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Purpose: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC). Patients and Methods: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4–6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control. Results: Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50–0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36–0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09–1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic. Conclusions: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.

The majority of HER2-positive breast or gastric cancers treated with T-DM1 eventually show resistance to this agent. We compared the effects of T-DM1 and ARX788, a novel anti-HER2 antibody-drug conjugate, on cell growth and apoptosis in HER2-positive breast cancer and gastric cancer cell lines sensitive to T-DM1, gastric cancer cell lines resistant to T-DM1, HER2-negative breast cancer cell lines, and T-DM1-resistant xenograft models. ARX788 was effective in T-DM1-resistant in vitro and in vivo models of HER2-positive breast cancer and gastric cancer. ARX788 showed a pronounced growth inhibitory effect on all five HER2-positive cell lines tested, of which two gastric cancer cell lines had acquired resistance to T-DM1. ARX788 evoked more apoptotic events compared to T-DM1. While JIMT-1 and RN-87 xenograft tumors progressed on T-DM1 treatment, all such tumors responded to ARX788, and four out of the six JIMT-1 tumors and nine out of the twelve RN-87 tumors disappeared during the ARX788 treatment. Mice treated with ARX788 survived longer than those treated with T-DM1. The data support evaluation of ARX788 in patients with HER2-positive breast cancer or gastric cancer including cancers that progress during T-DM1 therapy.

Objectives: Efforts to evaluate the health of solid organ transplant recipients are hampered by the lack of adequate patient-reported outcome measures (PROMs) targeting this group. We developed the Transplant ePROM (TXP), which is based on a novel measurement model and administered through a mobile application to fill this gap. The main objective of this article is to elucidate how we derived the weights for different items, and to report initial empirical results. Study design and setting: The nine health items in the TXP were fatigue, skin, worry, self-reliance, activities, weight, sexuality, stooling, and memory. Via an online survey solid organ recipient participating in the TransplantLines Biobank and Cohort study (NCT03272841) were asked to describe and then compare their own health state with six other health states. Coefficients for item levels were obtained using a conditional logit model. Results: A total of 232 solid organ transplant recipients (mean age: 54 years) participated. The majority (106) were kidney recipients, followed by lung, liver, and heart recipients. Fatigue was the most frequent complaint (54%). The strongest negative coefficients were found for activities and worry, followed by self-reliance and memory. Conclusion: A set of coefficients and values were developed for TXP. The TXP score approximated an optimal health state for the majority of respondents and recipients of different organs reported comparable health states. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Because of the current limits of immunological tests in the diagnosis of tuberculosis there is a need to identify new and rapid tests that can be carried out on a large scale in endemic countries and useful in the identification of infected subjects, but also able to discriminate those with latent infection from subjects with active. We have taken into consideration and analysed the LIODetect®TB-ST Tuberculosis Rapid Test, a membrane test for the qualitative detection of specific IgG, IgA, and IgM antibodies against Mycobacterium tuberculosis, performed on serum, plasma, or whole blood.85 samples positive to QuantiFERON TB-GOLD PLUS test were processed using this test and the results obtained were concordant with clinical diagnosis.To our knowledge, the LIODetect®TB-ST Tuberculosis Rapid Test is the only test; that identifies active tuberculosis disease with high sensitivity and specificity and its use might be of help in the diagnosis of tuberculosis, especially in endemic countries.

Background: Atezolizumab (ATZ) has demonstrated antitumor activity and manageable safety in previous studies of patients with metastatic platinum-resistant urothelial carcinoma. However, the response rate of Atezolizumab was modest. In the current study, we evaluated the pretreatment prognostic factors for overall survival in patients with metastatic urothelial carcinoma who have progressed after first-line chemotherapy in the Expanded-Access Program of Atezolizumab. Patients and methods: In this study, we present a retrospective analysis of 113 patients with urothelial cancer treated with ATZ after progression on first-line chemotherapy. Data of the patients was obtained from patient files and hospital records. Eligible patients included metastatic urothelial carcinoma patients treated with at least one course of ATZ. Univariate analysis was used to identify clinical and laboratory factors that significantly impact OS. Variables were retained for multivariate analysis if they had a statistical relationship with OS (p < 0.1), and then included a final model of p < 0.05. Results: The median follow-up duration was 23.5 months. Of the patients, 98 (86.7%) were male and 13.3% were female. The median age was 65 years of age (37–86). In univariate analysis, primary tumor location in the upper tract, increasing absolute neutrophil count (ANC), increasing absolute lymphocyte count, neutrophil-to-lymphocyte ratio (NLR) > 3, liver metastases, baseline creatinine clearance less (GFR) than 60 ml/min, Eastern Cooperative Oncology Group (ECOG) performance status (1 ?), and hemoglobin levels below 10 mg/dl were all the significantly associated with OS. Three of the five adverse prognostic factors according to the Bellmunt criteria were independent of short survival: liver metastases HR 3.105; 95% CI 1.673–5.761; p < (0.001), ECOG PS (1 ?) HR 2.184; 95% CI 1.120–4.256; p = 0.022, and Hemoglobin level below 10 mg/dl HR 2.680; 95% CI 1.558–4.608; p < (0.001). In addition, NLR > 3 hazard ratio [HR] 2.092; 95% CI 1.031–4.243; p = 0.041 and GFR less than 60 ml/min HR 1.829; 95% CI 1.1–3.041; p = 0.02, maintained a significant association with OS in multivariate analysis. Conclusions: This model confirms the Bellmunt model with the addition of NLR > 3 and GFR less than 60 ml/min and can be associated with clinical trials that use immunotherapy in patients with bladder cancer. © 2021, Japan Society of Clinical Oncology.

PURPOSE: The Bravos afterloader system was released by Varian Medical Systems in October of 2018 for high-dose-rate brachytherapy with Ir-192 sources, containing new features such as the CamScale (a new device for daily quality assurance and system recalibration), channel length verification, and different settings for rigid and flexible applicators. This study mechanically evaluated the Bravos system precision and accuracy for clinically relevant scenarios, using dummy sources.METHODS AND MATERIALS: The system was evaluated after three sets of experiments: (1) The CamScale was used to verify inter- and infra-channel dwelling variability and system calibration; (2) A high-speed camera was used to verify the source simulation cable movement inside a transparent quality assurance device, where dwell positions, dwell times, transit times, speed profiles, and accelerations were measured; (3) The source movement inside clinical applicators was captured with an imaging panel while being exposed to an external kV source. Measured and planned dwell positions and times were compared.RESULTS: Maximum deviations between planned and measured dwell positions and times for the source cable were 0.4 mm for the CamScale measurements and 0.07 seconds for the high-speed camera measurements. Mean dwell position deviations inside clinical applicators were below 1.2 mm for all applicators except the ring that required an offset correction of 1 mm to achieve a mean deviation of 0.4 mm.CONCLUSIONS: Features of the Bravos afterloader system provide a robust and precise treatment delivery. All measurements were within manufacturer specifications. (C) 2019 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Aims We aimed to compare digital image analysis (DIA) of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) in breast cancer by two platforms: (i) to validate DIA against standard diagnostics; and (ii) to evaluate the added value of DIA in clinical practice. Methods and results HER2 IHC and in-situ hybridisation (ISH) were performed on 152 consecutive invasive breast carcinomas. IHC scores were determined with DIA using two independent platforms. Manual scoring was performed by two independent observers. HER2 status was considered positive in 3+ and ISH-positive 2+ cases. HER2 status using DIA was compared to HER2 status with standard diagnostics (manual scoring with ISH in 2+ cases). Interplatform agreement of IHC scores was 'moderate' (linear weighted kappa = 0.58), agreement between manual scoring and platform A was 'moderate' (kappa = 0.60) and between manual scoring and platform B 'almost perfect' (kappa = 0.85). Compared to manual scoring, DIA resulted in a reduction of 2+ cases from 17.1 to 1.3% with platform A and from 17.1 to 15.8% with platform B. However, compared to standard diagnostics, there were three false-negative cases with DIA using platform A [81.3% sensitivity, 100% specificity, 100% positive predictive value (PPV), 97.8% negative predictive value (NPV)]. Sensitivity, specificity, PPV and NPV were 100% with DIA using platform B. Conclusions DIA of HER2 IHC is a valid tool in determining HER2 status in breast carcinoma. Algorithms in different platforms can behave differently, and optimal calibration is essential. In clinical practice, DIA offers an objective alternative to manual scoring, but a reduction in 2+ cases could result in loss of sensitivity.

This study aimed to compare drug costs and healthcare costs of a 1 year adjuvant course with intravenous biosimilar trastuzumab vs. subcutaneous reference trastuzumab in HER2-positive breast cancer from the Belgian hospital perspective. Our simulation is based on the methodology used by Tjalma and colleagues, and considered costs of drugs, healthcare professional time and consumables. We calculated intravenous drug costs for different body weights, and computed drug costs and healthcare costs to treat 100 patients with either trastuzumab formulation, assuming a binomial body weight distribution in this sample. Scenarios were run to account for drug discounts and intravenous vial sharing. Drug costs amounted to €1,431,282 with intravenous biosimilar trastuzumab and €1,522,809 with subcutaneous reference trastuzumab for a sample of 100 patients in the base case analysis. When healthcare professional time and consumables were also considered, healthcare costs with intravenous biosimilar trastuzumab were similar to those with subcutaneous reference trastuzumab. Differences in healthcare costs between intravenous biosimilar trastuzumab and subcutaneous reference trastuzumab depended on the level of discounts on these formulations and on intravenous vial sharing. Our case study demonstrates that comparing costs of intravenous vs. subcutaneous formulations is complex and multifactorial, and entails more than a simple cost comparison of products. ispartof: PHARMACEUTICALS vol:14 issue:5 ispartof: location:Switzerland status: published

Background: Patients with essential tremor were initially considered to have isolated tremor, but additional motor and non-motor features have been increasingly recognized. The term “essential tremor plus” was adopted by the Task Force on Tremor of the International Parkinson and Movement Disorder Society to describe essential tremor patients with additional neurologic signs. Objectives: To characterize essential tremor patients and their phenotypes in a movement disorders clinic population in the context of the new tremor classification. Methods: Demographic, clinical, historical, treatment, and diagnostic data were retrospectively collected on 300 patients diagnosed by movement disorder experts with essential tremor. Patients were classified as having essential tremor, essential tremor plus, or essential tremor-Parkinson’s disease combination, and features between these groups were compared. Results: Of the 300 patients, 20.7% were classified as isolated essential tremor, 53.3% as essential tremor plus, and 26.0% as essential tremor-Parkinson’s disease. There was no significant difference in the duration of tremor symptoms. Essential tremor plus patients were more likely to have dystonia, tandem gait abnormalities, head tremor and greater tremor severity. Essential tremor-Parkinson’s disease patients were more likely to have RBD symptoms. There was no significant difference in cognitive impairment between essential tremor plus and essential tremor-Parkinson’s disease patients. Conclusions: Additional motor and non-motor features, including parkinsonism, are common in patients with essential tremor. Further studies are needed to clarify essential tremor phenotypes and to provide insights into possible subtypes. Highlights: 300 patients with essential tremor from a movement disorders clinic were re-classified based on the Movement Disorder Society Consensus Statement on the Classification of Tremors. Additional motor and non-motor features, including parkinsonism, were common, and only 20.7% of patients remained classified as isolated essential tremor.

Background The aim of the study is to reveal the contribution of complete response (CR) to treatment to overall survival (OS) in patients with unresectable metastatic colorectal cancer. In addition, to evaluate progression-free survival (PFS) in patients who attained CR to treatment and to examine the clinicopathologic features of the patient group with CR. Methods This article is a retrospective chart review. Patients diagnosed with metastatic colorectal cancer were divided into two groups. The systemic treatment was compared with the patients who received a full response according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1) and those who did not attain CR (progression partial response and stable response) in terms of both PFS and OS data, and the effect of attaining CR to treatment on prognosis was evaluated. Results A total of 222 patients were included in the study. 202 of 222 patients could be evaluated in terms of complete response. All data from their files were tabulated and analyzed retrospectively. The mean age of diagnosis of the study group was 60.13 ± 12.52 years. The total number of patients who attained CR to treatment was 31 (15.3%); 171 (84.6%) patients did not attain CR. Patients who had a CR had longer median PFS times than patients who did not have a CR (15.2 vs. 7.4 months, P). Patients who had CR had longer median survival times than patients who did not have a CR (39.2 vs. 16.9 months, P). In subgroup patients who underwent primary surgery, the number of patients who attained CR was statistically higher compared with the number of patients who did not attain CR (p). Complete response was less common in the presence of liver metastasis and bone metastasis (p = 0.041 and p = 0.046, respectively), had a negative prognostic effect. In other words, 89.1% of patients with liver metastasis, 100.0% of patients with bone metastasis, and 88.7% of those who died did not have a CR to the treatment. According to multivariate analysis, CR to treatment, primary surgery, first-line chemotherapy (combination compared with fluoropyrimidine), and no bone metastasis were found to be predictors for OS. Conclusion Providing CR with systemic treatment in patients with unresectable metastatic colorectal cancer (mCRC) contributes to prognosis. The primary resection in our secondary acquisitions from the study, the number of metastatic regions and the combination therapy regimens also contributed to the prognosis.

Objectives. To evaluate the long-term effect of chlorhexidine (CHX) and dimethyl sulfoxide (DMSO) on the sealing ability and biomineralization of two different calcium silicate cements (CSC) in root canal. Methods. Sixty human third molar root canals were obturated with ProRoot MTA or Biodentine. Before obturation the canals were irrigated with saline (control), 2% CHX or 5% DMSO. Microleakage was tested after three days and after six months. After additional six months (12 months after root filling) the roots were cut into 2 mm thick dentine discs. The discs were stored in artificial saliva for one year. The bond strength was measured with the push-out method, and the failure mode was evaluated with a stereomicroscope. The most apical disc of each tooth was used for Vickers hardness test. Results. No significant differences between the groups was found in initial microleakage. The leakage increased significantly during the 6-month storage in all groups except in Biodentine-CHX group and Biodentine-DMSO group. CHX and DMSO irrigation significantly increased the leakage with ProRoot MTA with time, but there was no statistically significant difference compared to the ProRoot MTA-control group at six months' time point. CHX significantly reduced the push-out bond strength of ProRoot MTA. With Biodentine irrigation with CHX or DMSO resulted with significantly higher push-out strength compared to the Biodentine control group. Fracture analysis showed statistically significant difference in the distribution of the fractures between the groups, but neither CHX nor DMSO change the fracture pattern statistically significantly. With Vickers hardness test ProRoot MTA with and without DMSO as the final irrigant showed significantly higher dentin hardness than any Biodentine-group. Significance. Considering that aging increased the leakage in all groups except with Biodentine-DMSO and the differences in the push-out strength and surface microhardness data, it appears that the time-related biomineralizing effect of MTA and Biodentine does not improve sealing to dentin. CHX significantly reduced ProRoot MTA bond strength and increased pure adhesive failures with both cements. (C) 2020 Published by Elsevier Inc. on behalf of The Academy of Dental Materials.

[No abstract available], Amer Soc Clin Oncol

A major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials. Using a virtual clinical trial simulations approach, we present a mathematical framework to estimate the added value of combinatorial treatments in ovarian cancer. This approach was applied to identify effective targeted therapies that can be combined with the platinum-taxane regimen and overcome platinum resistance in high-grade serous ovarian cancer. We modeled and evaluated the effectiveness of three drugs that target the main platinum resistance mechanisms, which have shown promising efficacy in vitro, in vivo, and early clinical trials. Our results show that drugs resensitizing chemoresistant cells are superior to those aimed at triggering apoptosis or increasing the bioavailability of platinum. Our results further show that the benefit of using biomarker stratification in clinical trials is dependent on the efficacy of the drug and tumor composition. The mathematical framework presented herein is suitable for systematically testing various drug combinations and clinical trial designs in solid cancers.

In this paper the impact on the store’s energy use by different refrigeration systems, remote and centralised, is investigated as well as their environmental impact. The study is performed using the energy simulation program EnergyPlus in a reference baseline model which has been verified against measured energy and environmental conditions data. The refrigeration system of the case study includes plugged-in display cabinets to serve both medium temperature (MT) and low temperature (LT) refrigeration loads. Centralised systems are compared with the remote plugged-in refrigeration cabinets. The different refrigeration systems studied are, a) two parallel centralised systems for MT and LT loads, b) two parallel cascade systems (R134a/CO 2 ) for MT and LT loads and c) a transcritical CO 2 booster. The study is performed for DSY London weather file to capture the risk of warmer than a typical year consequences in centralised refrigeration systems operation. Besides these refrigeration systems, the CO 2 transcritical appears as the one of the most promising replacement in terms not only of energy use reduction due to its high efficiency in London climate but on its low contribution to global warming as well.

Due to the usually late diagnosis and lack of effective therapies, hepatocellular carcinoma (HCC), which poses a growing global health problem, is characterized by a poor prognosis. Angiogenesis plays an important role in HCC progression, and vascular endothelial growth factor (VEGF) and angiopoietins (Angs) are key drivers of HCC angiogenesis. VEGF-targeting strategies already represent an important component of today’s systemic treatment landscape of HCC, whereas targeting the Ang/Tie2 signaling pathway may harbor future potential in this context due to reported beneficial anticancer effects when targeting this pathway. In addition, a better understanding of the relation between Angs and HCC angiogenesis and progression may reveal their potential as predictive factors for post-treatment disease progression and prognosis. In this review, we give a comprehensive overview of the complex role of Ang/Tie2 signaling in HCC, pinpointing its potential value as biomarker and target for HCC treatments, aiding HCC diagnosis and therapy.

Introduction: Although targeting human epidermal growth factor receptor 2 (HER2) is a meaningful treatment in HER2-positive breast cancer, ultimately resistance develops. Androgen receptor (AR) expression and immune cell infiltration are thought to be involved in trastuzumab response and may, therefore, be of interest as additional targets for therapy in HER2-positive breast cancer.Aim: To improve insights into the presence among AR expression, immune cell infiltration and HER2, we analysed HER2-positive breast tumours.Methods: Primary tumours of 221 patients treated with trastuzumab for metastatic disease were selected. HER2 status was centrally confirmed. AR, T-cells (CD3 and CD8), programmed cell death protein 1 (PD-1) and PD-1 ligand 1 immunohistochemical staining and M2 tumour-associated macrophages (TAMs; CD68 and CD163) immunofluorescence were performed. Tumour-infiltrating lymphocytes were evaluated by haematoxylin and eosin staining.Results: Sufficient tumour material was available for 150 patients. Oestrogen receptor was expressed in 51.3% of the tumours andARin 81.3% of the tumours. AR expression was inversely correlated with M2 TAM (Pearson's r = -0.361, P Conclusion: AR expression inversely correlates with immune cell infiltration in HER2-positive breast cancer. (C) 2018 Elsevier Ltd. All rights reserved.

Background: The anterolateral (AntLat) surgical approach may spare the blood supply to the femoral head and improve the accuracy of cup positioning in metal-on-metal hip resurfacing arthroplasty. Thereby, potentially lessen complications such as avascular head necrosis, femoral neck narrowing and fracture, improve implant fixation, and lessen periprosthetic bone mineral density (BMD) loss.Methods: Between November 2008 and January 2012, a randomized clinical trial was performed at Aarhus University Hospital. A total of 49 patients (28 males) were allocated to metal-on-metal hip resurfacing arthroplasty by the AntLat (n = 25) or the posterior (Post; n = 24) surgical approach. Patients were followed with radiostereometric analysis, measurements of periprosthetic BMD, clinical outcome scores of Harris hip score and visual analogue scale, serum metal ions, and conventional radiographs.Results: At 3 months, cups in the AntLat group had higher total translations of mean 1.00 +/- 0.70 mm vs mean 0.64 +/- 0.45 mm in the post group (P = .04), and higher total rotations of mean 2.44 degrees +/- 1.36 degrees vs mean 1.39 degrees +/- 1.17 degrees in the Post group (P = .002). All migrations of cup and stem were similar at 1 and 2 years postoperative (P > .07). At 1 year, periprosthetic BMD since postoperative at the medial side of the stem was reduced to mean 98.45% +/- 8.57% in the AntLat group, and increased to mean 105.57% +/- 11.07% in the Post group (P = .02), but measurements were comparable at 2 years (P = .05).Conclusion: Cups inserted by the AntLat approach migrated more until 3 months postoperative. This illustrates a less good primary cup fixation with the AntLat approach; however, all cups were well-fixed after 3 months' follow-up indicating a good secondary fixation. (C) 2017 Elsevier Inc. All rights reserved.

Background and Purpose— Animal studies suggest that cooling improves outcome after ischemic stroke. We assessed the feasibility and safety of surface cooling to different target temperatures in awake patients with acute ischemic stroke. Methods— A multicenter, randomized, open, phase II, clinical trial, comparing standard treatment with surface cooling to 34.0°C, 34.5°C, or 35.0°C in awake patients with acute ischemic stroke and an National Institutes of Health Stroke Scale score of ≥6, initiated within 4.5 hours after symptom onset and maintained for 24 hours. The primary outcome was feasibility, defined as the proportion of patients who had successfully completed the assigned treatment. Safety was a secondary outcome. Results— Inclusion was terminated after 22 patients because of slow recruitment. Five patients were randomized to 34.0°C, 6 to 34.5°C, 5 to 35.0°C (cooling was initiated in 4), and 6 to standard care. No (0%), 1 (17%), and 3 (75%) patients, respectively, completed the assigned treatment ( P =0.03). No (0%), 2 (33%), and 4 (100%) patients reached the target temperature ( P =0.01). Pneumonia occurred in 8 cooled patients but not in controls (absolute risk increase, 53%; 95% confidence interval, 28–79%; P =0.002). Conclusions— In awake patients with acute ischemic stroke, surface cooling is feasible to 35.0°C, but not to 34.5°C and 34.0°C. Cooling is associated with an increased risk of pneumonia. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR2616.

Purpose To document the rate and outcome of trastuzumab-associated cardiac dysfunction in patients following 1 or 2 years of adjuvant therapy. Patients and Methods The Herceptin Adjuvant (HERA) trial is a three-arm, randomized trial comparing 2 years or 1 year of trastuzumab with observation in 5,102 patients with human epidermal growth factor receptor 2 (HER2) –positive early-stage breast cancer. Cardiac function was closely monitored. Eligible patients had left ventricular ejection fraction (LVEF) ≥ 55% at study entry following neoadjuvant chemotherapy with or without radiotherapy. This 8-year median follow-up analysis considered patients randomly assigned to 2 years or 1 year of trastuzumab or observation. Results The as-treated safety population for 2 years of trastuzumab (n = 1,673), 1 year of trastuzumab (n = 1,682), and observation (n = 1,744) is reported. Cardiac adverse events leading to discontinuation of trastuzumab occurred in 9.4% of patients in the 2-year arm and 5.2% of patients in the 1-year arm. Cardiac death, severe congestive heart failure (CHF), and confirmed significant LVEF decrease remained low in all three arms. The incidence of severe CHF (0.8%, 0.8%, and 0.0%, respectively) and confirmed significant LVEF decrease (7.2%, 4.1%, and 0.9%, respectively) was significantly higher in the 2-year and 1-year trastuzumab arms compared with the observation arm. Severe CHF was the same for 2-year and 1-year trastuzumab. Of patients with confirmed LVEF decrease receiving 2-year trastuzumab, 87.5% reached acute recovery. Of patients with confirmed LVEF decrease receiving 1-year trastuzumab, 81.2% reached acute recovery. Conclusion Long-term assessment at 8-year median follow-up confirms the low incidence of cardiac events for trastuzumab given sequentially after chemotherapy and radiotherapy, and cardiac events were reversible in the vast majority of patients.

Indonesia has turned its alleged role as global leader of land-based carbon emissions into a role as a global trailblazer exploring modalities for Reducing Emissions from Deforestation and Forest Degradation (REDD+). REDD+ readiness is largely about improving forest governance, but this itself is a multilayered concept. This article analyses how the processes and practices of REDD+ readiness are leading to various forest governance reforms in Indonesia. We analysed six dimensions of REDD+ readiness progress over the past six years and the way these interact with land tenure reform and land-use planning. We found evidence that (1) tenure issues are taken more seriously, as evidenced by the development of social safeguard mechanisms and efforts to accelerate the gazettement of forest boundaries, although a constitutional court recognition in 2013 for customary forest management is, however, yet to be operationalized; (2) spatial planning relates forests more clearly to other parts of the landscape in terms of compliance with Nationally Appropriate Mitigation Actions (NAMAs) commitments; and (3) the forest and peatland conversion moratorium initiative led to a revamping of forest management. Despite progress, there are still major obstacles to full REDD+ implementation in Indonesia. The discussion focuses on the weaker part of readiness and possible ways forward. Policy relevance Reducing Emissions from Deforestation and forest Degradation plus (REDD+) was introduced at the 13th Conference of the Parties (COP 13) 2007 in Bali designed to support the efforts of the parties to reduce emissions from deforestation and forest degradation and enhance the forest carbon stock, by means of forest conservation and the sustainable management of forests. This article aims to examine the impact of REDD+ readiness process in Indonesia on transforming existing forest governance. This paper focus the analysis on the two most contentious forest governance issues in Indonesia: land tenure and land-use planning. Such analysis and lessons are relevant for policy-makers in Indonesia in an effort to have a forest governance reform and also the future challenges of forest governance in national and sub-national level in the world of sustainable forest management as well as REDD+ implementation.

Lessons Learned First trial to report safety and activity of the microtubule inhibitor vinflunine plus the tyrosine kinase inhibitor sorafenib in post-platinum metastatic urothelial cancer (mUC) patients. A recommended phase II dose was identified for the treatment combination of vinflunine plus sorafenib, with main adverse events including fatigue, febrile neutropenia, neutropenia, hypertension, and hyponatremia. An overall response rate of 41% to second-line vinflunine plus sorafenib treatment in patients with platinum-resistant mUC was confirmed. Background Platinum-progressive metastatic urothelial carcinoma (mUC) is a clinical challenge. The tyrosine kinase inhibitor sorafenib has demonstrated varied activity in mUC. This trial was designed to examine safety and activity of vinflunine plus sorafenib in mUC. Methods In addition to standard dose of vinflunine (320 or 280 mg/m2), patients received sorafenib (400, 600, or 800 mg/day), in a 3 + 3 dose-escalation phase I design. Results Twenty-two patients (median age 62.5 years) were included. Five patients received vinflunine 320 mg/m2 and 17 received 280 mg/m2. The maximum tolerated dose (MTD) of sorafenib with vinflunine 280 mg/m2 was 600 mg, and with vinflunine 320 mg/m2 it was not determined, owing to toxicity. Adverse events (AEs) grades 3 + 4 consisted of neutropenia (6 patients), febrile neutropenia (5), and hyponatremia (5). The overall response rate (ORR) in the efficacy-evaluable patients was 41% (7 of 17), all partial responses evaluated by RECIST version 1.1. Median overall survival (OS) was 7.0 months (1.8–41.7). Conclusion The defined recommended phase II dose (RPTD) was vinflunine 280 mg/m2 plus sorafenib 400 mg. Sorafenib was too toxic in combination with vinflunine 320 mg/m2. The ORR of 41% to this second-line combination treatment of mUC is noteworthy and supports further trials.

International audience; There has been a large increase in anthropogenic emissions of CO 2 over the past century. The use of captured CO2 can become a profitable business, in addition to controlling CO2 concentration in the atmosphere. A process for producing fuel grade methanol from captured CO2 is proposed in this paper. The process is designed and simulated with Aspen Plus. The CO2 is captured by chemical absorption from the flue gases of a thermal power plant. The hydrogen is produced by water electrolysis using carbon-free electricity. The methanol plant provides 36% of the thermal energy required for CO2 capture, reducing considerably the costs of the capture. The CO2 balance of the process showed that it is possible to abate 1.6 t of CO2 per tonne of methanol produced if oxygen by-product is sold, or 1.2 t if it is not.

Regorafenib monotherapy is a potential option for metastatic colorectal cancer patients. However, the lack of predictive factors and the severe toxicities related to treatment have made its use in clinical practice challenging. Polymorphisms of VEGF and its receptor (VEGFR) genes might regulate angiogenesis and thus potentially influence outcome during anti-angiogenesis treatment such as regorafenib. Aim of our study was to evaluate the role of VEGF and VEGFR genotyping in determining clinical outcome for colorectal cancer patients receiving regorafenib. We retrospectively collected clinical data and samples (tumour or blood) of 138 metastatic colorectal cancer patients treated with regorafenib. We analysed the correlation of different VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs) with patients’ progression-free survival (PFS) and overall survival (OS). Results from angiogenesis genotyping showed that only VEGF-A rs2010963 maintained an independent correlation with PFS and OS. Among clinical factors only ECOG PS was independently correlated with OS, whereas no correlation with PFS was evident. Grouping together those results allowed further patients stratification into 3 prognostic groups: favourable, intermediate and unfavourable. VEGF-A rs2010963 genotyping may represent an important tool for a more accurate selection of optimal candidates for regorafenib therapy.

Fundamental trade-offs exist between different land uses for carbon, livelihoods, economic development, biodiversity, agriculture and energy (especially biofuels). This article analyses the scientific debates on REDD+ trade-offs, co-benefits and safeguards, and shows how the development and expanded scope of REDD+ mechanisms have shaped these debates over time. We find substantial evidence that the non-carbon values of biodiversity conservation, equity and sustainable livelihoods are critical to both the legitimacy and effectiveness of REDD+, and argue that they therefore are better viewed as prerequisites than as values to be safeguarded. Scientists can contribute to the development of a more integrative REDD+ through interdisciplinary research and through a ‘learning architecture’ that supports the REDD+ policy development process with research dedicated to finding durable solutions.

Contains fulltext : 53697.pdf (Publisher’s version ) (Closed access) AIM: Trastuzumab can induce cardiotoxicity, particularly when combined with anthracyclines. Myocardial human epidermal growth factor receptor 2 (HER2) expression may be transiently upregulated by a compensatory mechanism following cardiac stress. 111In-DTPA-trastuzumab, scintigraphy can detect HER2 positive tumour lesions, however previously, we found myocardial uptake in only 1 of the 15 anthracycline-pre-treated patients with a median of 11 months after the last anthracycline administration. To evaluate whether myocardial HER2 expression is upregulated by anthracycline-induced cardiac stress or in case of heart failure by chronic pressure or volume overload, we performed 111In-DTPA-trastuzumab scans in patients shortly after anthracyclines and with non-anthracycline-related heart failure. METHODS: Patients within 3 weeks after undergoing 4-6 cycles first-line anthracycline-based chemotherapy and patients with heart failure due to cardiac disease underwent gammacamera imaging 48 and 96 h after 111In-DTPA-trastuzumab intravenously. RESULTS: Myocardial 111In-DTPA-trastuzumab uptake was observed in 5 out of 10 anthracycline-treated patients, who all were without symptomatic cardiac dysfunction. None of the 10 heart failure patients showed myocardial uptake. CONCLUSION: Shortly after completion of anthracycline treatment, myocardial HER2 over-expression was detectable in 50% of the patients. 111In-DTPA-trastuzumab scintigraphy after anthracyclines prior to adjuvant trastuzumab potentially identifies patients susceptible for trastuzumab-related cardiotoxicity and thus may facilitate the optimal timing of trastuzumab therapy.

UNLABELLED: Human epidermal growth factor receptor 2 (HER2) status is one of the major tumor characteristics in breast cancer to guide therapy. Anti-HER2 treatment has clear survival advantages in HER2-positive breast carcinoma patients. Heterogeneity in HER2 expression between primary tumor and metastasis has repeatedly been described, resulting in the need to reassess HER2 status during the disease course. To avoid repeated biopsy with potential bias due to tumor heterogeneity, Nanobodies directed against HER2 have been developed as probes for molecular imaging. Nanobodies, which are derived from unique heavy-chain-only antibodies, are the smallest antigen-binding antibody fragments and have ideal characteristics for PET imaging. The primary aims were assessment of safety, biodistribution, and dosimetry. The secondary aim was to investigate tumor-targeting potential. METHODS: In total, 20 women with primary or metastatic breast carcinoma (score of 2+ or 3+ on HER2 immunohistochemical assessment) were included. Anti-HER2-Nanobody was labeled with (68)Ga via a NOTA derivative. Administered activities were 53-174 MBq (average, 107 MBq). PET/CT scans for dosimetry assessment were obtained at 10, 60, and 90 min after administration. Physical evaluation and blood analysis were performed for safety evaluation. Biodistribution was analyzed for 11 organs using MIM software; dosimetry was assessed using OLINDA/EXM. Tumor-targeting potential was assessed in primary and metastatic lesions. RESULTS: No adverse reactions occurred. A fast blood clearance was observed, with only 10% of injected activity remaining in the blood at 1 h after injection. Uptake was seen mainly in the kidneys, liver, and intestines. The effective dose was 0.043 mSv/MBq, resulting in an average of 4.6 mSv per patient. The critical organ was the urinary bladder wall, with a dose of 0.406 mGy/MBq. In patients with metastatic disease, tracer accumulation well above the background level was demonstrated in most identified sites of disease. Primary lesions were more variable in tracer accumulation. CONCLUSION: (68)Ga-HER2-Nanobody PET/CT is a safe procedure with a radiation dose comparable to other routinely used PET tracers. Its biodistribution is favorable, with the highest uptake in the kidneys, liver, and intestines but very low background levels in all other organs that typically house primary breast carcinoma or tumor metastasis. Tracer accumulation in HER2-positive metastases is high, compared with normal surrounding tissues, and warrants further assessment in a phase II trial.

Trastuzumab is a remarkably effective therapy for patients with human epidermal growth factor receptor 2 (HER2) - positive breast cancer (BC). However, not all women with high levels of HER2 benefit from trastuzumab. By integrating mRNA and protein expression data from Reverse-Phase Protein Array Analysis (RPPA) in HER2-positive BC, we developed gene expression metagenes that reflect pathway activation levels. Next we assessed the ability of these metagenes to predict resistance to adjuvant trastuzumab using gene expression data from two independent datasets. 10 metagenes passed external validation (false discovery rate [fdr] < 0.05) and showed biological relevance with their pathway of origin. These metagenes were further screened for their association with trastuzumab resistance. An association with trastuzumab resistance was observed and validated only for the AnnexinA1 metagene (ANXA1). In the randomised phase III Fin-her study, tumours with low levels of the ANXA1 metagene showed a benefit from trastuzumab (multivariate: hazard ratio [HR] for distant recurrence = 0.16[95%CI 0.05-0.5]; p = 0.002; fdr = 0.03), while high expression levels of the ANXA1 metagene were associated with a lack of benefit to trastuzmab (HR = 1.29[95%CI 0.55-3.02]; p = 0.56). The association of ANXA1 with trastuzumab resistance was successfully validated in an independent series of subjects who had received trastuzumab with chemotherapy (Log Rank; p = 0.01). In conclusion, in HER2-positive BC, some proteins are associated with distinct gene expression profiles. Our findings identify the ANXA1metagene as a novel biomarker for trastuzumab resistance., SCOPUS: ar.j, info:eu-repo/semantics/published

Oncologists disagree if chemotherapy in advanced cancer can improve quality of life (QoL), to prolong duration of life, or both. The objective of this study was to clarify the main treatment intention of palliative chemotherapy (PCT): the prolongation of life (PoL); or QoL. Randomized controlled clinical trials of PCT in advanced colorectal cancer that included HRQoL assessment were selected from PubMed and reviewed. Authors' conclusions were based on both PoL- and QoL-related outcomes. However, if PoL and QoL outcomes of the experimental arm were opposite, which was the case in 13 out of 28 trials, the authors generally based their conclusion on PoL outcomes. Authors' conclusions focused mainly on Pol.-related outcomes, while QoL-related outcomes were of overriding importance in only 1/28 case. QoL can therefore not be considered as the main outcome of PCT. The review shows that in the context of chemotherapy in advanced colorectal cancer, 'palliative' refers to a life-prolonging intention, whereas within palliative care it refers to an improvement in QoL. (c) 2005 Elsevier Ltd. All rights reserved.

Summary: Purpose: Mutations in the voltage-gated sodium channel subunit gene SCN1A have been associated with febrile seizures (FSs) in autosomal dominant generalized epilepsy with febrile seizures plus (GEFS+) families and severe myoclonic epilepsy of infancy. The present study assessed the role of SCN1A in familial typical FSs. Methods: FS families were selected throughout a collaborative study of the Italian League Against Epilepsy. For each index case, the entire coding region of SCN1A was screened by denaturant high-performance liquid chromatography. DNA fragments showing variant chromatograms were subsequently sequenced. Results: Thirty-two FS families accounting for 91 affected individuals were ascertained. Mutational analysis detected a single coding variant (A3169G) on exon 16. The extended analysis of all family members and 78 normal controls demonstrated that A3169G did not contribute to the FS phenotype. Conclusions: Our study demonstrated that SCN1A is not frequently involved in common FSs and suggested the involvement of specific FS genes.

Monitoring tropical deforestation and forest degradation is one of the central elements for the Reduced Emissions from Deforestation and Forest Degradation in developing countries (REDD+) scheme. Current arrangements for monitoring are based on remote sensing and field measurements. Since monitoring is the periodic process of assessing forest stands properties with respect to reference data, adopting the current REDD+ requirements for implementing monitoring at national levels is a challenging task. Recently, the advancement in Information and Communications Technologies (ICT) and mobile devices has enabled local communities to monitor their forest in a basic resource setting such as no or slow internet connection link, limited power supply, etc. Despite the potential, the use of mobile device system for community based monitoring (CBM) is still exceptional and faces implementation challenges. This paper presents an integrated data collection system based on mobile devices that streamlines the community-based forest monitoring data collection, transmission and visualization process. This paper also assesses the accuracy and reliability of CBM data and proposes a way to fit them into national REDD+ Monitoring, Reporting and Verification (MRV) scheme. The system performance is evaluated at Tra Bui commune, Quang Nam province, Central Vietnam, where forest carbon and change activities were tracked. The results show that the local community is able to provide data with accuracy comparable to expert measurements (index of agreement greater than 0.88), but against lower costs. Furthermore, the results confirm that communities are more effective to monitor small scale forest degradation due to subsistence fuel wood collection and selective logging, than high resolution remote sensing SPOT imagery.

Introduction: The human epidermal growth factor receptor 2 (HER2)-targeted therapies trastuzumab (T) and lapatinib (L) show high efficacy in patients with HER2-positive breast cancer, but resistance is prevalent. Here we investigate resistance mechanisms to each drug alone, or to their combination using a large panel of HER2-positive cell lines made resistant to these drugs. Methods: Response to L + T treatment was characterized in a panel of 13 HER2-positive cell lines to identify lines that were de novo resistant. Acquired resistant lines were then established by long-term exposure to increasing drug concentrations. Levels and activity of HER2 and estrogen receptor (ER) pathways were determined by qRT-PCR, immunohistochemistry, and immunoblotting assays. Cell growth, proliferation, and apoptosis in parental cells and resistant derivatives were assessed in response to inhibition of HER or ER pathways, either pharmacologically (L, T, L + T, or fulvestrant) or by using siRNAs. Efficacy of combined endocrine and anti-HER2 therapies was studied in vivo using UACC-812 xenografts. Results: ER or its downstream products increased in four out of the five ER+/HER2+ lines, and was evident in one of the two intrinsically resistant lines. In UACC-812 and BT474 parental and resistant derivatives, HER2 inhibition by T reactivated HER network activity to promote resistance. T-resistant lines remained sensitive to HER2 inhibition by either L or HER2 siRNA. With more complete HER2 blockade, resistance to L-containing regimens required the activation of a redundant survival pathway, ER, which was up-regulated and promoted survival via various Bcl2 family members. These L-and L + T-resistant lines were responsive to fulvestrant and to ER siRNA. However, after prolonged treatment with L, but not L + T, BT474 cells switched from depending on ER as a survival pathway, to relying again on the HER network (increased HER2, HER3, and receptor ligands) to overcome L's effects. The combination of endocrine and L + T HER2-targeted therapies achieved complete tumor regression and prevented development of resistance in UACC-812 xenografts. Conclusions: Combined L + T treatment provides a more complete and stable inhibition of the HER network. With sustained HER2 inhibition, ER functions as a key escape/survival pathway in ER-positive/HER2-positive cells. Complete blockade of the HER network, together with ER inhibition, may provide optimal therapy in selected patients.

Intrauterine seizure is a rare event. Genetic predisposition and trauma are possible risk factors. OBJECTIVE: To review and comment on the historical description of intrauterine events of a bastard daughter of Dom Pedro I (Maria Isabel Alcântara Brasileira - 1830-1896). METHOD: Review of historical facts about the health of Dom Pedro I's daughter according to primary and secondary historical data. RESULTS: According to historical accounts, Dom Pedro I's daughter suffered trauma during the intrauterine period that provoked intrauterine seizures. At the age of eight years, she developed self-limited and benign generalized epilepsy. Like her father, she had mood problems and also learning difficulties. CONCLUSION: Dona Maria Isabel's own report does not shown sufficient evidence to support the diagnosis of post-traumatic intrauterine seizures. Nevertheless, her family history suggests a genetic basis for her epilepsy. A convulsão intra-uterina é evento raro, sendo possíveis fatores de risco a genética e o traumatismo. OBJETIVO: Rever e comentar a descrição histórica de eventos intra-uterinas de uma filha bastarda de D. Pedro I (Maria Isabel Alcântara Brasileira - 1830-1896). MÉTODO: Revisão dos fatos históricos sobre a saúde da filha do D. Pedro I, de acordo com dados históricos primários e secundários. RESULTADOS: A filha de Dom Pedro I, de acordo com relatos históricos teria sofrido um traumatismo durante o período intra-uterino, o que provocou convulsões intra-uterinas. Na idade de oito anos a menina desenvolveu uma epilepsia generalizada limitada e benigna. Como seu pai, teve problemas do humor e, também, dificuldades de aprendizagem. CONCLUSÃO: O relato de Dona Maria Isabel não gera prova suficiente para sustentar o diagnóstico de convulsões intra-uterinas de origem traumática. Não obstante, seus antecedentes familiares sugerem uma base genética para sua epilepsia.

Purpose The cardiac and antineoplastic effects of trastuzumab may be related to specific uptake of trastuzumab in myocardium and tumor tissue, respectively. We evaluated whether indium-111 (111In) –labeled trastuzumab scintigraphy can predict cardiotoxicity and identify tumor lesions. In addition, we evaluated whether plasma markers for cardiac dysfunction can be used to predict cardiotoxicity. Patients and Methods Patients with human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer underwent gamma camera imaging from 15 minutes to 7 days after injection of 150 MBq 111In–diethylenetriamine penta-acetic acid anhydride (DTPA) –trastuzumab, after loading-dose trastuzumab, and after once-a-week trastuzumab doses for 11 weeks, and concomitant paclitaxel once every 3 weeks. Cardiac assessments were performed before treatment, and after four and six cycles. Plasma N-terminal probrain natriuretic peptide (NT-proBNP) and serum troponin I were measured with immunoassay. Results Fifteen of the 17 patients were available for cardiac and tumor uptake analysis. On the first scan, myocardial 111In-DTPA-trastuzumab uptake was observed in one patient with pre-existing cardiac arrhythmias, who did not develop heart failure during treatment. Severe cardiotoxicity occurred in three patients, without initial myocardial uptake, whereas one showed weak myocardial uptake after four cycles. The detection rate of single tumor lesions was 45%. New tumor lesions were discovered in 13 of 15 patients. Pretreatment plasma NT-proBNP levels were higher in patients with than without heart failure (mean, 534 [standard deviation, 236] v 105 [standard deviation, 79] ng/L; P = .009). Conclusion Radiolabeled trastuzumab scintigraphy was not valuable in predicting trastuzumab-related cardiotoxicity in metastatic breast cancer patients, but can identify HER2-positive tumors. Measurement of plasma NT-proBNP is promising regarding prediction of trastuzumab-related cardiotoxicity.

Purpose We investigated whether application of positron emission tomography (PET) immediately after first presentation might simplify staging while maintaining accuracy, as compared with traditional strategy in routine clinical setting. Methods At first presentation, patients with a provisional diagnosis of lung cancer without overt dissemination were randomly assigned to traditional work-up (TWU) according to international guidelines or early PET followed by histologic/cytologic verification of lesions, or imaging and follow-up. Patients with [18F] fluorodeoxyglucose (18FDG) –avid, noncentral tumors without suspicion of mediastinal or distant metastases on PET proceeded directly to thoracotomy. Follow-up in presumed benign lesions was at least 12 months. In patients treated with surgery or neoadjuvant therapy, the quality of staging was measured by comparing the clinical stage to the final stage (combination of peroperative staging and 6 months of follow-up). To investigate test substitution, we analyzed the number of (non)invasive tests to achieve clinical TNM staging, and its associated costs. Results Between 1999 and 2001, 465 patients (233 TWU, 232 PET) were enrolled at 22 hospitals. The mean (standard deviation) number of procedures to finalize staging was equal in the TWU arm and the PET arm: 7.9 (2.0) v 7.9 (1.9), P = .90, respectively. Mediastinoscopies occurred significantly less often in the PET arm. Agreement between clinical and final stage was good in both arms (κ = .85 v .78; P = .07). Costs did not differ significantly. Conclusion Up-front 18FDG-PET in patients with (suspected) lung cancer does not reduce the overall number of diagnostic test, but it maintains quality of TNM staging with the use of less invasive surgery.