Showing papers by "Gdańsk Medical University published in 2017"

Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation

Abstract: BackgroundOlaparib is an oral poly(adenosine diphosphate–ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation. MethodsWe conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)–negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician’s choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis. ResultsOf the 302 patients who underwent randomization, 205 were assigned to receive...

Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer

Abstract: BackgroundAlectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non–small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. MethodsIn a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee–assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. ResultsDuring a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in ...

Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial.

Abstract: Objective:Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties. The authors assessed the safety and effectiveness of CBD in patients with schizophrenia.Method:In an exploratory double-blind parallel-group trial, patients with schizophrenia were randomized in a 1:1 ratio to receive CBD (1000 mg/day; N=43) or placebo (N=45) alongside their existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S).Results:After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=−1.4, 95% CI=−2.5, −0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=−0.5, 95% CI=−0....

European position statement on lung cancer screening

Abstract: Lung cancer screening with low-dose CT can save lives. This European Union (EU) position statement presents the available evidence and the major issues that need to be addressed to ensure the successful implementation of low-dose CT lung cancer screening in Europe. This statement identified specific actions required by the European lung cancer screening community to adopt before the implementation of low-dose CT lung cancer screening. This position statement recommends the following actions: a risk stratification approach should be used for future lung cancer low-dose CT programmes; that individuals who enter screening programmes should be provided with information on the benefits and harms of screening, and smoking cessation should be offered to all current smokers; that management of detected solid nodules should use semi-automatically measured volume and volume-doubling time; that national quality assurance boards should be set up to oversee technical standards; that a lung nodule management pathway should be established and incorporated into clinical practice with a tailored screening approach; that non-calcified baseline lung nodules greater than 300 mm3, and new lung nodules greater than 200 mm3, should be managed in multidisciplinary teams according to this EU position statement recommendations to ensure that patients receive the most appropriate treatment; and planning for implementation of low-dose CT screening should start throughout Europe as soon as possible. European countries need to set a timeline for implementing lung cancer screening.

3rd ESO–ESMO international consensus guidelines for Advanced Breast Cancer (ABC 3)

Abstract: For the purpose of advanced breast cancer (ABC) guidelines, ABC comprises both inoperable locally advanced breast cancer (LABC) and metastatic breast cancer (MBC)1 , 2 Advanced/metastatic breast cancer remains a virtually incurable disease, with a median overall survival (OS) of about 3 years and a 5-year survival rate of around 25%,3 , 4 even in countries without major accessibility problems Survival is strongly related to breast cancer subtype, with the major advances seen in human epidermal growth factor receptor 2 (HER2)-positive ABC5, 6, 7, 8, 9 ABC is a treatable disease with several available therapies and many others in development However, their impact on survival and quality of life (QoL) of ABC patients has been slow3 and different for de novo versus recurrent ABC, with the latter becoming much harder to treat in recent years10 Outcomes are also strongly related to access to the best available care, which includes not only the most efficacious medicines, but also multidisciplinary, specialised care, implementation of guidelines, high-quality pathology, imaging and radiotherapy (RT) Lack of any of these crucial pillars of modern oncological care inevitably results in substantially worse outcomes, as exemplified in the New Zealand report “I am still here”11 While mortality rates have decreased in the majority of developed countries, most deaths are currently seen in less developed societies, and access issues explain the majority of these inequalities12 The application of the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS)13 to the field of ABC (P Shimon, personal communication) shows that the quality of clinical research has improved over the last decade and that better therapies have been developed, providing hope that a substantial improvement in the median OS of ABC patients might soon be seen However, some clinically relevant questions are still unanswered and may be difficult to address through traditional clinical trials, such as the best sequence of therapies for each individual patient The application of computer analytics to big data and real-world data is one of the potential ways forward In-depth discussion must take place regarding the impact of this ‘new’ level of evidence (LoE) in current treatment guidelines and their integration with clinical trial data The 5th International Consensus Conference for Advanced Breast Cancer (ABC 5) took place in Lisbon, Portugal, on 14th-16th November 2019, bringing together 1500 participants from 94 countries worldwide, including health professionals, patient advocates and journalists Since its first edition in 2011, the main goal of the ABC conference has been the development of high-quality international consensus guidelines for the management of ABC These guidelines are based on available evidence and on expert opinion when evidence is lacking They represent the best management options for ABC patients globally, assuming accessibility to all available therapies Adaptation of these guidelines is often needed in settings where access to care is suboptimal The ABC 5 guidelines are jointly developed by ESO and ESMO, and have been endorsed by several international oncology organisations, such as the European Society of Breast Cancer Specialists (EUSOMA), European Society for Radiotherapy and Oncology (ESTRO), European Society of Gynaecological Oncology (ESGO), Union for International Cancer Control (UICC), Senologic International Society (SIS)/International School of Senology (ISS), Federacion Latino-Americana de Mastologia (FLAM), European Oncology Nursing Society (EONS), European Society of Surgical Oncology (ESSO), Arbeitsgemeinschaft Gynakologische Onkologie eV (AGO) and the International Society of Geriatric Oncology (SIOG), and have official representation from the American Society of Clinical Oncology (ASCO) The ABC 5 conference was also organised under the auspices of the Organisation of European Cancer Institutes (OECI) and with the support of the Breast Cancer Research Foundation (BCRF), Susan G Komen and the ABC Global Alliance This manuscript summarises the guidelines developed at ABC 5, each of which are accompanied by the LoE, grade of recommendation (GoR), percentage of consensus reached at the conference and supporting references In addition, the ESMO-MCBS version 1113 (v11) was used to calculate scores for new therapies/indications approved by the European Medicines Agency (EMA) since the last ABC guidelines, as well as a few new therapies that have been scored but are still under EMA evaluation (https://wwwesmoorg/Guidelines/ESMO-MCBS) A table with these scores is included (see supplementary Table S1, available at https://doi/org/101016/jannonc202009010)

Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non–Small-Cell Lung Cancer

Abstract: Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naive squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.

Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration

Abstract: Summary Background Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the four major trial groups. To address this challenge, we formed a global coalition, the Children's Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer. Methods The CHIC steering committee—consisting of leadership from the four major cooperative trial groups (the International Childhood Liver Tumours Strategy Group, Children's Oncology Group, the German Society for Paediatric Oncology and Haematology, and the Japanese Study Group for Paediatric Liver Tumours)—created a shared international database that includes comprehensive data from 1605 children treated in eight multicentre hepatoblastoma trials over 25 years. Diagnostic factors found to be most prognostic on initial analysis were PRETreatment EXTent of disease (PRETEXT) group; age younger than 3 years, 3–7 years, and 8 years or older; α fetoprotein (AFP) concentration of 100 ng/mL or lower and 101–1000 ng/mL; and the PRETEXT annotation factors metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal bifurcation (P), contiguous extrahepatic tumour (E), multifocal tumour (F), and spontaneous rupture (R). We defined five clinically relevant backbone groups on the basis of established prognostic factors: PRETEXT I/II, PRETEXT III, PRETEXT IV, metastatic disease, and AFP concentration of 100 ng/mL or lower at diagnosis. We then carried the additional factors into a hierarchical backwards elimination multivariable analysis and used the results to create a new international staging system. Results Within each backbone group, we identified constellations of factors that were most predictive of outcome in that group. The robustness of candidate models was then interrogated using the bootstrapping procedure. Using the clinically established PRETEXT groups I, II, III, and IV as our stems, we created risk stratification trees based on 5 year event-free survival and clinical applicability. We defined and adopted four risk groups: very low, low, intermediate, and high. Interpretation We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare paediatric tumour. This achievement provides the structural framework for further collaboration and prospective international cooperative study, such as the Paediatric Hepatic International Tumour Trial (PHITT). Funding European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission (grant number 261474); Children's Oncology Group CureSearch grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research; and Swiss Cancer Research grant.

Cabazitaxel Versus Docetaxel As First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase III Trial-FIRSTANA.

Abstract: Purpose In patients with metastatic castration-resistant prostate cancer (mCRPC), overall survival (OS) is significantly improved with cabazitaxel versus mitoxantrone after prior docetaxel treatment. FIRSTANA ( ClinicalTrials.gov identifier: NCT01308567) assessed whether cabazitaxel 20 mg/m2 (C20) or 25 mg/m2 (C25) is superior to docetaxel 75 mg/m2 (D75) in terms of OS in patients with chemotherapy-naive mCRPC. Patients and Methods Patients with mCRPC and Eastern Cooperative Oncology Group performance status of 0 to 2 were randomly assigned 1:1:1 to receive C20, C25, or D75 intravenously every 3 weeks plus daily prednisone. The primary end point was OS. Secondary end points included safety; progression-free survival (PFS); tumor, prostate-specific antigen, and pain response; pharmacokinetics; and health-related quality of life. Results Between May 2011 and April 2013, 1,168 patients were randomly assigned. Baseline characteristics were similar across cohorts. Median OS was 24.5 months with C20, 25.2 months with C25, and 24.3 months with D75. Hazard ratio for C20 versus D75 was 1.01 (95% CI, 0.85 to 1.20; P = .997), and hazard ratio for C25 versus D75 was 0.97 (95% CI, 0.82 to 1.16; P = .757). Median PFS was 4.4 months with C20, 5.1 months with C25, and 5.3 months with D75, with no significant differences between treatment arms. Radiographic tumor responses were numerically higher for C25 (41.6%) versus D75 (30.9%; nominal P = .037, without multiplicity test adjustment). Rates of grade 3 or 4 treatment-emergent adverse events were 41.2%, 60.1%, and 46.0% for C20, C25, and D75, respectively. Febrile neutropenia, diarrhea, and hematuria were more frequent with C25; peripheral neuropathy, peripheral edema, alopecia, and nail disorders were more frequent with D75. Conclusion C20 and C25 did not demonstrate superiority for OS versus D75 in patients with chemotherapy-naive mCRPC. Tumor response was numerically higher with C25 versus D75; pain PFS was numerically improved with D75 versus C25. Cabazitaxel and docetaxel demonstrated different toxicity profiles, with overall less toxicity with C20.

Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study

Abstract: The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR4.5 (BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1IS)) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1IS⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2-58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).

SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis.

Abstract: Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naive patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naive patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.

Temporal trend in dementia incidence since 2002 and projections for prevalence in England and Wales to 2040: modelling study

Abstract: Objective To forecast dementia prevalence with a dynamic modelling approach that integrates calendar trends in dementia incidence with those for mortality and cardiovascular disease. Design Modelling study. Setting General adult population of England and Wales. Participants The English Longitudinal Study of Ageing (ELSA) is a representative panel study with six waves of data across 2002-13. Men and women aged 50 or more years, selected randomly, and their cohabiting partners were recruited to the first wave of ELSA (2002-03). 11392 adults participated (response rate 67%). To maintain representativeness, refreshment participants were recruited to the study at subsequent waves. The total analytical sample constituted 17 906 people. Constant objective criteria based on cognitive and functional impairment were used to ascertain dementia cases at each wave. Main outcome measures To estimate calendar trends in dementia incidence, correcting for bias due to loss to follow-up of study participants, a joint model of longitudinal and time-to-event data was fitted to ELSA data. To forecast future dementia prevalence, the probabilistic Markov model IMPACT-BAM (IMPACT-Better Ageing Model) was developed. IMPACT-BAM models transitions of the population aged 35 or more years through states of cardiovascular disease, cognitive and functional impairment, and dementia, to death. It enables prediction of dementia prevalence while accounting for the growing pool of susceptible people as a result of increased life expectancy and the competing effects due to changes in mortality, and incidence of cardiovascular disease. Results In ELSA, dementia incidence was estimated at 14.3 per 1000 person years in men and 17.0/1000 person years in women aged 50 or more in 2010. Dementia incidence declined at a relative rate of 2.7% (95% confidence interval 2.4% to 2.9%) for each year during 2002-13. Using IMPACT-BAM, we estimated there were approximately 767 000 (95% uncertainty interval 735 000 to 797 000) people with dementia in England and Wales in 2016. Despite the decrease in incidence and age specific prevalence, the number of people with dementia is projected to increase to 872 000, 1 092 000, and 1 205 000 in 2020, 2030, and 2040, respectively. A sensitivity analysis without the incidence decline gave a much larger projected growth, of more than 1.9 million people with dementia in 2040. Conclusions Age specific dementia incidence is declining. The number of people with dementia in England and Wales is likely to increase by 57% from 2016 to 2040. This increase is mainly driven by improved life expectancy.

Tenth European Consensus Conference on Hyperbaric Medicine: recommendations for accepted and non-accepted clinical indications and practice of hyperbaric oxygen treatment.

Abstract: The tenth European Consensus Conference on Hyperbaric Medicine took place in April 2016, attended by a large delegation of experts from Europe and elsewhere. The focus of the meeting was the revision of the European Committee on Hyperbaric Medicine (ECHM) list of accepted indications for hyperbaric oxygen treatment (HBOT), based on a thorough review of the best available research and evidence-based medicine (EBM). For this scope, the modified GRADE system for evidence analysis, together with the DELPHI system for consensus evaluation, were adopted. The indications for HBOT, including those promulgated by the ECHM previously, were analysed by selected experts, based on an extensive review of the literature and of the available EBM studies. The indications were divided as follows: Type 1, where HBOT is strongly indicated as a primary treatment method, as it is supported by sufficiently strong evidence; Type 2, where HBOT is suggested as it is supported by acceptable levels of evidence; Type 3, where HBOT can be considered as a possible/optional measure, but it is not yet supported by sufficiently strong evidence. For each type, three levels of evidence were considered: A, when the number of randomised controlled trials (RCTs) is considered sufficient; B, when there are some RCTs in favour of the indication and there is ample expert consensus; C, when the conditions do not allow for proper RCTs but there is ample and international expert consensus. For the first time, the conference also issued 'negative' recommendations for those conditions where there is Type 1 evidence that HBOT is not indicated. The conference also gave consensus-agreed recommendations for the standard of practice of HBOT.

Inhibition of cancer antioxidant defense by natural compounds

Abstract: // Alicja Sznarkowska 1 , Anna Kostecka 1 , Katarzyna Meller 1 and Krzysztof Piotr Bielawski 1 1 Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland Correspondence to: Alicja Sznarkowska, email: // Keywords : antioxidants, ROS, cancer, natural compounds, polyphenols Received : September 02, 2016 Accepted : November 22, 2016 Published : November 30, 2016 Abstract All classic, non-surgical anticancer approaches like chemotherapy, radiotherapy or photodynamic therapy kill cancer cells by inducing severe oxidative stress. Even tough chemo- and radiotherapy are still a gold standard in cancer treatment, the identification of non-toxic compounds that enhance their selectivity, would allow for lowering their doses, reduce side effects and risk of second cancers. Many natural products have the ability to sensitize cancer cells to oxidative stress induced by chemo- and radiotherapy by limiting antioxidant capacity of cancer cells. Blocking antioxidant defense in tumors decreases their ability to balance oxidative insult and results in cell death. Though one should bear in mind that the same natural compound often exerts both anti-oxidant and pro-oxidant properties, depending on concentration used, cell type, exposure time and environmental conditions. Here we present a comprehensive overview of natural products that inhibit major antioxidant defense mechanisms in cancer cells and discuss their potential in clinical application.

SNPs in microRNA target sites and their potential role in human disease.

Abstract: In the post-genomic era, the goal of personalized medicine is to determine the correlation between genotype and phenotype. Developing high-throughput genotyping technologies such as genome-wide association studies (GWAS) and the 1000 Genomes Project (http://www.internationalgenome.org/about/#1000G_PROJECT) has dramatically enhanced our ability to map where changes in the genome occur on a population level by identifying millions of single nucleotide polymorphisms (SNPs). Polymorphisms, particularly those within the coding regions of proteins and at splice junctions, have received the most attention, but it is also now clear that polymorphisms in the non-coding regions are important. In these non-coding regions, the enhancer and promoter regions have received the most attention, whereas the 3′-UTR regions have until recently been overlooked. In this review, we examine how SNPs affect microRNA-binding sites in these regions, and how mRNA stability changes can lead to disease pathogenesis.

Response to Rituximab Induction Is a Predictive Marker in B-Cell Post-Transplant Lymphoproliferative Disorder and Allows Successful Stratification Into Rituximab or R-CHOP Consolidation in an International, Prospective, Multicenter Phase II Trial

Abstract: Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20+ PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective.

The growing world of small heat shock proteins: from structure to functions

Abstract: Small heat shock proteins (sHSPs) are present in all kingdoms of life and play fundamental roles in cell biology. sHSPs are key components of the cellular protein quality control system, acting as the first line of defense against conditions that affect protein homeostasis and proteome stability, from bacteria to plants to humans. sHSPs have the ability to bind to a large subset of substrates and to maintain them in a state competent for refolding or clearance with the assistance of the HSP70 machinery. sHSPs participate in a number of biological processes, from the cell cycle, to cell differentiation, from adaptation to stressful conditions, to apoptosis, and, even, to the transformation of a cell into a malignant state. As a consequence, sHSP malfunction has been implicated in abnormal placental development and preterm deliveries, in the prognosis of several types of cancer, and in the development of neurological diseases. Moreover, mutations in the genes encoding several mammalian sHSPs result in neurological, muscular, or cardiac age-related diseases in humans. Loss of protein homeostasis due to protein aggregation is typical of many age-related neurodegenerative and neuromuscular diseases. In light of the role of sHSPs in the clearance of un/misfolded aggregation-prone substrates, pharmacological modulation of sHSP expression or function and rescue of defective sHSPs represent possible routes to alleviate or cure protein conformation diseases. Here, we report the latest news and views on sHSPs discussed by many of the world’s experts in the sHSP field during a dedicated workshop organized in Italy (Bertinoro, CEUB, October 12–15, 2016).

The antimicrobial volatile power of the rhizospheric isolate Pseudomonas donghuensis P482.

Abstract: Soil and rhizosphere bacteria produce an array of secondary metabolites including a wide range of volatile organic compounds (VOCs). These compounds play an important role in the long-distance interactions and communication between (micro)organisms. Furthermore, bacterial VOCs are involved in plant pathogens inhibition and induction of soil fungistasis and suppressivenes. In the present study, we analysed the volatile blend emitted by the rhizospheric isolate Pseudomonas donghuensis P482 and evaluated the volatile effect on the plant pathogenic fungi and bacteria as well as one oomycete. Moreover, we investigated the role of the GacS/GacA system on VOCs production in P. donghuensis P482. The results obtained demonstrated that VOCs emitted by P. donghuensis P482 have strong antifungal and antioomycete, but not antibacterial activity. The production of certain volatiles such as dimethyl sulfide, S-methyl thioacetate, methyl thiocyanate, dimethyl trisulfide, 1-undecan and HCN is depended on the GacS/GacA two-component regulatory system. Apparently, these compounds play an important role in the pathogens suppression as the gacA mutant entirely lost the ability to inhibit via volatiles the growth of tested plant pathogens.

Melatonin, mitochondria, and the skin.

Abstract: The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin–mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair.

Forecasted trends in disability and life expectancy in England and Wales up to 2025: a modelling study

Abstract: Summary Background Reliable estimation of future trends in life expectancy and the burden of disability is crucial for ageing societies Previous forecasts have not considered the potential impact of trends in disease incidence The present prediction model combines population trends in cardiovascular disease, dementia, disability, and mortality to forecast trends in life expectancy and the burden of disability in England and Wales up to 2025 Methods We developed and validated the IMPACT-Better Ageing Model—a probabilistic model that tracks the population aged 35–100 years through ten health states characterised by the presence or absence of cardiovascular disease, dementia, disability (difficulty with one or more activities of daily living) or death up to 2025, by use of evidence-based age-specific, sex-specific, and year-specific transition probabilities As shown in the English Longitudinal Study of Ageing, we projected continuing declines in dementia incidence (2·7% per annum), cardiovascular incidence, and mortality The model estimates disability prevalence and disabled and disability-free life expectancy by year Findings Between 2015 and 2025, the number of people aged 65 years and older will increase by 19·4% (95% uncertainty interval [UI] 17·7–20·9), from 10·4 million (10·37–10·41 million) to 12·4 million (12·23–12·57 million) The number living with disability will increase by 25·0% (95% UI 21·3–28·2), from 2·25 million (2·24–2·27 million) to 2·81 million (2·72–2·89 million) The age-standardised prevalence of disability among this population will remain constant, at 21·7% (95% UI 21·5–21·8) in 2015 and 21·6% (21·3–21·8) in 2025 Total life expectancy at age 65 years will increase by 1·7 years (95% UI 0·1–3·6), from 20·1 years (19·9–20·3) to 21·8 years (20·2–23·6) Disability-free life expectancy at age 65 years will increase by 1·0 years (95% UI 0·1–1·9), from 15·4 years (15·3–15·5) to 16·4 years (15·5–17·3) However, life expectancy with disability will increase more in relative terms, with an increase of roughly 15% from 2015 (4·7 years, 95% UI 4·6–4·8) to 2025 (5·4 years, 4·7–6·4) Interpretation The number of older people with care needs will expand by 25% by 2025, mainly reflecting population ageing rather than an increase in prevalence of disability Lifespans will increase further in the next decade, but a quarter of life expectancy at age 65 years will involve disability Funding British Heart Foundation

Long-Term Outcome of Steroid-Resistant Nephrotic Syndrome in Children.

Abstract: We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and <20 years of age): 612 had documented responsiveness to intensified immunosuppression (IIS), 1155 had kidney biopsy results, and 212 had an established genetic diagnosis. We assessed risk factors for ESRD using multivariate Cox regression models. Complete and partial remission of proteinuria within 12 months of disease onset occurred in 24.5% and 16.5% of children, respectively, with the highest remission rates achieved with calcineurin inhibitor-based protocols. Ten-year ESRD-free survival rates were 43%, 94%, and 72% in children with IIS resistance, complete remission, and partial remission, respectively; 27% in children with a genetic diagnosis; and 79% and 52% in children with histopathologic findings of minimal change glomerulopathy and FSGS, respectively. Five-year ESRD-free survival rate was 21% for diffuse mesangial sclerosis. IIS responsiveness, presence of a genetic diagnosis, and FSGS or diffuse mesangial sclerosis on initial biopsy as well as age, serum albumin concentration, and CKD stage at onset affected ESRD risk. Our findings suggest that responsiveness to initial IIS and detection of a hereditary podocytopathy are prognostic indicators of favorable and poor long-term outcome, respectively, in children with steroid-resistant nephrotic syndrome. Children with multidrug-resistant sporadic disease show better renal survival than those with genetic disease. Furthermore, histopathologic findings may retain prognostic relevance when a genetic diagnosis is established.