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Use of circulating tumour DNA (ctDNA) as a liquid biopsy has been proposed for potential identification and monitoring of solid tumours. We investigate a next-generation sequencing approach for mutation detection in ctDNA in two related studies using a targeted panel. The first study was retrospective, using blood samples taken from melanoma patients at diverse timepoints before or after treatment, aiming to evaluate correlation between mutations identified in biopsy and ctDNA, and to acquire a first impression of influencing factors. We found good concordance between ctDNA and tumour mutations of melanoma patients when blood samples were collected within one year of biopsy or before treatment. In contrast, when ctDNA was sequenced after targeted treatment in melanoma, mutations were no longer found in 9 out of 10 patients, suggesting the method might be useful for detecting treatment response. Building on these findings, we focused the second study on ctDNA obtained before biopsy in lung patients, i.e. when a tentative diagnosis of lung cancer had been made, but no treatment had started. The main objective of this prospective study was to evaluate use of ctDNA in diagnosis, investigating the concordance of biopsy and ctDNA-derived mutation detection. Here we also found positive correlation between diagnostic lung biopsy results and pre-biopsy ctDNA sequencing, providing support for using ctDNA as a cost-effective, non-invasive solution when the tumour is inaccessible or when biopsy poses significant risk to the patient. [ABSTRACT FROM AUTHOR]

IDO is the rate-limiting enzyme in the kynurenine pathway, catabolizing tryptophan to kynurenine. Tryptophan depletion by IDO-expressing tumors is a common mechanism of immune evasion inducing regulatory T cells and inhibiting effector T cells. Because mammalian cells cannot synthesize tryptophan, it remains unclear how IDO+ tumor cells overcome the detrimental effects of local tryptophan depletion. We demonstrate that IDO+ tumor cells express a novel amino acid transporter, which accounts for ~50% of the tryptophan uptake. The induced transporter is biochemically distinguished from the constitutively expressed tryptophan transporter System L by increased resistance to inhibitors of System L, resistance to inhibition by high concentrations of most amino acids tested, and high substrate specificity for tryptophan. Under conditions of low extracellular tryptophan, expression of this novel transporter significantly increases tryptophan entry into IDO+ tumors relative to tryptophan uptake through the low-affinity System L alone, and further decreases tryptophan levels in the microenvironment. Targeting this additional tryptophan transporter could be a way of pharmacological inhibition of IDO-mediated tumor escape. These findings highlight the ability of IDO-expressing tumor cells to thrive in a tryptophan-depleted microenvironment by expressing a novel, highly tryptophan. specific transporter, which is resistant to inhibition by most other amino acids. The additional transporter allows tumor cells to strike the ideal balance between supply of tryptophan essential for their own proliferation and survival, and depleting the extracellular milieu of tryptophan to inhibit T cell proliferation. [ABSTRACT FROM AUTHOR]

Neutrophils are the main effector cells during inflammation, but they can also control excessive inflammatory responses by secreting anti-inflammatory cytokines. However, the mechanisms that modulate their plasticity remain unclear. We now show that systemic serum amyloid A 1 (SAA-1) controls the plasticity of neutrophil differentiation. SAA-1 not only induced anti-inflammatory interleukin 10 (IL-10)-secreting neutrophils but also promoted the interaction of invariant natural killer T cells (iNKT cells) with those neutrophils, a process that limited their suppressive activity by diminishing the production of IL-10 and enhancing the production of IL-12. Because SAA-1-producing melanomas promoted differentiation of IL-10-secreting neutrophils, harnessing iNKT cells could be useful therapeutically by decreasing the frequency of immunosuppressive neutrophils and restoring tumor-specific immune responses. [ABSTRACT FROM AUTHOR]

Summary: Patients with cancer may present with one or more circulatory markers of haemostatic activation which may be associated with tumor growth and cancer cell dissemination. In our clinical practice we observed haemostatic abnormalities with or without thrombotic episodes in cancer patients. The aim of the present study was to detect the D-dimer plasma levels in advanced-stage lung cancer patients before, during and after chemotherapy, and to determine whether there is a correlation with response rate, disease recurrence and survival, in order to estimate the possible predictive value of D-dimer plasma levels. Forty-seven/52 patients were evaluable and analysed; 38 patients had non-small-cell lung cancer (NSCLC) and 9 small-cell lung cancer (SCLC) and all were at an advanced stage or inoperable. Two (4.3%) achieved complete response (CR), 17 (36.2%) partial response (PR), and 16 (34%) had progressive disease (PD). We found that 14/19 (73.7%) patients with CR or PR showed a reduction in D-dimer plasma values and 11/16 (68.8%) with PD showed increased values; also, in patients with recurrent disease (12/13, 92.3%), D-dimer plasma levels were increased. All of the above values were statistically significant. D-Dimer plasma levels decrease or increase after response and progressive disease, respectively, and can act as a predictive factor of the evolution of the disease. [Copyright &y& Elsevier]

Aims: The MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel., Patients and Methods: Seventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level., Results: The median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved., Conclusions: SelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. JJS reports institutional funding for trial delivery from Amgen, AstraZeneca, Bristol-Myers Squibb, Delcath Systems, Merck, Replimune, Transgene; research grants from AstraZeneca, Bristol-Myers Squibb, Immunocore; paint consultancy/advisory Board membership from Bristol-Myers Squibb, Delcath Systems, Immunocore, Merck; and sponsorship for congress attendance: Bristol-Myers Squibb, Merck. TRJE has received honoraria for consultancies (payable to the employing institution) from Ascelia, Astra Zeneca, Bayer, Bicycle Therapeutics, Bristol-Myers Squibb, Celgene, Eisai, Karus Therapeutics, Medivir, MSD, Otsuka, Roche, and Seagen; honoraria for speaker’s fees (payable to employing institution) from Astra Zeneca, Ascelia, Bayer, Bristol Myers Squibb, Celgene, Eisai, Nucana, MSD, Roche, Medivir, and United Medical; has received support of costs of commercial clinical trials (payable to employing institution) from Astra Zeneca, Basilea, Bayer, Celgene, Exscientia; Exelexis; MiNa Therapeutics, Roche, Pfizer, Sierra, Lilly, Eisai, GSK, Novartis, Bicycle Therapeutics, Johnson and Johnson, CytomX, Vertex, Plexxikon, Boehringer, Athinex, Adaptimmune, Bristol Myers Squibb, MSD, Medivir, Versatem, Nucana, Immunocore, Berg, Beigene, Iovance, Modulate, BiolinerX, Merck Serono, Nurix Therapeutics, T3P, Janssen Clovis, Sanofi-Aventis, Halozyme, Starpharma, UCB, Sapience, Seagen, Avacta, and Codiak; has received funding from Cancer Research UK, Chief Scientist’s Office Scotland, and the MRC; (payable to employing institution); has received support to attend national & international congresses from Bristol-Myers Squibb, Roche, MSD, Celgene, Pierre-Fabre (personal). SO reports honoraria from BMS. Merck, MSD, AstraZeneca and Janssen; and consulting fees from MSD, Immuncore, Janssen and Genmab. JL reports research funding from Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics; Consulting fees from iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte; and Honoraria from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMSIK reports consulting fees from Merck Serono; and research funding from Genetech, Achilles Therapeutics and Replimune. PL reports honoraria from Norvartis, PierreFabre, Merck , BMS, NeraCare GmbH, Amgen, Roche and oncology Education Canada; and research funding from BMS, PierreFabre. RP report honoraria for attending advisory boards from Pierre Faber, Bayer, Novartis, BMS, Ellipses, Immunocore, Genmab, Astex Therapeutics, MSD, Nerviano, AmLo, Incyte, Cybrexa Benevolent AI and Sanofi Aventis; honoraria for working as an IDMC member for Alligator Biosciences, GSK, Onxeo, SOTIO Biotech AG, and AstraZeneca; honoraria for delivery of educational talks or chairing educational meetings by AstraZeneca, Novartis, Bayer, MSD and BMS; and funds to support attendance at conferences from MSD and BMS. PP reports research funding from AstraZeneca. AO-B reports honoraria from BMS, MSD, Eisai, Roche, Novartis, AZ; and research Funding from BMS UCB pharma, Roche, Novartis and Eli Lily. HS report paid consultancy for Novartis, BMS, MSD, Immunocore, Idera, Iovance, Genmab, Sanofi Genzyme/Regeneron, Macrogenics, Roche, Agenus, Ideaya, iOnctura, CDR-Life, NovalGen, Therakos/Mallinkrodt Pharmaceuticals, ScanCelll; and speakers bureau for Novartis, BMS, MSD, Sanofi Genzyme/Regeneron, AstraZeneca, Eisai. SL reports consulting for Bayer, Immunocore; and expenses from Bayer. PN discloses Data and Safety Monitoring for 4SC, Achilles; and Consultant/Advisory Board for 4SC, Bristol-Myers Squibb, Immunocore, Merck, Merck Sharp and Dohme, Novartis, Pfizer; Research Grant/Contract: Immunocore. The other authors do not report any potential conflicting interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recent studies indicate that melphalan percutaneous hepatic perfusion (M-PHP) for liver metastases from ocular melanoma (mUM) improves survival. Importantly, this benefit must be carefully balanced with changes in a patient's quality of life (QoL). This study examines the QoL changes post-M-PHP., Methods: Retrospective analysis of the change in QoL using the Functional Assessment of Cancer Therapy-General (FACT-G) with mUM patients receiving M-PHP ( n  = 20). The FACT-G scores, which comprise physical (PWB), social (SWB), emotional (EWB) and functional (FWB) wellbeing were measured pre-procedure and at day 1, day of discharge (mean = 2.4 days), 7, 14 and 28 days after M-PHP therapy. Wilcoxon signed-rank test gauged QoL domain changes., Results: Baseline FACT-G median (IQR) scores were 101.8 (21.8). QoL scoring significantly decreased immediately after the procedure [day 1; 85 (27.5); P  = 0.002] and gradually improved over time. By day 28, QoL almost returned to pre-procedure levels [100.3 (13.8); P  = 0.31]. Subscore analysis revealed that the initial drop in QoL at day 1 post-procedure was attributable to the PWB (28 vs. 24; P  = 0.001) and FWB domains (26 vs. 18.5; P  < 0.001). By day 28 there was a statistically significant improvement in EWB ( P  = 0.01)., Conclusion: QoL following M-PHP decreases immediately after therapy and is not significantly different from baseline by the day of discharge. By day 28 there is improved emotional well-being. This study could help to optimize the time between treatment cycles when combined with toxicity data and blood count recovery., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

In the evolving landscape of Industry 4.0, the convergence of peer-to-peer (P2P) systems, LoRa-enabled wireless sensor networks (WSNs), and distributed hash tables (DHTs) represents a major advancement that enhances sustainability in the modern agriculture framework and its applications. In this study, we propose a P2P Chord-based ecosystem for sustainable and smart agriculture applications, inspired by the inner workings of the Chord protocol. The node-centric approach of WiCHORD+ is a standout feature, streamlining operations in WSNs and leading to more energy-efficient and straightforward system interactions. Instead of traditional key-centric methods, WiCHORD+ is a node-centric protocol that is compatible with the inherent characteristics of WSNs. This unique design integrates seamlessly with distributed hash tables (DHTs), providing an efficient mechanism to locate nodes and ensure robust data retrieval while reducing energy consumption. Additionally, by utilizing the MAC address of each node in data routing, WiCHORD+ offers a more direct and efficient data lookup mechanism, essential for the timely and energy-efficient operation of WSNs. While the increasing dependence of smart agriculture on cloud computing environments for data storage and machine learning techniques for real-time prediction and analytics continues, frameworks like the proposed WiCHORD+ appear promising for future IoT applications due to their compatibility with modern devices and peripherals. Ultimately, the proposed approach aims to effectively incorporate LoRa, WSNs, DHTs, cloud computing, and machine learning, by providing practical solutions to the ongoing challenges in the current smart agriculture landscape and IoT applications.

For inoperable esophageal adenocarcinoma (EAC), identifying patients likely to benefit from recently approved immunochemotherapy (ICI+CTX) treatments remains a key challenge. We address this using a uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable EAC patients received first-line immune checkpoint inhibitors for four weeks (ICI-4W), followed by ICI+CTX. Comprehensive biomarker profiling, including generation of a 65,000-cell single-cell RNA-sequencing atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, reveals a novel T cell inflammation signature (INCITE) whose upregulation correlates with ICI-induced tumor shrinkage. Deconvolution of pre-treatment gastro-esophageal cancer transcriptomes using our single-cell atlas identifies high tumor monocyte content (TMC) as an unexpected ICI+CTX-specific predictor of greater overall survival (OS) in LUD2015-005 patients and of ICI response in prevalent gastric cancer subtypes from independent cohorts. Tumor mutational burden is an additional independent and additive predictor of LUD2015-005 OS. TMC can improve patient selection for emerging ICI+CTX therapies in gastro-esophageal cancer., Competing Interests: Declaration of interests S.L.: consulting fees, honoraria, travel/accommodation or research funding (Sanofi, GLG Consulting, Rejuversen, Eisai, Prosigna, Roche, Pfizer, Novartis, Shionogi, Synthon, CRUK, Boehringer Ingelheim, Piqur Therapeutics, AstraZeneca, Carrick Therapeutics, Merck KGaA) and previous employment by Pfizer. A.R.: stock ownership (Amgen, Immunogen). I.K: honoraria, travel/accommodation (BMS , Delcath Inc, Immunocore, Pierre Fabre, Genentech, Merck Serono, Takeda Pharmaceuticals Int.). B.J.V.D.E.: consulting and ownership interests (iTeos Therapeutics, Oncorus, Amgen, Vaccitech). M.R.M.: grants or personal fees (AstraZeneca, Roche, G.S.K., Novartis, Immunocore, BMS, Pfizer, Merck/MSD, Regeneron, BiolineRx, Replimune, Kineta, Silicon Therapeutics and GRAIL). T.M.C.: founder, employee, and shareholder (Cleancard). X.L.: consulting (SimCell). A provisional patent related to applications of the INCITE signature has been filed. No other authors declare competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Management of liver metastases from uveal melanoma (LMUM) requires multimodal approach. This study describes evolution of liver resection for LMUM, reviewing current literature and institutional outcomes. Records of patients referred to the Melanoma Multi-Disciplinary Team between February 2005 and August 2018 were reviewed. All publications describing surgery for LMUM were identified from PubMed, Embase, and Google Scholar. Thirty-one of 147 patients with LMUM underwent laparoscopic liver biopsy, and 29 (14 females) had liver resections. Nineteen liver resections were performed locally [7 major (≥3 seg), 14 laparoscopic] without major complications or mortality. Overall survival positively correlated with the time from uveal melanoma to LMUM (Spearman's rho rs  = 0.859, P  < 0.0001). Overall and recurrence-free survivals were comparable following R1 or R0 resections (OS 25 vs. 28 months, P  = 0.404; RFS 13 vs. 6 months, P  = 0.596). R1 resection cohort had longer lead-time (median 100 vs. 24 months, P  = 0.0408). Eleven publications describing liver resection for LMUM were identified and included in the narrative review. Surgery for LMUM is safe and complements multidisciplinary management. Despite heterogeneity in literature, time from diagnosis of uveal melanoma to LMUM remains a key factor affecting survival after liver resection., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Uveal melanoma, the most common primary ocular malignancy in adults, carries a poor prognosis: 50% of patients develop the metastatic disease with a 10-25% 1-year survival and no established standard of care treatment. Prior studies of melphalan percutaneous hepatic perfusion (M-PHP) have shown promise in metastatic uveal melanoma (mUM) patients with liver predominant disease but are limited by small sample sizes. We contribute our findings on the safety and efficacy of the procedure in the largest sample population to date. A retrospective analysis of outcome and safety data for all mUM patients receiving M-PHP was performed. Tumour response and treatment toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events v5.03, respectively. 250 M-PHP procedures were performed in 81 patients (median of three per patient). The analysis demonstrated a hepatic disease control rate of 88.9% (72/81), a hepatic response rate of 66.7% (54/81), and an overall response rate of 60.5% (49/81). After a median follow-up of 12.9 months, median overall progression-free (PFS) and median overall survival (OS) were 8.4 and 14.9 months, respectively. There were no fatal treatment-related adverse events (TRAE). Forty-three grade 3 (29) or 4 (14) TRAE occurred in 23 (27.7%) patients with a significant reduction in such events between procedures performed in 2016-2020 vs. 2012-2016 (0.17 vs. 0.90 per patient, P < 0.001). M-PHP provides excellent response rates and PFS compared with other available treatments, with decreasing side effect profile with experience. Combination therapy with systemic agents may be viable to further advance OS., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Immune-checkpoint blockade (ICB) has shown remarkable clinical success in boosting antitumor immunity. However, the breadth of its cellular targets and specific mode of action remain elusive. We find that tumor-infiltrating follicular regulatory T (T FR ) cells are prevalent in tumor tissues of several cancer types. They are primarily located within tertiary lymphoid structures and exhibit superior suppressive capacity and in vivo persistence as compared with regulatory T cells, with which they share a clonal and developmental relationship. In syngeneic tumor models, anti-PD-1 treatment increases the number of tumor-infiltrating T FR cells. Both T FR cell deficiency and the depletion of T FR cells with anti-CTLA-4 before anti-PD-1 treatment improve tumor control in mice. Notably, in a cohort of 271 patients with melanoma, treatment with anti-CTLA-4 followed by anti-PD-1 at progression was associated with better a survival outcome than monotherapy with anti-PD-1 or anti-CTLA-4, anti-PD-1 followed by anti-CTLA-4 at progression or concomitant combination therapy., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Olive oil is a key ingredient in the Mediterranean diet and offers many health benefits. However, many factors affect the quality and quantity of olive oil such as olive tree diseases and olive-related pests. Unfortunately, the procedure of identifying pests or the outbreak of a disease is time-consuming, and it depends heavily on the size of the olive grove. Through the use of ICT, remote monitoring of the olive grove can be achieved, by collecting environment-related data and having an overview of the olive grove's overall health. In this paper we propose a low-cost dense network of sensors that collects daily data regarding the olive grove, thus, providing the possibility to prevent infestation of olive fruit fly and/or the outbreak of olive tree-related disease.

Background: Metastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M-PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy., Methods: Retrospective analysis of outcomes data of UM patients receiving M-PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) v4.03, respectively., Results: A total of 51 patients received 134 M-PHP procedures (median of 2 M-PHPs). 25 (49%) achieved a partial (N = 22, 43.1%) or complete hepatic response (N = 3, 5.9%). In 17 (33.3%) additional patients, the disease stabilized for at least 3 months, for a hepatic disease control rate of 82.4%. After median follow-up of 367 days, median overall progression free (PFS) and hepatic progression free survival (hPFS) was 8.1 and 9.1 months, respectively and median overall survival was 15.3 months. There were no treatment related fatalities. Non-hematologic grade 3-4 events were seen in 19 (37.5%) patients and were mainly coagulopathic (N = 8) and cardiovascular (N = 9)., Conclusions: M-PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients., (© 2017 The Authors. Journal of Surgical Oncology Published by Wiley Periodicals, Inc.)

Background: Acute cauda equina syndrome is an uncommon but significant neurologic presentation due to a variety of underlying diseases. Anatomical compression of nerve roots, usually by a lumbar disk hernia is a common cause in the general population, while inflammatory, neoplastic, and ischemic causes have also been recognized. Among human immunodeficiency virus (HIV) infected patients with acquired immunodeficiency syndrome, infectious causes are encountered more frequently, the most prevalent of which are: cytomegalovirus, herpes simplex virus 1/2, varicella zoster virus, and Mycobacterium tuberculosis infections. Studies of cauda equina syndrome in well-controlled HIV infection are lacking. We describe such a case of cauda equina syndrome in a well-controlled HIV-infected patient, along with a brief review of the literature regarding the syndrome's diagnosis and treatment in individuals with HIV infection., Case Presentation: A 36-year-old Greek male, HIV-positive patient presented with perineal and left hemiscrotal numbness, lumbar pain, left-sided sciatica, and urinary incontinence. Magnetic resonance imaging of the patient's lumbar spine revealed intrathecal migration of a fragment from an intervertebral lumbar disk exerting pressure on the cauda equina. A cerebrospinal fluid examination, brain computed tomography scan, spine magnetic resonance imaging, and serological test results were negative for central nervous system infections. Our patient underwent emergency neurosurgical spinal decompression, which resolved most symptoms, except for mild urinary incontinence., Conclusions: Noninfectious etiologies may also cause cauda equina syndrome in HIV-infected individuals, especially in well-controlled disease under antiretroviral therapy. Prompt recognition and treatment of the underlying cause is important to minimize residual symptoms. Targeted antimicrobial chemotherapy is used to treat infectious causes, while prompt surgical decompression is favored for anatomical causes of cauda equina syndrome in the HIV-infected patient.

Background: Untreated metastatic uveal melanoma (UM) carries a grave prognosis. Unlike cutaneous melanoma (CM), there are no established treatments known to significantly improve outcomes for a meaningful proportion of patients. Inhibition of the PD1-PDL1 axis has shown promise in the management of CM and we here report a two center experience of UM patients receiving pembrolizumab., Methods: To assess the efficacy and safety of pembrolizumab, we retrospectively analyzed outcome data of 25 consecutive UM patients participating in the MK3475 expanded access program (EAP) who received pembrolizumab at 2 mg/kg 3 weekly. Tumor assessment was evaluated using RECIST 1.1 and immune-related Response Criteria (irRC) by CT scanning. Toxicity was recorded utilizing Common Terminology Criteria for Adverse Events ("CTCAE") v4.03., Results: Twenty-five patients were identified receiving a median of six cycles of treatment. Two patients achieved a partial response and six patients stable disease. After a median follow-up of 225 d median progression free survival (PFS) was 91 d and overall survival (OS) was not reached. There was a significant trend for improved outcomes in patients with extrahepatic disease progression as opposed to liver only progression at the outset. Five patients experienced grade 3 or 4 adverse events (AEs); there were no treatment related deaths., Conclusions: Pembrolizumab 2mg/kg q3w is a safe option in UM patients. Disease control rates, particularly in the subgroup of patients without progressive liver disease at the outset are promising; these results merit further investigation in clinical trials possibly incorporating liver targeted treatment modalities.

Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX particles (NY-ESO-1 ISCOMATRIX) have shown to elicit combined NY-ESO-1 specific antibody and T cell responses. However, it remains unclear whether heterologous prime-boost strategies based on the combination with NY-ESO-1 ISCOMATRIX with different NY-ESO-1 boosting reagents could be used to increase NY-ESO-1 CD8(+) or CD4(+) T cell responses. To address this question, we carried out a randomized clinical trial in 39 high-risk, resected melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX, and then boosted with repeated injections of either recombinant fowlpox virus encoding full length NY-ESO-1 (rF-NY-ESO-1) (Arm A) or NY-ESO-1 ISCOMATRIX alone (Arm B). We have comprehensively analyzed NY-ESO-1 specific T cells and B cells response in all patients before and after vaccination for a total of seven time points per patient. NY-ESO-1 ISCOMATRIX alone elicited a strong NY-ESO-1 specific CD4(+) T cell and antibody response, which was maintained by both regiments at similar levels. However, CD8(+) T cell responses were significantly boosted in 3 out of 18 patients in Arm A after the first rF-NY-ESO-1 injection and such responses were maintained until the end of the trial, while no patients in Arm B showed similar CD8(+) T cell responses. In addition, our results clearly identified immunodominant regions in the NY-ESO-1 protein: NY-ESO-179-102 and NY-ESO-1115-138 for CD4+ T cells and NY-ESO-185-108 for CD8+ T cells in a large proportion of vaccinated patients. These regions of NY-ESO-1 protein should be considered in future clinical trials as immunodominant epitopes., (© 2014 UICC.)

The aim of our study was to investigate the prevalence of smoking in a Greek working population. A questionnaire regarding smoking habit was collected from 1,005 out of 1,200 blue and white-collar employees (response rate: 84%). The overall smoking prevalence was 48.4% and did not differ by sex, age, education, and occupation. The mean cigarette consumption per day was 25.54, with no difference observed by occupation. The above-mentioned findings, if confirmed by further research, are alarming and inconsistent with the prevalent pattern of smoking habits in the West.

There are reports of increasing incidence of focal extra-intestinal infections from non-typhoidal salmonellae during the past two decades. We present the first case of a parotid abscess caused by Salmonella enterica serovar Enteritidis (S. Enteritidis) in an apparently immunocompetent adult without other abnormality of the parotid glands. A 58-year-old man was admitted to our hospital because of a 3-day history of fever and painful swelling of the right parotid gland. His medical history was unremarkable. A CT scan revealed an abscess of the right parotid. S. Enteritidis was isolated from a sample of fluid aspirated from the parotid abscess under ultrasound guidance. The stool, urine, and blood cultures were negative. The patient was treated with ciprofloxacin 500 mg per os every 12 h for 10 days, with complete remission of symptoms. The infection did not recur during 3 years of follow up. Our case report adds to the literature regarding the extra-intestinal infections with S. Enteritidis, a common non-typhoidal salmonellosis.

Background: Percutaneous exposure incidents (PEIs) and blood splashes on the skin of health care workers are a major concern, since they expose susceptible employees to the risk of infectious diseases. We undertook this study in order to estimate the overall incidence of such injuries in a newly founded tertiary hospital, and to evaluate possible changes in their incidence over time., Methodology/principal Findings: We prospectively studied the PEIs and blood splashes on the skin of employees in a newly founded (October 2000) tertiary hospital in Athens, Greece, while a vaccination program against hepatitis B virus, as well as educational activities for avoidance of injuries, were taking place. The study period ranged from October 1, 2002 to February 28, 2005. Serologic studies for hepatitis B (HBV) and C virus (HCV) as well as human immunodeficiency virus (HIV) were performed in all injured employees and the source patients, when known. High-titer immunoglobulin (250 IU anti-HBs intramuscularly) and HBV vaccination were given to non-vaccinated or previously vaccinated but serologically non-responders after exposure. Statistical analysis of the data was performed using Mc Nemar's and Fisher's tests. 60 needlestick, 11 sharp injuries, and two splashes leading to exposure of the skin or mucosa to blood were reported during the study period in 71 nurses and two members of the cleaning staff. The overall incidence (percutaneous injuries and splashes) per 100 full-time employment-years (100 FTEYs) for high-risk personnel (nursing, medical, and cleaning staff) was 3.48, whereas the incidence of percutaneous injuries (needlestick and sharp injuries) alone per 100 FTEYs was 3.38. A higher incidence of injuries was noted during the first than in the second half of the study period (4.67 versus 2.29 per 100 FTEYs, p = 0.005). No source patient was found positive for HCV or HIV. The use of high-titer immunoglobulin after adjustment for the incidence of injuries was higher in the first than in the second half of the study period, although the difference was not statistically significant [9/49 (18.37%) vs 1/24 (4.17%), p = 0.15]., Conclusions/significance: Our data show that nurses are the healthcare worker group that reports most of PEIs. Doctors did not report such injuries during the study period in our setting. However, the possibility of even relatively frequent PEIs in doctors cannot be excluded. This is due to underreporting of such events that has been previously described for physicians and surgeons. A decrease of the incidence of PEIs occurred during the operation of this newly founded hospital.

We present our experience with skeletal involvement of Pneumocystis jiroveci (ex P. carinii) infection in an HIV-seropositive patient. The objective of this study was to alert clinicians to the possibility that extrapulmonary P. jiroveci could affect the skeletal system in HIV-infected patients with extremely rapid progression. P. jiroveci infection of skeletal system has been rarely described elsewhere. A 51-year-old man complained of fever for six weeks, cough, anorexia, fatigue, and chest pain. He was found to be HIV seropositive. Repetitive (six samples) sputum and bronchoalveolar lavage fluid microbiologic tests were negative. High-resolution chest computed tomography (CT) scan revealed a small pulmonary mass. Abdominal CT scan revealed lesions in liver, spleen, kidneys, adrenal glands, lumbar vertebrae, and sacrum. Brain and skull CT scan was normal. A fine-needle biopsy of the lung mass was unrevealing. Cytological examination of sputum specimens showed findings consistent with non-small-cell lung carcinoma. Nineteen weeks post-presentation, the patient reported low-back pain. Within 24 hours after the onset of low-back pain, he developed focal neurological deficits, and a magnetic resonance imaging (MRI) of the skull and spine showed osteolytic lesions of the temporal bones bilaterally, multiple vertebral lesions, and lesions of sacrum and iliac bones. Radiotherapy of the lumbar spine and pelvis was given. Sternal aspiration was performed. Cytological examination revealed P. jiroveci. In conclusion, we describe a rare case of disseminated P. jiroveci infection in an HIV-seropositive patient, with multiple skeletal lesions, especially in the skull and in vertebrae region, and concomitant non-small-cell lung cancer, with a very poor prognosis.

Background: Drug treatment is becoming more expensive due to the increased cost for the introduction of new drugs, and there seems to be an uneven distribution of medication cost for different therapeutic categories. We hypothesized that the cost of new antimicrobial agents may differ from that of other therapeutic categories and this may play a role in the stagnation of development of new antibiotics., Methodology/principal Findings: We performed a pharmaco-economical comparative analysis of the drug cost of treatment for new agents introduced in the United States drug market in various therapeutic categories. We calculated the drug cost (in US dollars) of a ten-day treatment of all new drugs approved by the FDA during the period between January 1997 and July 2003, according to the 2004 Red Book Pharmacy's Fundamental Reference. New anti-neoplastic agents were found to be the most expensive drugs in comparison to all other therapeutic categories, with a median ten-day drug-treatment cost of US$848 compared to the median ten-day drug-treatment costs of all other categories ranging from US$29 to US$301. On the other hand, new antimicrobial drugs were found to be much less expensive, with a median ten-day drug-treatment cost of US$137 and $US85 for all anti-microbial agents and for anti-microbial agents excluding anti-HIV medications, respectively., Conclusions/significance: The drug-treatment cost of new medications varies considerably by different therapeutic categories. This fact may influence industry decisions regarding the development of new drugs and may play a role in the shortage of new antimicrobial agents in the fight against the serious problem of antimicrobial resistance.

A significant percentage of children with beta-thalassemia major shows retardation in longitudinal growth as they progress towards puberty due to skeletal dysplasia, endocrine gland hypofunction or trace element deficiencies. The aim of this study was to evaluate GH/IGF-I secretion and action in prepubertal patients with beta-thalas-semia major. Eight prepubertal patients with short stature (group A) and seven prepubertal patients with normal stature (group B) were studied. Basal and stimulated (after administration of the hexapeptide Hexarelin) GH levels were measured with IRMA (Nichols); IGF-I and IGFBP-3 levels were measured with RIA (Nichols). IGF-I binding proteins (IGFBPs) were analyzed qualitatively with Western ligand blot. IGF-I binding to B-lymphocytes of the patients was also measured with competitive binding studies using human recombinant IGF-I and 125I-IGF-I (Amersham). Basal GH levels did not differ statistically between the groups. Peak GH levels after Hexarelin stimulation test were higher in group A (A: 27.9 +/- 15.6 ng/ml vs B: 9.1 +/- 4.7 ng/ml) (Wilcoxon test, p < 0.05). IGF-I levels in the two groups were low-normal and comparable (A: 168.0 +/- 81.6 ng/ml vs B: 126.6 +/- 25.5 ng/ml). IGFBP-3 levels were low in both groups (A: 1.21 +/- 0.27 microg/ml vs B: 1.08 +/- 0.20 microg/ml). Western ligand blot did not reveal any discernible difference in IGFBPs. However, IGF-I binding on B-lymphocytes was at least 20% lower in group A compared to group B (t-test, p < 0.01). IGF-I binding inversely correlated with peak GH levels (r = -0.54, p < 0.05). Patients in group A were older and chronological age correlated with IGF-I levels (r = 0.53, p < 0.05) whereas it inversely correlated with IGF-I binding (r = -0.63, p < 0.05). Moreover, patients in group A had higher ferritin levels. No correlation was found between ferritin levels, desferrioxamine dose/compliance or liver enzyme levels and the parameters of the GH axis studied. However, desferrioxamine dose x years correlated with IGFBP-3 (r = 0.56, p < 0.05) and correlated inversely with IGF-I binding (r = -0.74, p < 0.01). In conclusion, we have shown adequate GH secretion, higher secretive capacity after the administration of Hexarelin and lower IGF-I binding in prepubertal beta-thalassemic patients with short stature. Whatever the cause, reduced IGF-I action has to be considered when treating beta-thalassemic patients with short stature.

A collection of 64 fig (Ficus carica L.) accessions was characterized through the use of RAPD markers, and results were evaluated in conjunction with morphological and agronomical characters, in order to determine the genetic relatedness of genotypes with diverse geographic origin. The results indicate that fig cultivars have a rather narrow genetic base. Nevertheless, RAPD markers could detect enough polymorphism to differentiate even closely related genotypes (i.e., clones of the same cultivar) and a unique fingerprint for each of the genotypes studied was obtained. No wasteful duplications were found in the collection. Cluster analysis allowed the identification of groups in accordance with geographic origin, phenotypic data and pedigree. Taking into account the limited information concerning fig cultivar development, the results of this study, which provide information on the genetic relationships of genetically distinct material, dramatically increase the fundamental and practical value of the collection and represent an invaluable tool for fig germplasm management.