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Bhagat Manku,1 Tiam Mana Saffari,2 Vinesh Sandhu,3 Ankur Khajuria4,5 1Department of Surgery, South Warwickshire NHS Foundation Trust, Warwickshire, UK; 2Department of Plastic and Reconstructive Surgery, Ohio State University, Columbus, OH, USA; 3University College London Division of Medicine, University College London, London, UK; 4Kellogg College, University of Oxford, Oxford, UK; 5Department of Surgery & Cancer, Imperial College London, London, UKCorrespondence: Bhagat Manku, Email Bhagat.Manku@swft.nhs.ukBackground: Systematic reviews and meta-analyses allow a transparent, rigorous, and replicable analysis to summarize the results of multiple related studies and are considered top of the evidence-based medicine study hierarchy. The COVID-19 pandemic has shed light on the unmet educational needs of students worldwide, notably those from underprivileged backgrounds. This cross-sectional study aimed to ascertain students’ and junior doctors’ attitudes on their current knowledge, confidence and preparedness of appraising and conducting systematic reviews and meta-analysis internationally.Methods: A free online webinar was held in May 2021 by the senior author and a pre-event questionnaire was distributed. Responses collected were used for analysis anonymously to ascertain students’ knowledge, experience, and confidence in preparing a systematic review and meta-analysis using a 1– 5 Likert scale using IBM SPSS 26.0. Associations were examined using Chi-square and crosstabs analysis.Results: Out of 2004 responses from 104 countries included in the analysis, the majority of delegates were from lower middle-income countries and were not familiar with the PRISMA checklist (59.2% and 81.1% respectively of the total number of participants). The majority had never attended any formal training (83%) and felt their medical institute gave them minimal advice (72.5%) in preparing systematic reviews. Among those who had attended formal training, the proportion was significantly higher in those belonging to high and upper middle-income countries combined (20.3%) than lower and lower-middle-income countries combined (15%).Conclusion: This study highlights gaps that need addressing to enhance the knowledge of medical students and junior doctors performing systematic reviews and meta-analyses. Clear disparities are found in country income and the level of education. Future large-scale studies are needed to understand the rationale of working on online research projects and the opportunities available to medical students and junior doctors that may lead to medical curriculum changes.Keywords: medical education, systematic review, meta-analysis, inequity

Introduction: The assessment of micronuclei in exfoliated cells is a promising tool for the study of epithelial carcinogens and can be used to detect chromosome breakage or mitotic interference, thought to be relevant to carcinogenesis. Aim: The present study aimed to detect micronuclei in exfoliated oral mucosal cells in individuals using various tobacco forms from the last 5 years. Materials and Methods: A total of 75 healthy male subjects (25 smokeless tobacco users, 25 smokers, and 25 non-tobacco users) were selected for the study. Smears were obtained with moistened wooden spatula from buccal mucosa and fixed with 95% alcohol. All the cytologic smears were stained by Papanicolaou technique. From each slide, ~1000 cells were examined under the 400× magnification and where micronucleated (MN) cells were located, they were examined under the 1000× magnification. Result: MN cells were found to be significantly higher in smokeless tobacco users than in smokers and controls. Conclusion: A positive correlation is found between increased micronucleus frequency and tobacco-using habits. So micronucleus assay can be used as a biomarker of genotoxicity. [ABSTRACT FROM AUTHOR]

The authors discuss their study to examine the extent of adherence to American Academy of Ophthalmology recommendations by systemic lupus erythematosus providers at a single site. The goal is to encourage more prospective analyses and interventions to prevent hydroxychloroquine-induced retinopathy. Recruitment of patient was from the Southern California Lupus Registry. The study is limited by incomplete data on people not taking hydroxychloroquine.

Background: Denosumab effectively treats RANKL-mediated bone disorders by inhibiting osteoclast activity. While approved for giant cell tumours, its role in aneurysmal bone cysts (ABC) remains unclear. This review explores denosumab's application in ABCs, focusing on its role, outcomes, and adverse effects. Methods: A scoping review adhering to PRISMA Extension for Scoping Reviews guidelines was conducted. The search involved five databases from inception until 31 December 2023. Results: From an initial 390 studies, 29 were selected post-screening involving 67 patients. The most common ABC sites were the spine ( n = 42) and pelvis ( n = 7). Denosumab served as primary treatment in 25 patients (37.3%), neoadjuvant in 11 (16.4%), second-line therapies after inadequate initial therapies in 24 (35.8%), and adjunct therapy in seven cases. All patients demonstrated favourable clinical and radiological responses post-denosumab. 10 patients (15%) experienced tumour recurrences: six after denosumab discontinuation (3-17 months post-cessation), three post-surgery following neoadjuvant denosumab, and one during ongoing treatment. Adverse effects reported were hypocalcaemia ( n = 10), hypercalcemia ( n = 14), and sclerotic metaphyseal bands ( n = 2), all in the paediatric age group. While hypocalcaemia surfaced early in denosumab therapy, hypercalcaemia manifested 2.5-6 months post-discontinuation, mainly managed with bisphosphonates. Fewer than half of the studies had follow-ups that exceeded 2 years. Conclusion: Denosumab may be an effective therapy for ABC, especially for high-risk cases like spinal and pelvic tumours. It can also be utilized as a second-line for recurrence/failed initial intervention or as neoadjuvant therapy. Concerns exist about tumour recurrence and rebound hypercalcemia, necessitating careful monitoring, longer follow-up, and prophylactic measures. Prospective clinical trials are warranted for deeper insights., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML. We derived pharmacologic sensitivity for 22 AML PDX models using dynamic BH3 profiling (DBP), together with genomics and transcriptomics. Using in vivo acquired resistant PDXs, we found that resistance to unrelated, narrowly targeted agents in distinct PDXs was accompanied by broad resistance to drugs with disparate mechanisms. Moreover, baseline mitochondrial apoptotic priming was consistently reduced regardless of the class of drug-inducing selection. By applying DBP, we identified drugs showing effective in vivo activity in resistant models. This study implies evasion of apoptosis drives drug resistance and demonstrates the feasibility of the DBP approach to identify active drugs for patients with relapsed AML., Significance: Acquired resistance to targeted therapy remains challenging in AML. We found that reduction in mitochondrial priming and common transcriptomic signatures was a conserved mechanism of acquired resistance across different drug classes in vivo. Drugs active in vivo can be identified even in the multidrug resistant state by DBP., (©2024 American Association for Cancer Research.)

Acute myeloid leukemia (AML) is clinically and genetically a heterogeneous disease characterized by clonal expansion of abnormal hematopoietic progenitors. Genomic approaches to precision medicine have been implemented to direct targeted therapy for subgroups of AML patients, for instance, IDH inhibitors for IDH1/2 mutated patients, and FLT3 inhibitors with FLT3 mutated patients. While next generation sequencing for genetic mutations has improved treatment outcomes, only a fraction of AML patients benefit due to the low prevalence of actionable targets. In recent years, the adoption of newer functional technologies for quantitative phenotypic analysis and patient-derived avatar models has strengthened the potential for generalized functional precision medicine approach. However, functional approach requires robust standardization for multiple variables such as functional parameters, time of drug exposure and drug concentration for making in vitro predictions. In this review, we first summarize genomic and functional therapeutic biomarkers adopted for AML therapy, followed by challenges associated with these approaches, and finally, the future strategies to enhance the implementation of precision medicine., Competing Interests: The 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 © 2024 Bhatia, Sandhu, Wong, Iyer and Bhatt.)

Introduction: The foot is a complex structure composed of several tissues, each of which can be the origin of the proliferation and development of the tumour. Most lesions about the foot are reactive or inflammatory, but some are true neoplasms., Method: This is a retrospective analysis of 4997 patient records treated in the Orthopaedic Oncology Unit of University Malaya Medical Centre, Malaysia, between 1 January 2010 to 31 December 2020. Demographic data of 195 patients with foot tumours were analysed out of 4997 neoplasm patients., Results: There were 195 cases of foot tumours: 148 were benign, and 47 were malignant. 47 were bone tumours, 4 were metastases, and 144 were soft tissue tumours. Six patients succumbed to the disease, two cases of giant cell tumour (GCT) and one patient with synovial sarcoma had a recurrence. Treatment of foot tumours was wide resection in general. However, in metastasis cases, amputation was done. The majority of tumours were in the toes and dorsum of the foot. Soft tissue tumours of the foot occur in the elderly population in contrast to bone tumours, mainly in the second decade of life. The gender distribution was almost equal for foot tumours. Ganglion and Giant Cell Tumour of the bone are the commonest benign soft tissue and bone tumours. The most common malignant soft tissue and bone tumours are malignant melanoma and chondrosarcoma. The amputation rate is 5.64% the recurrence rate is 1.54%. Mortality rate is 3.08%. The MSTS score is 79%, and the TESS score is 76.23%., Conclusion: Foot tumours are relatively rare, mostly originating from soft tissue and exhibiting a benign nature. Nonetheless, a noteworthy proportion-approximately a quarter of these tumours-demonstrate malignancy. The surgical interventions undertaken in managing these tumours and associated functional outcomes generally yield acceptable results., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This scoping review evaluated 3D osteosarcoma (OS) models' biomimicry, examining their ability to mimic the tumour microenvironment (TME) and their drug sensitivity. Adhering to PRISMA-ScR guidelines, the systematic search revealed 293 studies, with 70 selected for final analysis. Overall, 64% of 3D OS models were scaffold-based, compared to self-generated spheroid models. Scaffolds generated using native matrix were most common (42%) with collagen I/hydroxyapatite predominating. Both scaffold-based and scaffold-free models were used equally for drug screening. The sensitivity of cancer cells in 3D was reported to be lower than that of cells in 2D in ~90% of the drug screening studies. This correlates with the observed upregulation of drug resistance. OS cells cultured in extracellular matrix (ECM)-mimetic scaffolds and native biomaterials were more resistant than cells in 2D. Co-cultures of OS and stromal cells in 3D models enhanced osteogenic differentiation, ECM remodelling, mineralisation, and angiogenesis, suggesting that tumour-stroma crosstalk promotes disease progression. Seven studies demonstrated selective toxicity of chemotherapeutics towards OS cells while sparing stromal cells, providing useful evidence for developing biomimetic tumour-stroma models to test selective drug toxicity. In conclusion, this review highlights the need to enhance biomimicry in 3D OS models for TME recapitulation, especially in testing novel therapeutics. Future research should explore innovative 3D biomimetic models, biomaterials, and advancements in personalised medicine.

Pharmacological management has advanced considerably since the 2015 British Society for Rheumatology axial spondyloarthritis (axSpA) guideline to incorporate new classes of biologic DMARDs (bDMARDs, including biosimilars), targeted synthetic DMARDs (tsDMARDs) and treatment strategies such as drug tapering. The aim of this guideline is to provide an evidence-based update on pharmacological management of adults with axSpA (including AS and non-radiographic axSpA) using b/tsDMARDs. This guideline is aimed at health-care professionals in the UK who care directly for people with axSpA, including rheumatologists, rheumatology specialist nurses, allied health professionals, rheumatology specialty trainees and pharmacists; people living with axSpA; and other stakeholders, such as patient organizations and charities., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Longitudinal data are limited on systemic lupus erythematosus (SLE) hospitalizations. We aim to study longitudinal trends of SLE hospitalizations in the last 2 decades in the United States (U.S)., Methods: Data were obtained from the National Inpatient Sample database (NIS). We performed a 21-year longitudinal trend analysis of NIS 1998-2018. We searched for hospitalizations for adult patients with a "principal" diagnosis of SLE (SLE flare group) and those with "any" diagnosis of SLE (all SLE hospitalization group) using ICD codes. All non-SLE hospitalizations for adult patients were used as the control. Multivariable logistic and linear regression were used appropriately to calculate adjusted p-trend for the outcomes of interest., Results: Incidence of SLE flare hospitalization reduced from 4.1 to 3.2 per 100,000 U.S persons from 1998 to 2018 (adjusted p-trend < 0.0001). The proportion of all hospitalized patients with SLE admitted principally for SLE reduced from 11.3% in 1998 to 5.7% in 2018 (adjusted p-tend < 0.0001). The proportion of hospitalized blacks in the SLE flare and all SLE hospitalization groups increased from 37.7% and 26.9% in 1998 to 44.7% and 30.7% in 2018 respectively (adjusted p-trend < 0.0001). The proportion of hospitalized Hispanics and Asians disproportionally increased in SLE flare hospitalizations compared to the control group., Conclusion: The incidence of hospitalization for SLE flare has reduced in the last 2 decades in the U.S. The proportion of hospitalized patients with SLE admitted principally for SLE has reduced significantly over time. However, the burden of SLE hospitalizations among ethnic minorities has increased over time. Key Points • The incidence of hospitalization for SLE flare has reduced in the last 2 decades in the U.S. • The proportion of hospitalized patients with SLE admitted principally for SLE has reduced significantly over time. • The burden of SLE hospitalizations among ethnic minorities such as blacks has increased over time., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

A man in his 70s, with a recent diagnosis of transitional cell carcinoma of the bladder, reported a 2-month history of discolouration, pain and paraesthesia affecting his fingers. Clinical assessment noted peripheral acrocyanosis with areas of digital ulceration and gangrene. Following further work-up to evaluate potential causes, he was diagnosed with paraneoplastic acrocyanosis. He proceeded to undergo robotic cystoprostatectomy and received adjuvant chemotherapy for the management of his cancer. In parallel to the chemotherapy, vasodilatory therapy was administered as two courses of intravenous synthetic prostacyclin analogue iloprost along with sildenafil. This resulted in a significant improvement in digital pain and gangrene with healing of ulceration., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Current standard of care (SOC) regimens against nontuberculous mycobacteria (NTM) usually result in unsatisfactory therapeutic responses, primarily due to multi-drug resistance and antibiotic susceptibility-guided therapies. In the midst of rising incidences in NTM infections, strategies to develop NTM-specific treatments have been explored and validated. Methods: To provide an alternative approach to address NTM-specific treatment, IDentif.AI was harnessed to rapidly optimize and design effective combination therapy regimens against Mycobacterium abscessus ( M. abscessus ), the highly resistant and rapid growth species of NTM. IDentif.AI interrogated the drug interaction space from a pool of 6 antibiotics, and pinpointed multiple clinically actionable drug combinations. IDentif.AI-pinpointed actionable combinations were experimentally validated and their interactions were assessed using Bliss independence model and diagonal measurement of n-way drug interactions. Results: Notably, IDentfi.AI-designed 3- and 4-drug combinations demonstrated greater %Inhibition efficacy than the SOC regimens. The platform also pinpointed two unique drug interactions (Levofloxacin (LVX)/Rifabutin (RFB) and LVX/Meropenem (MEM)) that may serve as the backbone of potential 3- and 4-drug combinations like LVX/MEM/RFB, which exhibited 58.33±4.99 %Inhibition efficacy against M. abscessus . Further analysis of LVX/RFB via Bliss independence model pointed to dose-dependent synergistic interactions in clinically actionable concentrations. Conclusions: IDentif.AI-designed combinations may provide alternative regimen options to current SOC combinations that are often administered with Amikacin, which has been known to induce ototoxicity in patients. Furthermore, IDentif.AI pinpointed 2-drug interactions may also serve as the backbone for the development of other effective 3- and 4-drug combination therapies. The findings in this study suggest that this platform may contribute to NTM-specific drug development., Competing Interests: Competing Interests: A.B., E.K.-H.C., and D.H. are co-inventors of previously filed pending patents on artificial intelligence-based therapy development. E.K.-H.C. and D.H. are co-founders and shareholders of KYAN Therapeutics, which is commercializing intellectual property pertaining to AI-based personalized medicine., (© The author(s).)

Personalised cancer treatment depends on identification of therapeutically relevant biological subgroups of patients for assessing effect of treatment and to discover new therapeutic options. By analyses in heterogeneous patient populations, the effects may be lost in noise. Squamous cell carcinoma of the lung is a major killer worldwide. Despite recent advances, mortality is high and response to therapies varies greatly from patient to patient. Target search in biologically relevant subgroups may identify treatment options not so far discovered. A total of 198 patients undergoing surgery for squamous cell carcinomas of the lung were included in the study. The tumours were analysed for copy number alterations (n = 152) and gene expression from tumour (n = 188) and normal lung (n = 21), with both data levels present in 140 patients. We studied alterations in tumours harbouring mutations in TP53 and in previously published gene expression subtypes. Genes with consistent alterations in both genomic levels were identified as putative biomarkers. Results were validated in TCGA. The most convincing biomarker in TP53 mutated squamous cell carcinomas of the lung was BIRC5 with amplification in 36% of mutated samples, 5% in wild-type samples and a 17%-fold change of expression between TP53 mutated tumours and normal lung tissue. BIRC5 was significantly altered in the classical and primitive subtypes. We suggest BIRC5 as a putative predictive biomarker and putative druggable target in squamous cell lung carcinomas harbouring TP53 mutation or classified as classical and primitive subtypes., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Animal studies suggest that decreased vascular mitochondrial DNA copy number can promote hypertension. We conducted a chart review of blood pressure and hemodynamics in patients with either mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS, n = 36) or individuals with variants in the mitochondrial DNA polymerase gamma (POLG, n = 26). The latter included both pathogenic variants and variants of unknown significance (VUS). Hypertension rates (MELAS 50%, POLG 50%) were elevated relative to Canadian norms in 20-39 (MELAS) and 40-59 (MELAS and POLG) years of age groups. Peripheral resistance was high in the hypertensive versus normotensive patients, potentially indicative of microvascular disease. Despite antihypertensive treatment, systolic blood pressure remained elevated in the POLG versus MELAS group. The risk of hypertension was not associated with MELAS heteroplasmy. Hypertension rates were not different between individuals with known pathogenic POLG variants and those with VUS, including common variants. Hypertension (HT) also did not differ between patients with POLG variants with (n = 17) and without chronic progressive external opthalmoplegia (n = 9) (CPEO). HT was associated with variants in all three functional domains of POLG. These findings suggest that both pathogenic variants and several VUS in the POLG gene may promote human hypertension and extend our past reports that increased risk of HT is associated with MELAS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors. Transcriptome analysis demonstrated that molecular subtypes are a product of a gene expression continuum driven by a mixture of intratumoral subpopulations, which was confirmed by single-cell analysis. Integrated whole-genome analysis uncovered that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6. By mapping tumor genetic histories, tetraploidization emerged as a key mutational process behind these events. Taken together, these data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype, and that disease heterogeneity is due to ongoing genomic instability during progression.

Pimecrolimus is a topical calcineurin inhibitor currently approved for second-line use in the management of mild-to-moderate atopic dermatitis in patients age 2 years and older. Given the safety profile and nonsteroidal mechanism of pimecrolimus, there has been significant interest in its use in the treatment of a variety of dermatological conditions. This article reviews research that has been published on the off-label uses of topical pimecrolimus, with a focus on published RCTs. Convincing evidence exists supporting pimecrolimus' efficacy in oral lichen planus and seborrheic dermatitis. For other conditions studied to date, pimecrolimus may prove to be a useful treatment alternative when conventional agents fail. Adverse events seen with its off-label use were typically application site reactions, the most common being a transient burning sensation. In summary, pimecrolimus appears to be an effective agent in the treatment of multiple dermatological conditions and may be worth considering as a pharmacologic alternative in several conditions when first-line treatment fails, or for areas that are more susceptible to the adverse effects of topical corticosteroids.

A wealth of transcriptomic and clinical data on solid tumours are under-utilized due to unharmonized data storage and format. We have developed the MetaGxData package compendium, which includes manually-curated and standardized clinical, pathological, survival, and treatment metadata across breast, ovarian, and pancreatic cancer data. MetaGxData is the largest compendium of curated transcriptomic data for these cancer types to date, spanning 86 datasets and encompassing 15,249 samples. Open access to standardized metadata across cancer types promotes use of their transcriptomic and clinical data in a variety of cross-tumour analyses, including identification of common biomarkers, and assessing the validity of prognostic signatures. Here, we demonstrate that MetaGxData is a flexible framework that facilitates meta-analyses by using it to identify common prognostic genes in ovarian and breast cancer. Furthermore, we use the data compendium to create the first gene signature that is prognostic in a meta-analysis across 3 cancer types. These findings demonstrate the potential of MetaGxData to serve as an important resource in oncology research, and provide a foundation for future development of cancer-specific compendia.

Purpose: With a dismal 8% median 5-year overall survival, pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy. Only 10% to 20% of patients are eligible for surgery, and more than 50% of these patients will die within 1 year of surgery. Building a molecular predictor of early death would enable the selection of patients with PDAC who are at high risk., Materials and Methods: We developed the Pancreatic Cancer Overall Survival Predictor (PCOSP), a prognostic model built from a unique set of 89 PDAC tumors in which gene expression was profiled using both microarray and sequencing platforms. We used a meta-analysis framework that was based on the binary gene pair method to create gene expression barcodes that were robust to biases arising from heterogeneous profiling platforms and batch effects. Leveraging the largest compendium of PDAC transcriptomic data sets to date, we show that PCOSP is a robust single-sample predictor of early death-1 year or less-after surgery in a subset of 823 samples with available transcriptomics and survival data., Results: The PCOSP model was strongly and significantly prognostic, with a meta-estimate of the area under the receiver operating curve of 0.70 ( P = 2.6E-22) and d-index (robust hazard ratio) of 1.9 (range, 1.6 to 2.3; ( = 1.4E-04) for binary and survival predictions, respectively. The prognostic value of PCOSP was independent of clinicopathologic parameters and molecular subtypes. Over-representation analysis of the PCOSP 2,619 gene pairs-1,070 unique genes-unveiled pathways associated with Hedgehog signaling, epithelial-mesenchymal transition, and extracellular matrix signaling., Conclusion: PCOSP could improve treatment decisions by identifying patients who will not benefit from standard surgery/chemotherapy but who may benefit from a more aggressive treatment approach or enrollment in a clinical trial.

Background: The introduction of immune check-point inhibition in non-small cell lung cancer (NSCLC) therapy represents improved prospects for the patients. The response rates to check-point inhibitors are approximately 20% in unselected NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with higher response rates. However, patients with low PD-L1 levels may also have durable responses, and improved strategies for patient stratification are needed., Material and Methods: In this study, we investigated circulating microRNAs aiming to identify circulating predictive biomarkers associated with increased overall survival after immune check-point treatment. Using next generation sequencing, we performed microRNA profiling in serum from NSCLC patients (n = 20) treated with nivolumab. Serum samples from 31 patients were used for validation using qPCR assays. Serum samples were collected prior to immune therapy initiation., Results: Based on multivariate regression analysis, we identified a signature of seven microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p, miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) > 6 months in discovery cohort (p = .0003). We further validated this in another similar set of samples (n = 31) and the model was significantly associated with overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of 71% and 90%, respectively., Conclusions: In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.

Purpose: Radiation therapy effectively kills cancer cells and elicits local effects in the irradiated tissue. The aim of this study was to investigate the kinetics of cytokines in the serum of patients with lung cancer undergoing radiation therapy and to identify associations with metabolic tumor burden as determined by 2-deoxy-2-fluoro-D-glucose ( 18 F-FDG) positron emission tomography (PET)., Methods and Materials: Forty-five patients with advanced non-small cell lung cancer were included in a phase 2 clinical trial and randomized between fractionated thoracic radiation therapy alone or concurrent with an epidermal growth factor receptor inhibitor. Blood was sampled at 4 different time points: prior to treatment, midtherapy, at the end of therapy, and 6 to 8 weeks after the start of treatment. The serum concentrations of 48 cytokines and 9 matrix metalloproteinases were measured with multiplex immunoassays. A subset of patients was examined by 18 F-FDG PET/computed tomography before, during, and after radiation therapy. The maximum standardized uptake values (SUV max ) of the primary lung tumor, whole-body metabolic tumor volume, and total lesion glycolysis were calculated, and correlations between the PET parameters and cytokines were investigated., Results: The SUV max decreased from baseline through midtherapy to posttherapy 18 F-FDG PET/computed tomography ( P  = .018). The serum levels of C-C motif chemokine ligand (CCL) 23, CCL24, C-X3-C motif chemokine ligand 1, and interleukin-8 (C-X-C motif ligand [CXCL]8) were significantly correlated to SUV max , metabolic tumor volume, and total lesion glycolysis before, during, and after radiation therapy. CXCL2 ( P  = .030) and CXCL6 ( P  = .010) decreased after the start of therapy and changed significantly across the sample time points. Serum concentrations of CCL15 ( P  = .031), CXCL2 ( P  = .028), and interleukin-6 ( P  = .007) were positively correlated to the irradiated volume during the second week of treatment., Conclusions: Cytokine serum levels vary and correlate with metabolic tumor burden in patients with advanced non-small cell lung cancer undergoing palliative thoracic radiation therapy.

Background: Systemic Lupus Erythematosus (SLE) is an incurable autoimmune disorder with complement activation playing a key role in the pathogenesis of immune-mediated tissue injury. While quantifying complement to monitor SLE disease activity has been the standard of care since the 1950s, decreased complement levels are not consistently associated with flares., Objective: We seek to clarify the SLE phenotype in which complement deficiency is causative, concomitant, or coincidental., Methods: A PUBMED literature review was conducted using key words 'complement,' 'SLE,' and 'SLE flares' in English-only journals from 1972-2017. Relevant clinical studies and review articles were found that examined the measurement of complement levels in SLE, and more specifically, interpretation of low serum complement levels regardless of disease activity., Conclusion: Complement activation plays a key role in the pathophysiology of SLE and it is recommended to continue monitoring serum levels of C3 and C4 to assess for disease activity. However, it is important to note that decreased serum complement is not consistently associated with disease flares.It is clinically important to find novel ways to assess disease activity in SLE. Reduced serum levels of cell-bound complement activation products may more accurately reflect disease activity than conventional serum C3 and C4 monitoring.

It has been hypothesized based on accumulated data that a class of small noncoding RNAs, termed microRNAs, are key factors in intercellular communication. Here, microRNAs present in interstitial breast tumor fluids have been analyzed to identify relevant markers for a diagnosis of breast cancer and to elucidate the cross-talk that exists among cells in a tumor microenvironment. Matched tumor interstitial fluid samples (TIF, n = 60), normal interstitial fluid samples (NIF, n = 51), corresponding tumor tissue specimens (n = 54), and serum samples (n = 27) were collected from patients with breast cancer, and detectable microRNAs were analyzed and compared. In addition, serum data from 32 patients with breast cancer and 22 healthy controls were obtained for a validation study. To identify potential serum biomarkers of breast cancer, first the microRNA profiles of TIF and NIF samples were compared. A total of 266 microRNAs were present at higher level in the TIF samples as compared to normal counterparts. Sixty-one of these microRNAs were present in > 75% of the serum samples and were subsequently tested in a validation set. Seven of the 61 microRNAs were associated with poor survival, while 23 were associated with the presence of immune cells and adipocytes. To our knowledge, these data demonstrate for the first time that profiling of microRNAs in TIF can identify novel biomarkers for the prognostic classification and detection of breast cancer. In addition, the present findings demonstrate that microRNAs may represent the cross-talk that occurs between tumor cells and their surrounding stroma., (© 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Development of lung cancer is closely related to smoking in a majority of patients. Most smokers, however, do not develop lung cancer in spite of a high mutational load accumulating in the lung tissue. Here we investigate whether a cancer-specific footprint can be revealed by investigating circulating inflammatory markers in patients with non-small cell lung cancer (NSCLC) compared with patients with chronic obstructive pulmonary disease (COPD), both cohorts characterised by similar smoking history. Serum concentrations of 57 cytokines and matrix metalloproteinases (MMPs) from 43 patients with advanced NSCLC were evaluated by multiplex immunoassays and compared with serum samples from 35 patients with COPD. Unsupervised hierarchical clustering and non-parametric analyses were performed. False discovery rate was used to adjust for multiple testing. Clustering of cytokine and MMP concentrations in the serum revealed a distinct separation of the NSCLC patients from the COPD group. Individual concentrations of thymus and activation-regulated cytokine (C-C motif chemokine ligand 17), Gro-b (C-X-C motif chemokine ligand 2 (CXCL2)), CXCL13, interleukin (IL)-1ra, IL-6, IL-8 (CXCL8), IL-16, IL-17A, macrophage migration inhibitory factor (MIF), granulocyte colony-stimulating factor, platelet-derived growth factor subunit B, MMP-2, MMP-8 and MMP-12 were significantly different in serum from NSCLC and COPD patients. Moreover, the interferon-γ/IL-10 ratio was lower in cancer patients compared with COPD patients, consistent with a cytokine milieu favouring tumour tolerance. Our results suggest that NSCLC is characterised by a distinct inflammatory signature in serum. The different cytokine profiles in NSCLC and COPD patients may represent tumour-promoting and tumour-suppressing immune responses developing in response to mucosal inflammation and mutations induced by smoking.

Despite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo University Hospital to identify genome-wide copy number aberrations, putative driver genes, deregulated pathways, and potential prognostic markers. Results were validated in a separate cohort derived from The Cancer Genome Atlas Consortium (n = 127). In contrast to many other solid tumors, periampullary adenocarcinomas exhibited more frequent genomic deletions than gains. Genes in the frequently codeleted region 17p13 and 18q21/22 were associated with cell cycle, apoptosis, and p53 and Wnt signaling. By integrating genomics and transcriptomics data from the same patients, we identified CCNE1 and ERBB2 as candidate driver genes. Morphologic subtypes of periampullary adenocarcinomas (i.e., pancreatobiliary or intestinal) harbor many common genomic aberrations. However, gain of 13q and 3q, and deletions of 5q were found specific to the intestinal subtype. Our study also implicated the use of the PAM50 classifier in identifying a subgroup of patients with a high proliferation rate, which had impaired survival. Furthermore, gain of 18p11 (18p11.21-23, 18p11.31-32) and 19q13 (19q13.2, 19q13.31-32) and subsequent overexpression of the genes in these loci were associated with impaired survival. Our work identifies potential prognostic markers for periampullary tumors, the genetic characterization of which has lagged. Cancer Res; 76(17); 5092-102. ©2016 AACR., (©2016 American Association for Cancer Research.)