lead exposure and/or effect revealed alarming blood lead levels [(3.92±0.94) µmol L-1], 50 % reduction in the activity of δ-aminolevulinic acid dehydratase [(24.67±5.12) U L-1] and an increase in zinc protoporphyrin [(1228±480) µg L-1]. Liver function tests showed an increase in serum alkaline phosphatase [(170.41±41.82) U L-1]. All other liver function test parameters were normal. Renal function tests showed an increase in serum uric acid [(515.81±86.29) µmol L-1] while urea and creatinine were normal. Serum calcium was low [(1.90±0.42) mmol L-1 in women and (2.09±0.12) mmol L-1 in men], while blood pressure was high in the head of the family and his wife and normal in children. Lead concentration in well water was estimated to 180 µg L-1. The family was referred to the National Referral Centre for Lead Poisoning in India, were they were received treatment and were informed about the hazards of lead poisoning. A follow up three months later showed a slight decrease in blood lead levels and a significant increase in haemoglobin. These findings can be attributed to behavioural changes adopted by the family, even though they continued producing lead batteries.Olovo je sveprisutni metal s mnogo namjena, a čovječanstvo ga rabi već više od 6000 godina. Danas je olovo među najrasprostranjenijim toksinima u okolišu, a drugi je na popisu toksičnih metala, odmah iza arsena. Mnogi još nisu svjesni njegova toksičnoga djelovanja te se i dalje izlažu olovu. Ovdje je opisana obitelj koja proizvodi olovne akumulatore i koja je pretrpjela trovanje olovom zahvaljujući svojoj neobaviještenosti. Ova peteročlana obitelj živjela je u jednome kućanstvu čiji je dio namijenjen različitim fazama proizvodnje akumulatora već 14 godina. Akumulatori su se sušili na otvorenome. Na imanju je bio i bunar s pitkom vodom. Mjerenja biopokazatelja izloženosti olovu i njegova djelovanja u svih pet članova obitelji dovela su do alarmantnoga saznanja o razinama olova u krvi [(3,92±0,94) µmol L-1], 50 %-tnom padu aktivnosti dehidrataze δ-aminolevulinske kiseline [(24,67±5,12) U L-1] te povišenom cinkovu protoporfirinu [(1228±480) µg L-1]. Jetrene probe otkrile su povišene razine alkalne fosfataze u serumu [(170,41±41,82) U L-1]. Ostali su parametri jetrene funkcije bili normalni. Testovi funkcije bubrega otkrili su povišene razine mokraćne kiseline u serumu [(515,81±86,29) µmol L-1], dok su razine ureje i kreatinina bile normalne. Također je zabilježen pad razina kalcija u serumu [(1,90±0,42) mmol L-1 u žena te (2,09±0,12) mmol L-1 u muškaraca]. Povišeni krvni tlak zamijećen je u glave obitelji i njegove supruge, dok je u djece bio normalan. Koncentracija olova u bunarskoj vodi bila je izrazito visoka, prema procjeni 180 µg L-1. Obitelj je upućena u indijski Državni referalni centar za otrovanje olovom (National Referral Centre for Lead Poisoning) gdje je primila lijekove i bila upoznata s činjenicama vezanim uz otrovanje olovom. Tromjesečno je praćenje pokazalo blagi pad razina olova u krvi te značajan porast hemoglobina. Ovi se nalazi mogu pripisati promjenama u ponašanju obitelji, bez obzira na to što je nastavila proizvoditi akumulatore

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma

Background: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I–V and of grade III–V immune-related adverse events (irAEs) was 37% and 7%, respectively. Methods: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. Results: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over (‘crossover’). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 (‘rechallenge’). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7–15.2) and the 3-year PFS rate was 32% (95% CI 25–40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48–83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6–NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I–IV irAE and 11 (6%) had a grade III–IV irAE. Conclusions: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged