Search

Yu-Ying Wu,1,2 I-Fan Lin,1,3 Po-Yuan Chen,1,2 Cheng-Kai Lin,1,2 Cheng-Chun Wu,1 Cheng-Loong Liang,1,2 Yi-Che Lee,1,4 Chi-Wei Lin,1,5 Wei-Leng Chin,1,5 Hao Kuang Wang1,2,6 1School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 2Department of Neurosurgery, E-Da Hospital, Kaohsiung, Taiwan; 3Division of Infectious Diseases, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan; 4Department of Nephrology, E-Da Hospital, Kaohsiung, Taiwan; 5Department of Family Medicine, E-Da Hospital, Kaohsiung, Taiwan; 6Department of Neurosurgery, E-Da Cancer Hospital, Kaohsiung, TaiwanCorrespondence: Hao Kuang WangDepartment of Neurosurgery, E-Da Hospital/ I-Shou University, No. 1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, TaiwanTel +866-975106080Email ed101393@gmail.comBackground: Osteoporotic fractures are a significant cause of morbidity and mortality affecting population worldwide. All guidelines recommended vertebral fracture assessment by dual-energy X-ray absorptiometry (DXA). This study aimed at evaluation of any associated benefits of screening with DXA in patients who had received vertebroplasty in Taiwan.Methods: Data were obtained from the National Health Insurance Research Database (NHIRD) in Taiwan. We retrospectively compared the data of patients, who were admitted for vertebroplasty, whether they received DXA screening or not. The outcomes of interest were recurrence of spinal fracture and mortality during a follow-up period of 10 years.Results: From this Taiwan national database, the screening rate of osteoporosis in patient who received vertebroplasty was 11.7%. The mean age in the non-DXA screened cohort (n=32,986) was 74.03± 12.21 years (71.98% female). In the DXA screened cohort (n=4361), the mean age was 76.43± 9.19 years (79.91% female). During the 10-year follow-up period, after matching, non-DXA patients had significantly higher mortality rates than their DXA counterparts, which were 42.37% and 37.73% (p-value < 0.0001), respectively. The re-fracture rates between non-DXA and DXA patients were not significantly different at 17.26% and 16.89% (p-value = 0.1766), respectively.Conclusion: The rate of DXA screening before patients receiving vertebroplasty was extremely low, at 11.7%. Our results showed that DXA screening before vertebroplasty in spinal fractures patients had lower mortality. From this national retrospective cohort study, routine screening of osteoporosis in spinal fracture patients can lead to reduction in mortality.Keywords: osteoporosis, vertebroplasty, DXA, mortality

Introduction: Defining recurrent weight gain after metabolic bariatric surgery poses a significant challenge. Our study aimed to standardize recurrent weight gain measurements in patients undergoing laparoscopic sleeve gastrectomy (LSG) and ascertain its association with comorbidity progression., Methods: We conducted a retrospective data analysis on 122 patients who underwent LSG, tracking their progress over 2-7 years. Data on weight, blood pressure measurements, and laboratory tests were collected, focusing on the postoperative period to identify nadir weight, total weight loss, and recurrent weight gain., Results: Significant weight loss and comorbidity remission were noted, with diabetes, hypertension, and dyslipidemia showing substantial remission rates of 85.71%, 68.24%, and 85.37%, respectively. The median recurrent weight gain was 6.30 kg within 12 months of the nadir. Progression proportion of diabetes, hypertension, and dyslipidemia were 8.20%, 44.26%, and 40.98%, respectively. Hypertension progression was strongly associated with a recurrent weight gain ≥ 10 kg and ≥ 20% of maximum weight loss. Dyslipidemia progression was significantly correlated with recurrent weight gain ≥ 10 kg and ≥ 20% of maximum weight loss. Diabetes progression was significantly correlated with recurrent weight gain ≥ 10% of pre-surgery body weight and ≥ 25% of maximum weight loss. A ≥ 10% weight gain of maximum weight loss did not significantly impact the progression of these conditions., Conclusion: Recurrent weight gain ≥ 20% of maximum weight loss can be treated as a specific threshold indicating comorbidity progression post-LSG. Standardizing the measurement of recurrent weight gain can help healthcare providers to implement targeted management strategies to optimize long-term health outcomes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Time-critical transcriptional events in the immune microenvironment are important for response to immune checkpoint blockade (ICB), yet these events are difficult to characterise and remain incompletely understood. Here, we present whole tumor RNA sequencing data in the context of treatment with ICB in murine models of AB1 mesothelioma and Renca renal cell cancer. We sequenced 144 bulk RNAseq samples from these two cancer types across 4 time points prior and after treatment with ICB. We also performed single-cell sequencing on 12 samples of AB1 and Renca tumors an hour before ICB administration. Our samples were equally distributed between responders and non-responders to treatment. Additionally, we sequenced AB1-HA mesothelioma tumors treated with two sample dissociation protocols to assess the impact of these protocols on the quality transcriptional information in our samples. These datasets provide time-course information to transcriptionally characterize the ICB response and provide detailed information at the single-cell level of the early tumor microenvironment prior to ICB therapy., (© 2024. The Author(s).)

Purpose: The NIPU-trial investigates the effect of adding the telomerase vaccine UV1 to treatment with ipilimumab and nivolumab for patients with pleural mesothelioma (PM)., Methods: In this phase 2 open-label trial, patients with PM progressing after first-line chemotherapy were randomised to receive ipilimumab and nivolumab alone (arm B) or combined with UV1 (arm A). The primary endpoint was progression-free survival (PFS) as determined by BICR. It was estimated that 69 PFS events were needed to detect a hazard ratio (HR) of 0.60 with 80% power and a one-sided alpha level of 0.10., Results: 118 patients were randomised. The median PFS determined by blinded independent central review (BICR) was 4.2 months (95%CI 2.9-9.8) in arm A and 4.7 months (95%CI 3.9-7.0) in arm B (HR 1.01, 80%CI 0.75-1.36 P = 0.979), after a median follow-up of 12.5 months (95%CI 9.7-15.6). The investigator-determined median PFS was 4.3 months (95%CI 3.0-6.8) in arm A and 2.9 months (95%CI 2.4-5.5) in arm B (HR 0.60, 80%CI 0.45-0.81 P = 0.025). Confirmed objective response rate (ORR) by BICR was 31% in arm A and 16% in arm B (odds ratio 2.44 80%CI 1.35-4.49 P = 0.056). After a median follow-up time of 17.3 months (95%CI 15.8-22.9), the OS was 15.4 months (95%CI 11.1-22.6) in arm A and 11.1 months (95%CI 8.8-18.1) in arm B, (HR 0.73, 80%CI 0.53-1.0, P = 0.197)., Conclusion: The primary endpoint was not met. Predefined analyses of response rates are in favour of adding the vaccine., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vilde Drageset Haakensen - Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Roche, Takeda, Pfizer, BMS, MSD, Janssen. Participation on a Data Safety Monitoring Board or Advisory Board: Novartis, Astra Zeneca, BMS. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Board member of lung cancer patient organization from 2022. Support from the South-Eastern Norway Regional Health Authorities, grant number 2021083. Maria Bjaanæs - Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Pfizer, BMS. Weronika Maria Szejniuk – none declared. Solfrid Thunold - Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS. Susana Cedres - Participation on a Data Safety Monitoring Board or Advisory Board: F. Hoffmann La Roche AG, MSD Oncology, Pfizer, Amphera, Boehringer Ingelheim, BMS Wee L Chin – none declared. Tonje Sofie Dalen – none declared. Saima Farooqi - Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Merck. Oscar Grundberg – none declared. Åslaug Helland - All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): South-Eastern Norway Regional Health Authorities, grant number 202007 and 2016056, Ultimovacs, BMS. Grants or contracts from any entity: Roche, InCyte, Astra Zeneca, Merck, Novartis, Eli Lilly, GSK, Illumina, Nanopore. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Janssen, Medicovver, Bayer, Eli Lilly, MSD, BMS, Merck, Sanofi, Abbvie, Pfizer, Takeda, Novartis, Roche. Participation on a Data Safety Monitoring Board or Advisory Board: AMGEN (DSMC), AdBoard: Roche, AstraZeneca, Pfizer, Janssen, BMS, EliLilly, Abbvie, Bayer, Sanofi, Merck, Takeda. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Board member of lung cancer patient organization until 2022 Marius Lund Iversen – none declared. Anna K Nowak - Grants or contracts from any entity: Astra Zeneca. Participation on a Data Safety Monitoring Board or Advisory Board: AstraZeneca, BMS, Douglas Pharmaceuticals Åsa Kristina Öjlert – none declared. Jens Benn Sørensen - Participation on a Data Safety Monitoring Board or Advisory Board: BMS, Merck, Astra Zeneca., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study aims to establish advanced sampling methods in free-text data for efficiently building semantic text mining models using deep learning, such as identifying vertebral compression fracture (VCF) in radiology reports. We enrolled a total of 27,401 radiology free-text reports of X-ray examinations of the spine. The predictive effects were compared between text mining models built using supervised long short-term memory networks, independently derived by four sampling methods: vector sum minimization, vector sum maximization, stratified, and simple random sampling, using four fixed percentages. The drawn samples were applied to the training set, and the remaining samples were used to validate each group using different sampling methods and ratios. The predictive accuracy was measured using the area under the receiver operating characteristics (AUROC) to identify VCF. At the sampling ratios of 1/10, 1/20, 1/30, and 1/40, the highest AUROC was revealed in the sampling methods of vector sum minimization as confidence intervals of 0.981 (95%CIs: 0.980-0.983)/0.963 (95%CIs: 0.961-0.965)/0.907 (95%CIs: 0.904-0.911)/0.895 (95%CIs: 0.891-0.899), respectively. The lowest AUROC was demonstrated in the vector sum maximization. This study proposes an advanced sampling method, vector sum minimization, in free-text data that can be efficiently applied to build the text mining models by smartly drawing a small amount of critical representative samples.

While FRAX with BMD could be more precise in estimating the fracture risk, DL-based models were validated to slightly reduce the number of under- and over-treated patients when no BMD measurements were available. The validated models could be used to screen for patients at a high risk of fracture and osteoporosis., Purpose: Fracture risk assessment tool (FRAX) is useful in classifying the fracture risk level, and precise prediction can be achieved by estimating both clinical risk factors and bone mineral density (BMD) using dual X-ray absorptiometry (DXA). However, DXA is not frequently feasible because of its cost and accessibility. This study aimed to establish the reliability of deep learning (DL)-based alternative tools for screening patients at a high risk of fracture and osteoporosis., Methods: Participants were enrolled from the National Bone Health Screening Project of Taiwan in this cross-sectional study. First, DL-based models were built to predict the lowest T-score value in either the lumbar spine, total hip, or femoral neck and their respective BMD values. The Bland-Altman analysis was used to compare the agreement between the models and DXA. Second, the predictive model to classify patients with a high fracture risk was built according to the estimated BMD from the first step and the FRAX score without BMD. The performance of the model was compared with the classification based on FRAX with BMD., Results: Approximately 10,827 women (mean age, 65.4 ± 9.4 years) were enrolled. In the prediction of the lumbar spine BMD, total hip BMD, femoral neck BMD, and lowest T-score, the root-mean-square error (RMSE) was 0.099, 0.089, 0.076, and 0.68, respectively. The Bland-Altman analysis revealed a nonsignificant difference between the predictive models and DXA. The FRAX score with femoral neck BMD for major osteoporotic fracture risk was 9.7% ± 6.7%, whereas the risk for hip fracture was 3.3% ± 4.6%. Comparison between the classification of FRAX with and without BMD revealed the accuracy rate, positive predictive value (PPV), and negative predictive value (NPV) of 78.8%, 64.6%, and 89.9%, respectively. The area under the receiver operating characteristic curve (AUROC), accuracy rate, PPV, and NPV of the classification model were 0.913 (95% confidence interval: 0.904-0.922), 83.5%, 71.2%, and 92.2%, respectively., Conclusion: While FRAX with BMD could be more precise in estimating the fracture risk, DL-based models were validated to slightly reduce the number of under- and over-treated patients when no BMD measurements were available. The validated models could be used to screen for patients at a high risk of fracture and osteoporosis., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Atypical symptoms of cervical spondylosis include headache, nausea, gastrointestinal discomfort, blurred vision, tinnitus, hypomnesia, and palpitations. Successful treatment of these atypical symptoms has been achieved after conservative non-invasive and surgical spinal treatments, although the role of these interventions in mitigating atypical symptoms of cervical spondylosis is unclear. Our study introduces and elaborates on the visual dysfunction caused by cervical spondylosis. Although there are reports in the literature that spinal manipulation and surgery can improve visual dysfunction, the correlation has remained unclear and controversial. The article reviews the latest research to identify the possible mechanisms of visual dysfunction caused by cervical spine diseases.

While chemotherapy remains the first-line treatment for many cancers, it is still unclear what distinguishes responders from non-responders. Here, we characterize the chemotherapy-responsive tumor microenvironment in mice, using RNA sequencing on tumors before and after cyclophosphamide, and compare the gene expression profiles of responders with progressors. Responsive tumors have an inflammatory and highly immune infiltrated pre-treatment tumor microenvironment characterized by the enrichment of pathways associated with CD4 + T cells, interferons (IFNs), and tumor necrosis factor alpha (TNF-α). The same gene expression profile is associated with response to cyclophosphamide-based chemotherapy in patients with breast cancer. Finally, we demonstrate that tumors can be sensitized to cyclophosphamide and 5-FU chemotherapy by pre-treatment with recombinant TNF-α, IFNγ, and poly(I:C). Thus, a CD4 + T cell-inflamed pre-treatment tumor microenvironment is necessary for response to chemotherapy, and this state can be therapeutically attained by targeted immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C + /CD11b + inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response., (© 2022. The Author(s).)

Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti-CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8 + T cell activation and upregulation of IFNγ, TNFα and IL-1β signaling. The effective anti-tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8 + T cells but was unaffected when TNFα or IL-1β cytokine signaling pathways were blocked. Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy., Competing Interests: LB was employed by JJP Biologics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Principe, Aston, Hope, Tilsed, Fisher, Boon, Dick, Chin, McDonnell, Nowak, Lake, Chee and Lesterhuis.)

Mesothelioma is a rare and universally fatal cancer linked to exposure to asbestos. Until recently, standard of care treatment was chemotherapy; a treatment resulting in a minimal survival extension, and not improved upon for almost twenty years. However, the advent of cancer immunotherapy - and in particular the immune checkpoint inhibitor class of drugs - has resulted in recently approved new treatment options, with more currently under investigation. Here, we review clinical trials of both single agent and combination checkpoint inhibitors in mesothelioma, plus studies investigating their combination with chemotherapy. We also describe current advances in biomarker identification regarding prediction of patient response to checkpoint inhibitors. Finally, we assess the probable future direction of the field; including where current and developing technologies are likely to lead - in terms of both biomarker discovery and treatment options., (Copyright © 2021. Published by Elsevier B.V.)

Advances in cancer immunology have increased the use of immune checkpoint inhibitors in clinical practice, however not all patients respond, and treatment can have severe side-effects. Blood-based immunological biomarkers are an attractive method for predicting which patients will respond to therapy, however, reliable biomarkers for immune checkpoint blockade are lacking. This study aimed to identify patients before or early in treatment who would best respond to PD-1 inhibitors. We hypothesised that higher baseline PD-L1 and/or PD-1 on peripheral blood T cells could predict radiological response to PD-1 inhibitors. This pilot prospective cohort study assessed 26 patients with melanoma or non-small cell lung cancer, treated with pembrolizumab, nivolumab, or nivolumab/ipilimumab combined. Response was assessed by RECIST 1.1. Peripheral blood lymphocytes collected at baseline, after one cycle, 10 weeks and at discontinuation of therapy were analysed by flow cytometry. Patients with a higher proportion of PD-L1 + T cells at baseline had improved objective response to PD-1 inhibitor therapy, and patients with a lower proportion of regulatory T cells at baseline experienced more immune-related adverse events. These findings may prove useful to assist in clinical decision making. Further studies with larger cohorts are required to validate these findings., (© 2021. The Author(s).)

Objectives: The aim of this study is to investigate the impact of bariatric surgery on non-traffic accident-related fractures in patients with obesity., Methods: This retrospective cohort study was conducted using the Taiwan National Health Insurance Research Database. Patients aged 18 to 55 years with obesity diagnosis between 2003 and 2008 were enrolled and divided into two groups: non-surgical and bariatric surgery groups. Patients with endocrine bone disease and malignancy history were excluded. Healthy patients were also randomly selected from the database and assigned to the general population group. The development of fracture was the primary end point. All patients were followed until the end of 2013 or death, whichever came first., Results: After propensity score matching, 1322, 1322, and 4359 subjects were included in the bariatric surgery (BS), non-surgical (NS), and general population (GP) groups, respectively. Based on multivariate analysis, the risk of overall fractures is similar between the BS group (hazard ratio [HR] = 0.774, p = 0.164) and the NS group; nevertheless, the risk of overall fractures was higher in the BS group (HR = 2.210, p<0.001) than in the GP group. The BS group had a significantly lower risk of non-traffic accident-related fractures (HR = 0.542, p = 0.010) than the NS group but a higher risk of non-traffic accident-related fractures (HR = 1.693, p = 0.023) than the GP group., Conclusions: Bariatric surgery may decrease the risk of non-traffic accident-related fractures; however, the risk remains higher in patients with obesity than in the general population.

Purpose: This study aims to determine whether bariatric surgery (BS) decreases the risk of respiratory tract infections (RTIs) in obese patients., Materials and Methods: This retrospective, population-based, matched cohort study utilized data from the Taiwan National Health Insurance Research Database. All patients 18 to 55 years of age with obesity diagnosed between 2005 and 2010 were enrolled. Patients were separated into two groups based on whether they underwent BS. Two groups were selected using 1:1 propensity score matching according to age, sex, and comorbidities. The general population was also enrolled for comparison. The primary endpoint was the incidence of RTIs, including pneumonia, influenza, and bronchitis. All patients were followed up until the end of 2013, the primary endpoint, or death., Results: Compared to the non-surgery group, the BS group was at significantly lower risk for RTIs (aHR 0.432, 95% CI 0.340-0.549, p < 0.001) with shorter length of hospital stay (LOH) and lower cost. Regardless of the RTI-related mortality, pneumonia, influenza, and bronchitis rates, BS did have significant protective effects on the non-surgery group. Compared to the general population, the BS group was at higher risk for RTIs (aHR 3.601, 95% CI 2.742-4.728, p < 0.001) with similar LOH and lower cost., Conclusion: Patients with obesity who underwent BS were at significantly lower risk for RTIs than obese patients who did not undergo BS but were at higher risk for RTIs than the general population. BS may result in a long-term reduction of the RTI risk.

Purpose: This study evaluated the differences in long-term cardiovascular events between obese patients who received bariatric surgery (BS), those who did not, and the general population (GP)., Methods: Between 2003 and 2008, patients with severe obesity, aged 18-55 years, were divided into the non-surgical (NS) and BS groups and were included in this retrospective study. We also extracted data of healthy civilians defined as the GP. The incidence of cardiovascular events, including myocardial infarction, intracranial hemorrhage, epidural hemorrhage, ischemic stroke, and transient ischemic attack, was defined as the primary end point. Patients were followed up either until the end of 2013, upon reaching the primary end point, or death., Results: After propensity score matching, 1436 patients were included in both the BS and NS groups, and 4829 subjects were enrolled as the GP. Of these, 57 (3.9%), 10 (0.6%), and 30 (0.62%) subjects in the NS, BS, and GP, respectively, experienced cardiovascular events. Multivariate analysis revealed that patients with BS had a significantly lower risk of cardiovascular events (HR = 0.168; 95% CI 0.085-0.328; p < 0.001) than those in the NS group, but it was not significantly different in the BS group compared with the GP (HR = 1.202; 95% CI 0.585-2.471; p = 0.617)., Conclusion: Long-term risk of cardiovascular events was significantly lower among patients who had BS, compared to the NS obese patients. Thus, the long-term cardiovascular risk between those who received BS and the GP had no significant difference, in a retrospective view.

Purpose of this study is to develope a scoring system to predict the likelihood of excess body weight loss (EBWL) ≥ 50% 6-months after laparoscopic sleeve gastrectomy (LSG). From April 2016 to September 2018, data was collected from 160 patients (BMI ≥ 32) who underwent primary LSG with at least 6-months follow-up. They were separated into score generation (operated by one surgeon, n = 122) and validation groups (operated by 3 different surgeons, n = 38). EBWL at 6-months ≥ 50% was considered adequate weight loss. Independent variables including age, gender, initial body mass index (BMI), comorbidities, life-style habits, percentage of EBWL and percentage of total body weight loss at 1-week, 1-month, and 3-months were analyzed with mutivariate logistic regression to generate the scoring system. The system was applied to internal and external validation groups to determine efficacy. As results, between the score generation and internal validation groups, the only significant difference in patient characteristics was in exercise participation. EBWL at 1-month > 19.5% (1 point) and EBWL at 3-months > 37.7% (2 points) were identified as independent factors to predict EBWL at 6-months ≥ 50%. When scores were > 1, the system had 94.03% positive predictive value (PPV) and 81.82% negative predictive value (NPV) (AUC: 0.923). Internal validation scores > 1 had a 95.83% PPV and 85.71% NPV (AUC: 0.975). External validation results showed 88.59% PPV and 72.00% NPV (AUC: 0.802). We concluded that this scoring system provides a reliable, objective prediction of EBWL at 6-months ≥ 50%. Patients requiring more aggressive clinical follow-up and intervention can be detected as early as 1- to 3-months after LSG.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, providing remarkable clinical responses in some patients. However, the majority of patients do not respond. It is therefore crucial both to identify predictive biomarkers of response and to increase the response rates to immune checkpoint therapy. In this review we explore the current literature about the predictive characteristics of the tumor microenvironment and discuss therapeutic approaches that aim to change this toward a milieu that is conducive to response. We propose a personalized biomarker-based adaptive approach to immunotherapy, whereby a sensitizing therapy is tailored to the patient's specific tumor microenvironment, followed by on-treatment verification of a change in the targeted biomarker, followed by immune checkpoint therapy. By incorporating detailed knowledge of the immunological tumor microenvironment, we may be able to sensitize currently non-responsive tumors to respond to immune checkpoint therapy., (Copyright © 2020 Zemek, Chin, Nowak, Millward, Lake and Lesterhuis.)

Objectives: Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1-3 inhibitor, as a second or third-line treatment., Materials and Methods: We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon's two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients., Results: 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes., Conclusions: The FGFR 1-3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to define the pretreatment microenvironment associated with an effective outcome by using the fact that inbred mouse strains bearing monoclonal cancer cell line-derived tumors respond in a dichotomous manner to immune checkpoint blockade (ICB). We compared the cellular composition and gene expression profiles of responsive and nonresponsive tumors from mice before ICB and validated the findings in cohorts of patients with cancer treated with ICB antibodies. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with up-regulation of signal transducer and activator of transcription 1 (STAT1) and Toll-like receptor 3 (TLR3) signaling and down-regulation of interleukin-10 (IL-10) signaling. In addition, responsive tumors had more infiltrating-activated natural killer (NK) cells, which were necessary for response. Pretreatment of mice with large established tumors using the STAT1-activating cytokine interferon-γ (IFNγ), the TLR3 ligand poly(I:C), and an anti-IL-10 antibody sensitized tumors to ICB by attracting IFNγ-producing NK cells into the tumor, resulting in increased cure rates. Our results identify a pretreatment tumor microenvironment that predicts response to ICB, which can be therapeutically attained. These data suggest a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Siblings of children with life limiting conditions (LLC) are an important part of the broader family system and require consideration in the holistic care of the family. There can be considerable variation in the functioning and adjustment of these siblings. The current paper explores the resilience paradigm, particularly in the context of siblings of children with LLC and serious medical conditions. The potential impact of children living with a seriously ill brother or sister will be overviewed, and a range of functional outcomes considered. Factors contributing to sibling resilience are detailed, including individual, family, and broader external and social factors. Given the limited research with siblings of children with LLC, literature has also been drawn from the siblings of children with serious and/or chronic medical conditions. Implications for clinical practice and future research are considered. Pediatric palliative care services may be well placed to contribute to this body of research as they have commonly extended relationships with the families of children with LLC, which span across the child's disease trajectory.

KMT2/Set1 is the catalytic subunit of the complex of proteins associated with Set1 (COMPASS) that is responsible for the methylation of lysine 4 of histone H3 (H3K4) in Saccharomyces cerevisiae. Whereas monomethylated H3K4 (H3K4me1) is found throughout the genome, di- (H3K4me2) and tri- (H3K4me3) methylated H3K4 are enriched at specific loci, which correlates with the promoter and 5'-ends of actively transcribed genes in the case of H3K4me3. The COMPASS subunits contain a number of domains that are conserved in homologous complexes in higher eukaryotes and are reported to interact with modified histones. However, the exact organization of these subunits and their role within the complex have not been elucidated. In this study we showed that: (1) subunits Swd1 and Swd3 form a stable heterodimer that dissociates upon binding to a modified H3K4me2 tail peptide, suggesting a regulatory role in COMPASS; (2) the affinity of the subunit Spp1 for modified histone H3 substrates is much higher than that of Swd1 and Swd3; (3) Spp1 has a preference for H3K4me2/3 methylation state; and (4) Spp1 contains a high-affinity DNA-binding domain in the previously uncharacterised C-terminal region. These data allow us to suggest a mechanism for the regulation of COMPASS activity at an actively transcribed gene., ((c) 2010 Elsevier Ltd. All rights reserved.)

Coronary artery disease is responsible for much of the morbidity and mortality in patients with essential hypertension, and these complications have proven to be relatively resistant to antihypertensive therapy. However, the diagnosis of coronary disease in the hypertensive population has been considered problematic. In the present study, 30 asymptomatic patients with mild to moderate hypertension with positive exercise electrocardiograms (ECG) or stress thallium-201 scintigrams underwent coronary angiography to determine the accuracy of these tests for coronary artery disease. The exercise ECG was positive in 25 subjects, of whom 15 had significant coronary lesions and 10 did not. Thallium-201 scintigraphy proved more accurate: 17 of 18 patients with reversible abnormalities had significant obstructive coronary disease anatomically corresponding to the defect, one patient with a fixed defect had normal coronary arteries and was found to have an idiopathic cardiomyopathy, and 9 of 11 without defects had no significant lesions. The results were similar in populations with and without echocardiographic criteria for left ventricular hypertrophy. These findings indicate that despite previous suggestions to the contrary, thallium-201 scintigraphy can accurately diagnose coronary artery disease in most patients with asymptomatic essential hypertension, and that most asymptomatic hypertensive patients with physiologic evidence of myocardial ischemia have associated coronary artery disease.

Conditions have been developed that permit highly efficient conversion in vitro of all serogroups of Neisseria meningitidis to the L-form. During the course of the studies, optimal parameters for cultivation and propogation were determined and compared with those found in studies done by previous workers on meningococci. The plasma expander polyvinylpyrrolidone (PVP) (molecular weight, 40,000) has been incorporated into the medium as an osmotic stabilizer. A method is outlined for removing toxicity (due to impurities in PVP) reported in some earlier studies done in this laboratory. Light and scanning electron microscopy of the L-form inductants and of a stable L-form have shown characteristics distinctive among the strains observed. Finally, the effects of both cell wall and other antibiotics were studied. It was shown that cell wall antibiotics other than the commonly used potassium penicillin G could induce N. meningitidis to the L-form, using the PVP-stabilized medium base. Furthermore, the antibiotics vancomycin, colistin, nystatin, and trimethoprim, used at the concentrations found in commercially prepared Transgrow formulations, did not adversely affect meningococcal L-form induction. The system described herein will hopefully serve as an effective tool, specifically in the study of "aseptic" meningitis and possible meningococcal L-form etiology and, more generally, in evaluating the ability of bacterial L-forms to cause disease.